Pediatric Neurology 65 (2016) 14e30

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Pediatric Neurology
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Topical Review

Acute Ataxia in Children: A Review of the Differential Diagnosis

and Evaluation in the Emergency Department
Mauro Caffarelli MD a,1, Amir A. Kimia MD b, Alcy R. Torres MD a, *
a
Division of Neurology, Boston Medical Center, Boston, Massachusetts
b
Division of Emergency Medicine, Department of Medicine, Boston Children’s Hospital, Boston, Massachusetts

abstract

Acute ataxia in a pediatric patient poses a diagnostic dilemma for any physician. While the most common etiol-
ogies are benign, occasional individuals require urgent intervention. Children with stroke, toxic ingestion,
infection, and neuro-inflammatory disorders frequently exhibit ataxia as an essentialdif not the onlydpresenting
feature. The available retrospective research utilize inconsistent definitions of acute ataxia, precluding the ability
to pool data from these studies. No prospective data exist that report on patients presenting to the emergency
department with ataxia. This review examines the reported causes of ataxia and attempts to group them into
distinct categories: post-infectious and inflammatory central and peripheral phenomena, toxic ingestion, neuro-
vascular, infectious and miscellaneous. From there, we synthesize the existing literature to understand which
aspects of the history, physical exam, and ancillary testing might aid in narrowing the differential diagnosis. MRI is
superior to CT in detecting inflammatory or vascular insults in the posterior fossa, though CT may be necessary in
emergent situations. Lumbar puncture may be deferred until after admission in most instances, with suspicion for
meningitis being the major exception. There is insufficient evidence to guide laboratory evaluation of serum,
testing should be ordered based on clinical judgementdrecommended studies include metabolic profiles and
screening labs for metabolic disorders (lactate and ammonia). All patients should be reflexively screened for toxic
ingestions.

Keywords: acute ataxia, cerebellar ataxia, toxic ingestion, Guillain-Barré syndrome, differential diagnosis, children, magnetic
resonance, lumbar puncture
Pediatr Neurol 2016; 65: 14-30
Ó 2016 Elsevier Inc. All rights reserved.

Introduction described as a “wide-based gait” with “truncal instability.”

Ataxia is a neurological disorder in which coordination of
motor activity is impaired, preventing the execution of fluid
movements. Children with ataxia classically present with an
inability to ambulate as manifested by an ataxic gait, often
Article History:
Received October 31, 2015; Accepted in final form August 26, 2016
* Communications should be addressed to: Dr. Torres; Division of
Neurology; Boston Medical Center; One Boston Medical Center Place;
Boston, MA 02118.
E-mail address: artorres@bu.edu
1
Present address: Department of Pediatrics, University of California San
Francisco, 550 16th Street, 4th Floor, San Francisco, CA 94143. Electronic
address: mauro.caffarelli@ucsf.edu.
Young children, especially, may manifest ataxia as a simple
inability or refusal to ambulate.1-4 The key to assessment of
acute ataxia in children is a thorough physical examination,
which may reveal many possible associated findings and
shed light on the location of the primary pathology. In this
review, we present a broad differential diagnosis ranging
from primary central causes to those secondary to infection
or toxic exposure. We hope this will serve as a guide for
physicians in the emergency department and consulting
pediatric neurologists who are evaluating children pre-
senting with acute-onset ataxia.
The causes of ataxia can be organized in an anatomic
fashion. Although an “ataxic gait” on examination is typi-
cally associated with cerebellar deficit, an abnormality in

0887-8994/$ e see front matter Ó 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.pediatrneurol.2016.08.025
 M. Caffarelli et al. / Pediatric Neurology 65 (2016) 14e30
gait can present as a consequence of deranged function in
many locations along the central nervous system (CNS).
Motor weakness can originate from a lesion in the cerebral
cortex, brainstem, spinal cord, peripheral nerves, or
neuromuscular junction.1-4 Impaired balance often results
from dysfunction of the vestibular apparatus in the inner
ear or the eighth cranial nerve.5
A thoughtful history and physical examination technique
will aid in localizing the source of dysfunction. Children who
present with developmental delay or regression in mile-
stones may suffer from a metabolic derangement such as an
aminoaciduria (e.g., Hartnup and maple syrup urine disease),
pyruvate dehydrogenase deficiency, or biotinidase defi-
ciency.6 A prior ataxic event in an otherwise healthy child
may suggest a paroxysmal disorder as is seen in genetic ion
channel mutations (i.e., the “episodic” ataxias) or in complex
migraines, in which the frequency and duration of attacks can
vary widely between patients. Similarly, a previous history of
extremity weakness or vision loss may indicate a polyfocal
demyelinating disease such as multiple sclerosis (MS). Pri-
mary “infectious” or secondary “postinfectious” cerebellitis
may be implied, respectively, with an either concurrent or
recent viral syndrome, prompting the physician to elicit such
a history and examine the patient for signs of rash.
Most disorders discussed herein demonstrate depressed
mentation or speech abnormalities such as fluctuations in
clarity, tone, rhythm, and volume. The cranial nerve ex-
amination may reveal a deficit, nystagmus, or palatal
myoclonus. These patients may have hypotonia and their
strength may appear diminished. Finger-to-nose may show
under- or overshooting of the limbs. Patients may have
difficulty with rapid alternating movements and intention
tremor. Patients with peripheral neuropathies are usually
hyporeflexive, conversely those with cerebellar insult may
have pendular reflexes. Finally, gait testing may demon-
strate poor maintenance of truncal position and titubation,
or no ability to walk at all.
The temporal course of ataxia is diagnostically useful if
acute toxic, traumatic, infectious, or postinfectious causes
are suspected. Chronic or episodic ataxias, on the other
hand, are generally the result of an inborn error of meta-
bolism or hereditary channelopathies. Although an acute
onset of ataxia has historically been associated with a
benign course,1 it can present a unique challenge to physi-
cians as a few possible causes can pose a real concern for
irreversible neurological damage.
Only a handful of studies have documented the di-
agnoses one can encounter in children presenting with
acute ataxia. Gieron-Korthals et al.7 in 1994 summarized 40
children who had been symptomatic for less than 48 hours.
They demonstrated that most instances of acute ataxia are
due to a postinfectious cerebellar process, toxic ingestion, or
GuillaineBarré syndrome (GBS). Martínez-González et al.8
in 2006 similarly evaluated 39 children with symptoms
for less than 48 hours and found a similar array of etiologies,
providing support to the findings of Gieron-Korthals et al.
Rudloe et al.9 in 2014 demonstrated that clinically signifi-
cant intracranial pathologydtumors, infarcts, and acute
disseminated encephalomyelitis (ADEM)dis frequently
documented in children with symptoms up to seven days
but is far less likely in young children with symptoms for
less than 72 hours. Finally, Thakkar et al.10 in 2016 described
15
120 children referred to a pediatric neurologist with
symptoms up to four weeks in which the leading diagnosis
remained postinfectious in nature and the frequency of
toxic ingestion was much lower than preceding studies had
reported. The disparate conclusions that arise from these
studies are rooted in their different designdall the afore-
mentioned studies are retrospectivedand each uses a
different definition for the duration of symptoms as well as
different inclusion and exclusion criteria.
Here we expand the differential diagnosis of acute ataxia
into broad categories, as one might do with a patient
presenting to care for the first time in the emergency
department. We then discuss the clinical, laboratory, and
imaging features reported with each entity, so that a clini-
cian may be able to begin prioritizing their evaluation based
on historical and examination features they may encounter.
We give special attention to the evidence that supports the
evaluation of acute ataxia in the emergency department to
optimize the initial diagnosis, keeping in mind that ongoing
evaluation and follow-up of these patients may require a
different set of clinical tools and practices. We then sum-
marize the different aspects of evaluation (history, physical
examination, laboratory tests, imaging, and lumbar punc-
ture [LP]) and give our recommendations. Finally, we hope
this article will demonstrate the need for carefully designed
prospective research to understand which circumstances
might require close attention and swift action compared
with those in which patients may be simply observed for a
period of time.
Classification of etiologies
Central postinfectious and inflammatory causes
The most recognizable and generally most common
causes of acute ataxia are postinfectious cerebellar processes
that are self-limited and resolve spontaneously.4,8 The term
“acute cerebellar ataxia” has been firmly established in the
literature to imply a postinfectious process, but for the pur-
pose of this review, we will use the term “acute post-
infectious cerebellar ataxia” (APCA) as proposed by Poretti
et al.11 for the sake of avoiding the less descriptive term.
In this section, we discuss APCA, cerebellitis, and
ADEM as the three major postinfectious syndromes that
frequently present with ataxia. An important caveat in
the discussion of these postinfectious phenomena in-
volves the introduction of the varicella vaccine in 1995
and the understanding that many of the epidemiologic
data herein were collected in the period beforehand.
Although neurological complications of varicella (i.e.,
postcerebellar ataxia) occurs in nearly one of every 4000
cases,12 estimates of the rate of cerebellar ataxia in the
postvaccine era approach 1.5 for every 1,000,000 vaccine
doses.13
Acute postinfectious cerebellar ataxia
The observation of a sudden-onset ataxia in children after
an infectious illness was first documented for more than a
century ago.2 As other causes for cerebellar dysfunction
emerged, this remained a puzzling cause of ataxia for which
the pathology remained unknown.1,3 Evidence for an auto-
immune basis of APCA emerged with reports showing
16 M. Caffarelli et al. / Pediatric Neurology 65 (2016) 14e30
oligoclonal bands in the cerebrospinal fluid (CSF), with
several subsequent studies demonstrating immunoglobulin
G and immunoglobulin M reactive to cerebellar Purkinje
cells after varicella,14 EpsteineBarr virus (EBV),15,16 and
mycoplasma17 infections. However, the mechanisms un-
derlying both the pathologic specificity to and the physio-
logic disruption of the cerebellum are unknown.
Our best understanding of the epidemiology and
outcome of APCA stems from work done by Connolly et al.,
the only group to have prospectively studied the disorder,
collecting data for more than a 23-year period. Of the 73
children who satisfied entry criteria, 19 (26%) had a priori
infection with varicella, two (3%) had EBV, and 36 (49%) had
a nonspecific “viral” prodrome, whereas 14 (19.2%) had no
identifiable prodrome. The latency period from infection to
ataxia ranged from only a few days to three weeks with a
mean between nine and 11 days for all but EBV infections,
which had a mean latency of 17.5 days. The mean age at
presentation was 5.37
4.00, although the data are skewed
such that 60% of children are aged between two and
four years. Of 69 children who underwent LP, roughly half
had leukocytes less than 5/mm3 and all bacterial and viral
cultures were negative. Computed tomography (CT) was
unremarkable in all children imaged, whereas magnetic
resonance imaging (MRI) showed cerebellar T2 hyper-
intensity in only one of nine children imaged. Of the in-
dividuals who were followed, 70% returned to baseline
within eight months of initial presentation.18
Since the study by Connelly et al., one other retrospective
study with essentially similar results has emerged.19 How-
ever, without a good understanding of the pathophysiology
of the APCA, no tests are available to confirm the diagnosis.
The work of Connelly et al. shows us that the mainstays in
neurological diagnosis such as a thorough examination,
imaging, and LP are not specific either.
Whelan et al.4 and others19-21 favor a combination of a
normal mental status, a nonfocal neurological examination,
and a clear history of recent infection as reasons to defer
imaging or CSF studies for close neurological follow-up.
However, clear criteria do not exist that reliably exclude
concerningdalthough perhaps less commonddiagnoses
that may require immediate intervention.
Postinfectious cerebellitis
The term “cerebellitis” appeared in the 1950s and 1960s
and was used interchangeably with cerebellar encephalitis,
a cerebellar syndrome in the setting of a recent infectious
disease such as infectious mononucleosis22 and varicella.23
These earlier descriptions of the term did not differentiate it
from APCA, and thus it is unclear whether they were
describing the same disease process.1,3 Horowitz et al. in
1991 documented a patient with severe ataxia and en-
cephalitis along with cerebellar edema on CT and MRI,24
invoking the subsequent use of cerebellitis to describe an
ataxia syndrome with the distinct feature of cerebellar
edema on imaging.25,26
Sawaishi and Takada27 summarized patients with post-
infectious ataxia who had cerebellar edema with mass ef-
fect on imaging. Although these patients varied in severity
with a few mimicking APCA, many of them were life
threatening or fatal, necessitating surgical decompres-
sion.25,26 Sawaishi and Takada thus argued the diagnosis of
acute cerebellitis should be reserved for severe cases with
positive imaging findings, with the implication that it
would convey an urgent need for surgical evaluation.
Desai and Mitchell28 in 2012 argued that cerebellitis and
APCA should be thought of as two ends of a spectrum, with
the former diagnosis being applied largely to cases with
cerebellar edema on imaging. However, Connelly et al.
demonstrated that mild cerebellar edema may occur in
children with ataxia who are otherwise well. In their study,
Thakkar et al. report three (2.5%) of 120 patients diagnosed
with acute cerebellitis, which they defined as the presence
of imaging abnormalities in the setting of acute ataxiadone
of the patients developed fulminant brain swelling
requiring decompressive occipital craniectomy. This
compared with 71 (59.2%) patients with symptoms and
normal imaging findings diagnosed with APCA.10
Our view of cerebellitis aligns with Sawaishi and Takada,
that it should denominate ataxia with the clinical distinc-
tion of an abnormal mental status to suggest increased
intracranial pressure and thus the need for immediate im-
aging. Without clear prospective data on the epidemiologic,
clinical, laboratory, or imaging features of cerebellitis, it will
be crucial to have a low clinical threshold for imaging and
surgical evaluation should a child begin to show signs of
altered mental status in the setting of a postinfectious
cerebellar ataxia. Although MRI may be more sensitive and
specific imaging compared with CT,29,30 CT may be neces-
sary in more clinically urgent scenarios.
ADEM, the clinically isolated syndrome, and MS
ADEM, clinically isolated syndrome (CIS), and MS
describe three disease processes that have tremendous
overlap yet differ in their definition as delineated by specific
clinical and imaging features.31 All three are characterized
by polyfocal immune-mediated demyelinating lesions of
the CNS. The diagnosis of MS requires either evidence of a
prior demyelinating event or new lesions on imaging
follow-up, whereas CIS and ADEM are differentiated by the
presence of encephalopathy (Table).31,33
When evaluating a patient with acute ataxia, a history of
prior episodes of neurological deficit is important for
making the diagnosis of MS. However, a patient presenting
with a first time demyelinating CNS event woulddby sake
of the definitiondbe diagnosed with ADEM or CIS unless
MRI were to reveal evidence of an older (i.e., nonenhancing)
demyelinating lesion.31 However, the diagnosis of ADEM or
CIS does not preclude a later diagnosis of MS. One study of
40 children initially diagnosed with ADEM or CIS demon-
strated that one of 15 children diagnosed with ADEM was
later reclassified as having MS, whereas 14 of 28 patients
with CIS had a relapse event, causing 13 of them to be
diagnosed with MS.34 The presence of oligoclonal bands in
the CSF may indicate a higher likelihood of relapse and
subsequent reclassification to MS.35
Although we do not wish to diminish the importance of
differentiating between these entities, further discussion of
a patient with demyelinating disease would likely occur
after imaging reveals the presence of lesions. Because CIS is
a relatively recent disease description that was first rigor-
ously defined in 2007,32 prospective studies have not yet
been published that identify the rate of ataxia as a pre-
senting feature of the disease.
 M. Caffarelli et al. / Pediatric Neurology 65 (2016) 14e30 17

TABLE.
Definitions of MS, ADEM, and CIS Based on Clinical Findings and Imaging Findings as Described in Krupp et al. 201332

Diagnosis Clinical Findings Imaging Findings

MS (Any of the following)  Demonstration of DIT and DIS
 Two or more nonencephalopathic clinical CNS events
separated by more than 30 days
 One nonencephalopathic episode with MRI findings that
show DIS and follow-up MRI that shows DIT
 One ADEM attack followed by a nonencephalopathic
clinical event separated by 3 months with new MRI
lesions
 First, single, acute event that does not meet ADEM criteria
and whose MRI findings demonstrate DIS and DIT
ADEM  First time, polyfocal, clinical CNS event  Diffuse, >1-2 cm lesions of white matter
 Encephalopathy that is not explained by fever  Absence of DIT
CIS  Monofocal or polyfocal clinical CNS event  Absence of DIT or DIS
 Absence of prior clinical evaluation of CNS demyelinating
disease
 No encephalopathy
Abbreviations:
ADEM ¼ acute disseminated encephalomyelitis
CIS ¼ clinically isolated syndrome
CNS ¼ central nervous system
DIS ¼ dissemination in space
DIT ¼ dissemination in time
MRI ¼ magnetic resonance imaging
MS ¼ multiple sclerosis
Definition of DIT and DIS from Polman et al., 2010.33 DIT: a new T2 or contrast-enhancing lesion on follow-up MRI with reference to baseline or the simultaneous presence of
enhancing and nonenhancing lesions at any time. DIS: at least one T2 lesion in two of the following four areas of the CNSdperiventricular, juxtacortical, infratentorial, and
spinal cord.

ADEM is an acute inflammatory demyelinating disorder
that is generally preceded by an infection and affects the
white matter tracts of the brain, brainstem, spinal cord, and
optic nerves.32 The incidence is approximately 0.4/100,000
among children and a mean age 6.5 years, with 64% of pa-
tients aged between 2 and 10 years.36 The diagnosis re-
quires polyfocal clinical CNS findings, encephalopathy not
explained by fever, and demonstration of characteristic
multifocal demyelinating lesions on MRI.31,37
Ataxia is a common presenting feature of ADEM. In a
prospective study spanning 12 years, 42 (50%) of 84
consecutive patients with ADEM presented with ataxia.
Although it is unclear for how many patients ataxia was the
only presenting feature, the study identified long tract signs
in 71 (85%), hemiparesis in 64 (76%), and encephalopathy in
58 (69%) patients, of whom 16 progressed into a coma.38
Encephalopathy can be defined broadly as any change in
mental status, as patients can present with irritability,
sleepiness, confusion, or obtundation.39 It is important to
keep in mind that because this study was published in 2002,
the operational difference between ADEM and CIS had not
yet been formalized to differentiate between patients with
and without encephalopathy.31,32
Of 82 patients prospectively included in the study by
Tenembaum et al., MRI showed only small (less than 5 mm)
lesions in 52 (62%), large confluent lesions were observed in
20 (24%), bithalamic involvement was seen in 10 (12%), and
acute hemorrhagic lesions were seen in two patients. CSF
studies were abnormal in 24 children (28%), showing either
lymphocytic pleocytosis (more than 180 cells/mm3) or
increased protein levels (more than 1 g/dL).38
Classic ADEM should be easy to clinically differentiate
from APCA, as it will typically involve focal neurological
deficits along with a possible change in mental status
concurrent with ataxia, both of which are generally in-
dications for rapid imaging. However, the relative incidence
of ADEM versus APCA is unknown, and no studies exist that
allow us to clinically differentiate ADEM from other causes
of acute ataxia. Although Martínez-Gonzáles et al. identified
ADEM as the cause of ataxia in one of 39 patients studied,8
the relative incidence of ADEM compared with other causes
of ataxia is otherwise unknown. For the wary clinician, a
period of observation may be useful in determining an
“illness curve” of how symptoms are progressing.
Nearly all patients will eventually demonstrate complete
neurological recovery,40 although patients should be closely
monitored for relapse.34,41 Although randomized controlled
treatment trials for ADEM have not been performed, rapid
initiation of high-dose intravenous methylprednisolone is a
mainstay in treatment.37 However, some cases may be more
severe, and stabilization of the patient may be necessary
before diagnostic evaluation can be initiated: a fraction of
cases will require intensive care unit admission as patients
with ADEM have been shown to progress to fulminant brain
injury and even death.42 Furthermore, approximately 17% of
patients were prospectively shown to present with lesions
in the brainstem that interfered with respiratory drive,
necessitating prompt respiratory support.38 The adminis-
tration of intravenous immunoglobulin in severe cases is
not unwarranted, although its efficacy in treatment has not
been prospectively studied.43
Spinal and peripheral postinfectious and inflammatory causes
Sensory and motor deprivation of the lower extremities
because of inflammation of the spine or peripheral nerves
can often present as ataxia with no change in mental status.
One of the more common classical causes of acute ataxia is
18 M. Caffarelli et al. / Pediatric Neurology 65 (2016) 14e30
GBS, an idiopathic, postinfectious inflammatory disorder of
the peripheral nerves.7 The spinal and peripheral post-
infectious phenomena are a series of immune-mediated
disorders including GBS, Miller Fisher syndrome (MFS),
and Bickerstaff brainstem encephalitis (BBE). Although
these syndromes are often thought to be distinct, they
frequently overlap in their features with ataxia being a
major component of their clinical presentation. The
nonspecific finding of anti-GQ1b and anti-GM antibodies in
the serum of affected patients suggests GBS, MFS, and BBE
are variants of a single disease process.44,45 The classical
association with antecedent campylobacter infection is also
bolstered by the association between the organism and
anti-GM1 antibodies.43 Transverse myelitis, with its asso-
ciated disorders, is also discussed in this section as a cause
of acute ataxia.
GuillaineBarré syndrome
GBS is a postinfectious polyneuropathy that can affect
individuals from 12 months into adulthood, with a peak
incidence at five to six years.46 Patients generally present
with symmetric lower extremity weakness and areflex-
iadthe two major defining criteria for GBS diagnosis.47 A
small percentage of patients (less than 5%) may present
with normal or exaggerated reflexes.48 Autonomic insta-
bility may also occur, resulting in heart-rate variability and
cardiovascular collapse.49
Several minor criteria aid in differentiating GBS from
other causes of ataxia. For example, a prospective study
showed that 85% of adult patients with GBS complained of
pain on admission.50 Another prospective study by Paradiso
et al.51 showed 44 of 61 (72%) children with GBS com-
plained of pain, although it is unclear whether pain was part
of the initial presentation or if it appeared later on in the
course of illness. Another retrospective study found that
children greater than five years of age with GBS were more
likely to initially complain of limb pain (53%) than their
younger counterparts (24%).52
A characterizing feature of GBS is increased protein levels
in the CSF with albuminocytologic dissociation, meaning
that the cell counts are typically normal despite an
increased protein level.53 Although we intuitively realize
this is an important test for diagnosing GBS, CSF protein
levels are commonly normal in the first week of presenta-
tion. Early work by Ropper54 demonstrated that only 50% of
patients initially presented with CSF protein greater than
0.55 g/L. A more recent prospective study conducted by
Nishimoto et al.44 showed only 44% of patients with GBS
have abnormal protein levels in the first week of illness.
Published European guidelines for the diagnosis of GBS
argue that CSF studies are of very limited value, and the
diagnosis should usually be made on clinical grounds
alone.55 Our view is that, although CSF studies may be
useful in characterizing the course of disease and subse-
quent response to treatment, they may be deferred until
after the patient is admitted from the emergency depart-
ment as they will rarely direct immediate management.
Imaging is not a part of diagnostic criteria in GBS and can
be deferred in cases with little clinical ambiguity.56 How-
ever, as there can be overlap with MFS and BBE, which can
respectively involve the cranial nerves and brainstem, MRI
may be a diagnostic necessity. Zuccoli et al.57 gathered
retrospective neuroimaging data on 17 patients who pre-
sented with clinical GBS, of whom 14 (82%) showed
enhancement of the cauda equina.
Most patients who are adequately treated with immu-
nomodulatory therapy will generally recover their neuro-
logical function within the first year after the initial
presentation.58 However, as with most postinfectious dis-
ease, GBS presents within a spectrum of varying severity
where approximately 13% of children will progress to res-
piratory failure requiring ventilator support.51
Miller Fisher syndrome
Although the most common form of GBS involves
ascending paralysis in the extremities, several variant forms
have been described, which often involve prominent cranial
nerve involvement. MFS is one such variant, which also
differs from typical GBS, in that it tends to have a more rapid
onset and greater severity.59 Although MFS is strongly
associated with the clinical triad of ataxia, areflexia, and
ophthalmoplegia, it is important to note that any ascending
polyneuropathy can present with dysfunction of any of the
cranial nerves. One study prospectively found that of all
children presenting with GBS-like symptoms such as lower
extremity weakness and areflexia, 27% also presented with
cranial nerve dysfunction and another 46% developed some
kind of cranial nerve dysfunction during the course of
hospitalization.46
Ancillary testing plays a similar role with MFS as it does
with GBS. CSF shows increased protein levels in 25% of
patients during the first week of presentation, again sug-
gesting the limited role of LP in the initial evaluation of
MFS.44 As discussed previously, the presence of anti-GQ1b
antibodies is highly suggestive of MFS but has also been
shown in polyneuropathies that do not have cranial nerve
involvement.45
Bickerstaff brainstem encephalitis
BBE is a relatively obscure medical condition described
as a clinical triad of ataxia, ophthalmoplegia, and a
“disturbance of consciousness.”60 It is generally character-
ized as occurring with an antecedent history of infection,
albuminocytologic dissociation in the CSF, and anti-GQ1b
antibodies in the serum.45 One group delineated criteria
as being “definite” when opthalmoplegia, ataxia, and
impaired consciousness are present in the setting of posi-
tive serum anti-GQ1 antibodies and the absence of other
excludable conditions.61
A nationwide survey of Japanese physicians was con-
ducted to collect data on all patients with likely BBE be-
tween 2006 and 2009. Thirty-seven patients were found to
fulfill criteria for either definite (19) or probable (18) BBE. Of
these, 54% presented with limb weakness and 67% with
absent or decreased reflexes. Ninety-two percent of patients
presented with ataxia, 100% with ophthalmoplegia, 41%
with facial palsy, and 72% with oropharyngeal palsy. Labo-
ratory investigation showed normal CSF cell counts (less
than 5/mm3) in 56% and normal protein (less than 45 mg/
dL) in 62% of patients. Brain MRI was abnormal, showing T2
hyperintensity of the brainstem, thalamus, and cerebellum
in eight (23%) of 35 patients. Patients were treated with
 M. Caffarelli et al. / Pediatric Neurology 65 (2016) 14e30
immunologic therapydintravenous immunoglobulin (92%),
steroid (49%), or acyclovir (24%)dwith 91% of patients able
to walk independently at one-year follow-up.61
There is speculation that BBE is under-reported because
it is not widely recognized as distinct from GBS or MFS.62
Although data on the disorder are scarce, one series docu-
mented several patients with clinical brainstem lesions who
had simultaneous motor axonal neuropathy on electro-
diagnostic studies suggesting a clinical overlap with GBS.60
The shared finding of serum anti-GQ1 antibodies provides
further evidence of shared etiologic factors.45
BBE presents an interesting diagnostic problem, because
imaging and LP appear to have little utility as with all other
postinfectious phenomena discussed so far. The challenge
presents itself with the presence of lesions that clearly
localize to the brainstem, which would be a certain indi-
cation for imaging. Our view is that BBE may serve as a
diagnosis of exclusion in the face of cranial nerve abnor-
malities with negative imaging findings.
Transverse myelitis
Acute transverse myelitis (ATM) is a rare focal inflam-
matory disorder of the spine that affects one to four in every
million persons per year, with a bimodal age distribution
between the ages ten and 19 years and 30 and 39 years.63
The Transverse Myelitis Consortium Working Group out-
lined a diagnostic algorithm in 2002, which included muscle
weakness with upper motor neuron signs and sphincter
dysfunction with a clear sensory level. With this clinical
suspicion, the recommendation is to obtain a contrast-
enhanced MRI within four hours to rule out compressive
myelopathy, which may necessitate a surgical evaluation or a
course of intravenous methylprednisolone.63
Idiopathic ATMdthe isolated and monophasic form of
the diseasedwas retrospectively studied in children of a
period spanning 23 years. Of 27 patients studied, ten (39%)
had an antecedent infection and 20 (74%) presented with
paraparesis. The mean age of onset was 9.5
5.7 years.
Although ataxia is not explicitly stated as a clinical feature, a
sudden onset of paraparesis would present with an inability
to walk, which in younger individuals might be difficult to
distinguish from cerebellar ataxia. CSF pleocytosis was seen
in ten (37%) and increased protein levels in 12 (44%) pa-
tients. Imaging revealed T2 hyperintensity most often in the
gray matter of the cervical and thoracic spine. Although
surrounding white matter was occasionally involved, iso-
lated white matter lesions were not seen. Of 21 patients
who were imaged with MRI, seven (33%) had multifocal
lesions whereas six (28%) showed no abnormalities,
although some of these data may have been collected with
older, less sensitive, imaging techniques.64
Although ATM can occur as a postinfectious process, it is
also known to be a rare feature in several connective tissue
disorders (sarcoidosis, Behçet’s disease, Sjögren’s syn-
drome, systemic lupus erythematosus, and so forth) and is
also a common first presentation of MS.63 The presence of
optic neuritis will suggest either neuromyelitis optica or MS
as the underlying etiology. All cases of ATM eventually
require CSF studies to examine for specific markers of dis-
ease, although these tests do not need to be immediately
done.65 A discussion on diagnosing the different causes of
ATM is out of the scope of this review, as it would likely be
19
done after imaging is performed and the patient is admitted
from the emergency department.
Toxic ingestion
Toxic ingestion is a common problem in the pediatric
population. In 2013, 1.3 million children aged less than
19 years in the United States were reported to poison con-
trol centers for accidental and intentional ingestion of
prescription and nonprescription medicationsd78% of vic-
tims less than six years of age.66 Medication ingestion in
children accounted for an estimated 9490 emergency hos-
pitalizations between 2007 and 2011, 75% of which were
children either one or two years of age. Benzodiazepine
ingestion accounts for approximately 10% of these patients,
representing one of the most frequent classes pharmaceu-
tical agents to be ingested.67 Although major efforts are
currently being made to introduce safer packaging for
commonly ingested pharmaceuticals,68 toxic ingestion re-
mains an important cause of ataxia.
Gieron-Korthals et al. showed that approximately one
third of acute ataxia in children resulted from toxic inges-
tion. Although benzodiazepines were the most common
offender, phenytoin, phenobarbital, and carbamazepine
were also important substances identified by the study.7
Martínez-Gonzáles et al.8 reported dextromethorphan and
ethanol to as two other toxic causes of acute ataxia. New
studies are needed to evaluate which substances are
currently implicated in acute ataxia, as the incidence of
poisonings may have changed for more than the past
20 years.
Benzodiazepines
Benzodiazepines are one of the most commonly ingested
substances by children and have been repeatedly published
FIGURE 1.
Relative rates of benzodiazepine, carbamazepine, and phenytoin ingestion
in children aged less than six years. The comparison between 2009 to
201369-71,76,77 and 1988 to199278-82 is made to highlight the relative
reduction of carbamazepine and phenytoin ingestion juxtaposed with the
relative increase in benzodiazepine ingestions in the time since Gieron-
Korthals et al. published their study on the causes of ataxia. Patients
greater than six years of age could not be compared, because the age
ranges used to categorize the data had changed between the two periods of
time.
20 M. Caffarelli et al. / Pediatric Neurology 65 (2016) 14e30
as a frequent cause of acute ataxia.4,7,8,11 An average of
10,000 ingestions per year occur in children.69-71 Clinical
features include lethargy advancing to coma, with respira-
tory depression as an important feature to be aware of.72
Although the sedative effects of many substances can
cause pupillary constriction,73 benzodiazepines have been
shown to not affect the pupil size in the same way opiates
might.74 Amnesia and diplopia are two other features that
have been described in the dental literature.75
The landmark 1994 study by Gieron-Korthals et al.
demonstrated that only five (12.5%) of their 40 patients
with acute ataxia had ingested benzodiazepines, yet that
group represented the most cases of ataxia attributed to a
single drug class.7 Data collected by the American Associ-
ation of Poison Control Centers show that, in children less
than six years of age, benzodiazepine ingestion rates are
higher in recent years compared with the time period when
Gieron-Korthals et al. collected their data (Fig 1).69,70,76,78-82
Despite the strong association between benzodiazepines
and acute ataxia in children, relatively few studies have
examined this relationship. Wiley and Wiley in 1998 pub-
lished a two-center retrospective analysis of children
admitted for benzodiazepine ingestion, reporting ataxia in
40 (87%) of 45 patients of which eight (20%) presented with
no other symptom. Altered mental status defined by a
Glasgow coma scale (GCS) less than 15 was apparent in 32
(70%) patients, of whom six (19%) had a GCS less than 6.
Twenty-seven patients (60%) had a clearly identified time of
ingestion.72
It is difficult to understand how these datadpublished
nearly 20 years agodfit into the evaluation of acute ataxia
today. However, it is clear that accidental ingestion of
benzodiazepines in young children is still occurring at a rate
unchanged, if not greater, than 20 years ago. The relative
frequency of ataxia caused by benzodiazepine ingestion
compared with other noningestion causes remains an
important question to tease out in future studies. Further-
more, understanding what proportion of cases present with
an a priori history of ingestion will be helpful in determining
whether to maintain a high index of suspicion in cases
where such a history is absent. Toxicologic screening of
urine or serum is a rapid test that may be useful for children
in clinically vague scenarios.
Antiepileptics: carbamazepine and phenytoin
Gieron-Korthals et al. reported that, apart from benzo-
diazepines, carbamazepine and phenytoin were the two
antiepileptic drugs (AEDs) most commonly implicated in
acute ataxia. Three of their 40 patients had ingested
phenytoin and two had ingested carbamazepine.7 A retro-
spective study by Lifshitz et al. reported ataxia in slightly
less than one third of children with carbamazepine
poisoning, with clinical improvement seen in all patients.
Nystagmus is the most common presenting feature, and
although ataxia may be seen as a more concerning symp-
tom, the combination of the two may suggest carbamaze-
pine poisoning.83
Carbamazepine ingestions have also decreased in the
past 20 years, most notably in children aged less than
six years (Fig 1).69-71,76-82 This finding coincides with a
generally reduced prescription rate of carbamazepine, and
the increasing use of newer AEDs.84,85 Oxcarbazepine, a
newer generation AED with a similar mechanism of action,
has been shown to have more benign toxic profile in over-
dosing, which does not seem to include ataxia, although
dizziness and vertigo is a feature in about 1% of cases.86
Phenytoin toxicity is also classically associated with
ataxia, often in conjunction with vertical downbeat
nystagmus and vomiting.87 Gieron-Korthals et al. described
three patients with acute ataxia who were ultimately found
to have overingested phenytoin.7 However, average
phenytoin ingestions for more than the past five years are
ten-fold less than in the five years preceding their publi-
cation,69-71,76-82 which may also be in part because of a
reduction in phenytoin prescriptions.85
Cough syrup: dextromethorphan
Dextromethorphan is the main ingredient in widely
available over-the-counter cough suppressants with CNS
adverse effects that makes it a popular drug of abuse.88
Different effect “plateaus” have been described in which
increasing concentrations of dextromethorphan will lead to
distinct symptoms: euphoria (2.5 mg/kg), imbalance and
visual sensations (7.5 mg/kg), altered consciousness and
delayed reaction times (15 mg/kg), hallucinations, ataxia,
and complete dissociation (greater than 15 mg/kg).89
One 30-month-old child with an approximate 38 mg/kg
ingestion of dextromethorphan presented to the emergency
department with opisthotonos that resolved with admin-
istration of diphenhydramine, although the patient
demonstrated ongoing ataxia and nystagmus until the next
morning.90 It is important to recognize that although some
over-the-counter formularies contain dextromethorphan as
its only active ingredient, other products may also contain
pseudoephedrine, which may induce irritability and hy-
peractivity in a child superimposed on ataxia and
nystagmus.91 Fortunately, the rate of cough syrup ingestions
has been rapidly declining for more than the past five years
(Fig 2).69-71,76 Data are needed to determine the incidence of
cough syrup ingestion as a cause of acute ataxia.
Ethanol
Ethanol toxicity can present with a range of mental sta-
tus changes and respiratory depression, with children often
at a risk of hypothermia and hypoglycemia.92 Ethanol is
well-documented cause of cerebellar dysfunction, although
the mechanism is not fully understood.93 Research in ani-
mal models has shown that adolescents have a higher
threshold to motor dysfunction compared with adults,94
although a similar dose-dependent relationship has not
been shown in humans. Other than the single patient
retrospectively identified by Martínez-González et al.8 from
a group of 39, the rate of ataxia in children with ethanol
ingestion has not been studied; therefore the blood con-
centrations of ethanol needed to generate ataxia are
unknown.
There appears to have been a large reduction in child-
hood ethanol ingestion for more than the last several years.
The American Association of Poison Control Centers’ Na-
tional Poison Data System documented 22,137 ethanol in-
gestions in 2009, 72% of which were children less than six
years of age who ingested nonbeverage ethanol. This
number dropped to 7,093 after two years, and in 2013 was
5,839 (Fig 2).69-71,76 The reason for this sharp decline is
 M. Caffarelli et al. / Pediatric Neurology 65 (2016) 14e30 21

FIGURE 2.
Rates of reported ingestions of different substances known to cause ataxia in children. Data gathered from the Poison Control Centers’ National Poison Data
System.69-71,76,77

unclear, although one possible explanation is a trend away
from the sale and home-use of alcohol-based mouthwash.95
Whether this trend is the reason for fewer childhood
alcohol ingestions or has had an appreciable effect on the
rate of ataxia in children is unknown.
Marijuana
Ataxia can be a result of marijuana use, which usually
occurs in adolescents participating in risky behavior. How-
ever, young children presenting with ataxia, tachycardia,
and vertical and horizontal nystagmus have been docu-
mented to have cannabinoids in their serum.96,97 Marijuana
and the many synthetic cannabinoids are known to have a
wide range of toxidromic features: patients initially believe
a sense of euphoria, but can progress to paranoia, delusions,
hallucinations, panic attacks, nausea, vomiting, seizures,
and dizziness.98
The rate of reported ingestions of marijuana and
cannabinoid-containing edibles has steadily increased
in the past five years, especially in children less than six
years of age (Fig 2),69-71,76 suggesting that they may be
important considerations as the cause of acute ataxia in
the face of the increasing liberalization of these sub-
stances. A thorough history should include the presence
of these substances in the household, including inhaled
and edible forms. Marijuana is commonly baked into
cookies or brownies, which has been shown to be a cause
of accidental ingestion in children leading to coma.97
Cannabinoids may not be routinely tested as part of
toxicology screens; thus it is important to actively
22 M. Caffarelli et al. / Pediatric Neurology 65 (2016) 14e30
consider marijuana toxicity in the differential diagnosis
of acute ataxia.
Cerebrovascular
Childhood stroke is an extremely rare but devastating
event, with cerebellar involvement occurring in an
even smaller subset of this group of patients.99 There
are documented examples of both hemorrhagic and non-
hemorrhagic cerebellar stroke in children, with listed
outcomes ranging from complete recovery to permanent
neurological dysfunction and occasionally death.100,101 In
such individuals, intervention must be initiated early to ach-
ieve optimal outcomes. Ataxia can be a major presenting
feature for these children, and although rare, early diagnosis is
critical. Although we do include case reports and case series
in this section, there is a knowledge gap in understanding
how acute ataxia may be the initial presentation of stroke.
Further study is needed to help in differentiating stroke
from other causes of ataxia, as it is one of the etiologies that
can be missed when there is much to gain from rapid
intervention.
Hemorrhagic
Intracranial bleeding is a medical emergency, necessi-
tating prompt imaging and neurosurgical evaluation. A
retrospective study documented four children with cere-
bellar hemorrhage that presented with acute-onset ataxia.
For these patients, other neurological signs and symptoms
were highly variable and occasionally absent. Headache was
a common accompanying symptom, where the timing
ranged from sudden onset to progressive for more than the
course of three days. The GCS for these patients was normal
in all except one. Cerebellar hemorrhage in children was
frequently found to reveal underlying cavernous angioma
or an arteriovenous malformation in the posterior fossa.102
Although these conditions may require eventual surgical
correction, the need for immediate surgical intervention is
dictated by the extent of fourth ventricle effacement and a
GCS less than 13.103 Although most neurosurgical outcome
data are from studies done in adults, childhood does not
appear to significantly influence indications for surgery.104
Headache appears to be the most frequent accompanying
symptom, and is an indication for rapid imaging in children
who describe their headache as being “unusual,” “sudden,”
or “worst.” A GCS less than 13 is also an important indication
for imaging, with rapid imaging preferable over sensitive
imaging. Rapid MRI protocols allow a time in the scanner
(“table time”) that is comparable with that of rapid CT
scanning, although its use in children has only been studied
in its ability to assess for ventriculoperitoneal shunt mal-
function.105,106 Furthermore, its use in emergency settings
has been limited to retrospective studies.65 As a result, the
sensitivity of rapid MRI protocols in detecting intracranial
pathology in the posterior fossa cannot reasonably be
inferred and remains to be elucidated. Evidence of hemor-
rhage in the posterior fossa in children less than three years
of age may alert the physician to nonaccidental trauma.107
Nonhemorrhagic
Acute ataxia can be the result of an ischemic cerebellar
insult resulting from an occlusion in the posterior
circulation. Ischemic stroke in the brainstem is uncommon.
One review documented 36 published examples of verte-
bral artery dissection (VAD) in children for more than a span
of ten years.108 Another review of posterior circulation
stroke in children indicated that slightly less than half of
cases were attributable to VAD.100 In the Gieron-Korthals
et al. report, only one of the 40 patients identified in a
ten-year interval had a cerebellar infarction, and this indi-
vidual was not described in detail.7
Posterior circulation ischemic stroke can occur at any
age.109 Hasan et al. suggested that about half of children
with VAD present with ataxia and that half of the patients
have no clear history of trauma to the head or neck region.
Impairment of consciousness occurs in a third of the pa-
tients. After ataxia, headache and vomiting were the two
most common presenting symptoms, each occurring in 38%
and 34% of cases, respectively. Neurological examination
showed a deficit in the visual system in 72% of cases,
manifesting as either nystagmus, visual field deficits, ptosis,
pupillary abnormality, or abducens (sixth) nerve palsy.
Furthermore, 54% of cases occur with gross motor deficit
manifesting as either hemiparesis, hemiplegia, or
quadriplegia.108
Hasan et al. reported abnormalities in CT angiography for
all the cases they identified. Only ten of 63 children had
signs “pathognomonic” for VAD, showing either an intimal
flap (six) or eccentric filling defect (four) in the vertebral
artery. The remaining 53 cases had signs “highly suggestive”
of VAD, including occlusion, pseudoaneurysm, irregularity,
stenosis, narrowing, thrombosis, or a “string of beads”
appearance suggestive of fibromuscular dysplasia.108 With
the low pretest probability of VAD in children, however, it is
important to be cautious in interpreting abnormal results.
Without data on the rate of these findings in asymptomatic
children, the positive predictive value for such highly sug-
gestive findings is unknown.
A retrospective cohort study at Boston Children’s iden-
tified three of 364 children presenting to the emergency
department with ataxia duration of less than seven days
who had a cerebellar infarct. Of the three patients identified
in this study, MRI provided the standard of imaging,
whereas CT failed to identify an abnormality in one of the
cases.9
Venous sinus thrombosis
Cerebellar venous infarction can occur as a result of
isolated venous sinus thrombosis (VST) in the posterior
fossa, accounting for about 2% to 4% of all intracranial
thromboses.110 One study by Ruiz-Sandoval et al. uncovered
nine patients that presented with isolated cerebellar venous
infarction. Of these patients, all except one presented with
ataxia, with seven complaining of dizziness and seven with
a depression in mental status (ranging from drowsiness to
coma). Three patients were aged 18 years (14, 15, and
18 years), with all of them found to have an underlying
coagulopathy (puerperium and protein C deficiency).110
CT is insensitive and nonspecific in diagnosing cerebellar
VST, and MRI with magnetic resonance venography proves
to be the diagnostic study of choice. Kulkarni et al.111
showed diagnostic findings in three of five patients
imaged, with MRI detecting the venous abnormality in the
remaining two. Ruiz-Sandoval et al. reported CT as showing
 M. Caffarelli et al. / Pediatric Neurology 65 (2016) 14e30
abnormalities in all patients studied (hypodensities, mass
effect, and hydrocephalus), although in none of the patients
was VST detected. MRI was abnormal in all patients
assessed, with the VST and cerebellar involvement detected
in all cases.110 These data included adolescents and adults,
so their validity for younger individuals is unclear.
Infectious
Meningitis
Meningitis is commonly included in the differential
diagnosis of acute ataxia,4,8,21 with one group advocating
for LP in children who have altered mental status and
negative CT findings to rule out meningitis.19 Bacterial
meningitis is a serious life-threatening infection of the
meningeal membranes that demands rapid diagnosis and
subsequent treatment with antibiotics.112 Thompson
et al.113 described the onset and time course of clinical signs
and symptoms in 544 children, teasing out that fever, sepsis
features, hemorrhagic rash, impaired mental state, and
meningism and the main features that appear within the
first 48 hours of disease. A systematic review of prospective
data further characterized the sensitivity and specificity of
26 different signs and symptoms seen with bacterial men-
ingitis.114 Neither study mentions ataxia as an important
presenting feature of disease.
A 1972 series described four children with bacterial
meningitis who presented with ataxia as a major feature of
illness. All had elevated temperatures and three exhibited
altered mental status.115 Gieron-Korthals et al.7 included
one child with acute ataxia and viral meningitis; this pa-
tient’s clinical details are not described in detail but there
was CSF pleocytosis. Thakkar et al.10 mentioned one pa-
tient with ataxia and meningitis, but they did not specify
whether it was bacterial or viral and did not include the
CSF findings.
Bacterial meningitis is an unlikely cause of acute ataxia,
especially in a child without the classic features of fever or
meningismus. Furthermore, the introduction of the Hae-
mophilus influenzae type-b and conjugate Pneumococcal
vaccines has dramatically reduced the incidence of bacterial
meningitis in the United States to approximately 200 cases
per year, at a mean age 0.6 (0.2 to 4.0) years.116 However,
culture-negative (i.e., aseptic) meningitis remains a com-
mon occurrence that is difficult to clinically distinguish
from bacterial meningitis.117 A close examination of the rate
of meningitis in the setting of acute ataxia is critical for
determining the diagnostic utility of LP in the emergency
department.
Rhombencephalitis
Rhombencephalitis is an extremely rare manifestation of
disseminated listeria or varicella infection, which has been
reported predominantly in immunosuppressed adults.118,119
In one case series of adults with Listeria rhombencephalitis,
ataxia was shown in 27% of patients in whom fever was
universally present with meningismus in 64% of patients.
All patients with CSF studies were shown to have pleocy-
tosis, CT was positive in only eight of 21 patients.118 One
report documented lesions in the brainstem and cerebellum
on MRI.119
23
Enterovirus 71 is a cause of hand, foot, and mouth dis-
ease that can have devastating neurological sequelae and is
notorious for a 1998 epidemic in Taiwan leading to the
hospitalization of 320 children with neurological disease, of
whom 55 died. A total of 41 of these patients were studied,
of whom 37 (90%) had rhombencephalitis, 20 (54%) of
which had grade I disease characterized by myoclonus with
either tremor or ataxia or both. Seven (19%) had grade III
disease, which entails fulminant neurogenic pulmonary
edema because of rapid cardiopulmonary failure. Despite
mechanical ventilation and cardiopulmonary support, five
of these patients died. Milder forms of rhombencephalitis
were varied in their clinical presentation, although none
presented with changes in mental status. MRI showed le-
sions restricted to the brainstem and not affecting any
supratentorial tissue.120 A treatment for enteroviral rhom-
bencephalitis has not been proposed other than to provide
appropriate supportive care.
Labyrinthitis
Labyrinthitis refers to the neurological manifestations of
otitis media, usually as a result of bacterial toxins or host
inflammatory mediators migrating into the inner ear
without invasion of bacteria per se. Although older children
will usually report vertigo to their parents, younger children
who are unable to verbalize their complaint may appear to
have ataxic gait. Although it is a very unusual cause of
ataxia, a clinical evaluation of otitis media should raise
suspicion for this condition. Children stereotypically pre-
sent with nausea and vomiting, along with nystagmus.121
Gieron-Korthals et al.7 and Martínez-González et al.8 did
not attribute ataxia to labyrinthitis in any of their patients.
MRI is the most sensitive means of detecting labyrinthitis,
with the affected cochlea showing contrast enhance-
ment.122 Symptoms typically resolve with antibiotics,
although a child with multiple occurrences should be
evaluated by otolaryngology.121
Miscellaneous
Opsoclonus-myoclonus syndrome
Opsoclonus-myoclonus syndrome (OMS) is commonly
associated with occult neuroblastoma, although historically
the failure to recognize the syndrome has led to a delay in
diagnosing the tumor by more than a year after initial
presentation.123 Thakkar et al.10 noted that 10 (8.3%) of their
120 patients had OMS, although the clinical details of these
cases are otherwise unreported. A prospective survey in the
United Kingdom identified 19 individuals with OMS, two of
whom presented with acute ataxia. In this study, mean age
of presentation was 18 months, and the children presented
with a combination of ataxia, opsoclonus (chaotic conjugate
eye movements often referred to as “dancing eyes”), and
irritability. LP was abnormal in one of 10 patients, showing
an unspecified pleocytosis.124
The prevalence of neuroblastoma in individuals with
OMS has increased during the last several decades, probably
due to a combination of improvements in imaging and an
increasing recognition of the disorder. A retrospective study
of OMS showed a diagnostic prevalence of neuroblastoma
in 43% of patients evaluated in 2000. The diagnostic focus
24 M. Caffarelli et al. / Pediatric Neurology 65 (2016) 14e30
with OMS has thus transitioned to excluding the presence
of occult neuroblastoma.125
Urine catecholamines have only a 24% sensitivity in
diagnosing neuroblastoma in the presence of OMS.125
Although significantly increased numbers may help guide
diagnosis, further investigation for neuroblastoma is better
deferred for a time after the acute evaluation in the ED,
either when the patient has been admitted or in clinical
follow-up if the symptoms of ataxia do not subside.
Celiac disease
Celiac disease is an autoimmune disease triggered by
gluten ingestion. Its onset can be at any age, and children
typically present with vomiting, diarrhea, constipation, and
abdominal pain with infants often demonstrating failure to
thrive.126 Gluten sensitivity has been associated with ataxia,
with one series demonstrating 16 of 48 children presenting
at the onset of their celiac disease with one or more
neurological symptomsdtwo children presented with
cerebellar ataxia and had cerebellar atrophy on CT, although
it is unclear what the timing of symptoms was.127 A
different study, however, prospectively followed 835 chil-
dren with gluten sensitivity, defined as any child with
gluten sensitivity-associated antibodies in their sera and
positive intestinal biopsy. This study showed no children
with ataxia or other cerebellar manifestations, with only a
slightly higher incidence of neurological manifestations
compared with control subjects.128 In one small series of
patients with “gluten ataxia,” 12 of 13 patients showed
antibodies in their sera that bound to Purkinje cells in rat
tissue, suggesting a pathologic basis for the association.129
The association of ataxia in children with celiac disease is
controversial and poorly studied. No individuals with
gluten ataxia were documented in either the Gieron-
Korthals et al.7 or Martínez-González et al.8 series of acute
ataxia.
Pseudoataxia
The final diagnosis we will discuss is ataxia of a nonor-
ganic nature, or pseudoataxia. Gieron-Korthals et al.7
described one patient in their retrospective cohort as hav-
ing had a “conversion reaction,” but detailed clinical fea-
tures were not included. Many such terms are encountered
in the medical field that imply a nonorganic disorder,
among them are “dissociative,” “functional,” “somatoform,”
“psychogenic,” “supratentorial,” “hysterical,” and “medi-
cally unexplained.” A gait disorder of this nature is often
referred to as an “idiopathic” gait disorder.
One study evaluated 103 children with acquired gait
disorders, eight of whom had idiopathic ataxia amounting
to an estimated incidence of 2.9 per 1,000,000 children. Of
these eight children, five were female and three were male,
and they ranged between ten and 15 years of age. All chil-
dren with idiopathic gait disorder had significant school
absence and were scholastically above average before their
illness. Most of these children had many laboratory in-
vestigations completed, including six patients who had MRI
of either brain, spine, or both, and five who underwent
electroencephalography.130
Although laboratory and imaging investigations are
normal in this situation, there are no validated methods with
which a physician could diagnose pseudoataxia. One opinion
piece offers clinical methods for detecting functional gait
disorders in children, such as an age-appropriate cognitively
challenging task when walking.131 Although these methods
may intuitively make sense, their sensitivity and specificity
in detecting functional gait disorders have not been studied
and are thus unknown.
Evaluation of acute ataxia
Evaluating a child with acute ataxia is challenging,
especially in the absence of clear guidelines to direct clinical
management. Physicians in the emergency department are
faced with the dilemma of obtaining imaging or spinal fluid
or deferring such testing for the wards. Until recently, the
only two studies that have examined all patients who pre-
sented with acute ataxia are those by Gieron-Korthals et al.7
and Martínez-González et al.,8 both of which were retro-
spective and only included approximately 40 patients.7,8
As initially discussed, one cannot undervalue the utility
of careful history taking and physical examination skills in
evaluating a child with acute ataxia. More often than not, a
straightforward cause of ataxia can be derived without
ancillary testing. However, the presence of lateralizing
findings on neurological examination poses a real concern
for acute intracranial pathology that must be aggressively
investigated.
The current literature offers some guidelines on the
evaluation of ataxia based on features of the clinical eval-
uation and examination, but the positive and negative
predictive values of clinical findings rarely play a role in
guiding testing. Furthermore, the sensitivity of certain
testing will play a major role in deciding which tests to
order, or whether to continue testing in the face of negative
findings. In this section of our review, we cover the differ-
entiation between patients with isolated ataxia or those
with concurrent altered mental status as well as the role of
ancillary testing in the emergency department for a child
presenting with acute ataxia.
The history
The sudden onset of ataxia can be very distressing to
parents and patients alike. It is important that the provider
elicits much of the history by thorough questioning, as the
patient or their caretakers may not be able to associate prior
events with the current presentation. For the most acute
cases in which there is concern for an evolving intracranial
process or where the child is medically unstable, a brief
history should include the presence of any other symptoms,
known allergies, current medications, past medical history,
last oral intake, and events leading up to the presenting
symptoms. In such scenarios, it may be appropriate to forgo
detailed history taking for the sake of triage and timely
intervention.
The timing of symptoms can be helpful in narrowing the
differential. Ataxia evolving for a period of less than
72 hours is unlikely to be of neoplastic origin.7,8 The pres-
ence of an infectious syndrome or vaccine administration as
far as 2 weeks before presentation may implicate one of the
many postinfectious phenomena as the cause of ataxia. Any
associated trauma to the head and neck is important to note
 M. Caffarelli et al. / Pediatric Neurology 65 (2016) 14e30
and merits thorough examination, close monitoring, and
potentially imaging.
Hemiplegic ataxia caused by weakness in the postictal
state has been described,132 although it has not been seen in
any studies evaluating the different causes of acute ataxia in
children. Nevertheless, a history focused on the possibility
of epilepsy is important in ambiguous cases as these pa-
tients stand to benefit greatly from early diagnosis and
intervention. A prior history of intermittent paroxysmal
headachesdwhich caregivers may believe is not relevant to
a new onset of ataxia and thus may not readily offerdmay
indicate complex migraine or hemiplegic migraine as the
causative entity.133 Recurrence of ataxia in an otherwise
undiagnosed patient should raise suspicion for migraine
and seizures as the causative diagnosis. On the other hand, a
headache that is sudden in onset or described as the “worst
headache of my life” should trigger suspicion for hemor-
rhage. Any unclear or inconsistent history that is concerning
for nonaccidental trauma should be taken seriously, as
hemorrhage in the posterior fossa has been shown to have a
high occurrence in such cases.107
An ingestion-focused history is important in this popu-
lation, as toxic ingestion may mimic concerning pathology.
Caretakers should be asked about any medications both
they and the patient may have been taking. Be sure to ask
specifically if anyone who had been caring for the child
suffers from anxiety or seizures, as they may respectively
indicate access to benzodiazepines or AEDs.
The birth history, other than usual questions surround-
ing pregnancy, perinatal, and neonatal events, should focus
on whether the child has had newborn screening for com-
mon metabolic disorders. Ideally, these records would be
available for review but if they are not, one should never
assume the results to be normal. Parents should be asked
about any history of spontaneous abortions or if any siblings
had abnormal results on their newborn screen. Although
metabolic disorders associated with ataxia tend to manifest
gradually, the presentation is often “unmasked” by the
onset of systemic illness or a discontinuation in their daily
vitamins.134
Physical and neurological examination
The initial examination should focus on signs of systemic
illness, including an assessment of vital signs and an ex-
amination of the skin for rash. Vital signs should be assessed
for abnormal temperature to assess for infection. The triad
of hypertension, bradycardia, and hypopnea may occur with
increased intracranial pressure and has been shown to
occur with ischemia arising from the posterior
circulation.135
A careful examination of the eyes is critical. Fundoscopic
examination should be performed to assess for signs of
increased intracranial pressure, whereas retinal hemor-
rhaging signals a high likelihood of nonaccidental trauma.
Unilateral pupillary dilation can be the harbinger of tem-
poral lobe herniation requiring immediate decompression.
Bilateral nystagmus is often seen with toxic ingestion,
whereas unilateral nystagmus implies a lateralizing defect
and is therefore an indication for imaging. Any oph-
thalmoplegia can result from a lesion in the corresponding
cranial nerve or their nuclei in the brainstem, an assessment
25
of hearing and corneal sensation will help differentiate
between the two possibilities. Sudden onset ocular findings,
such as nystagmus or ophthalmoplegia, should be consid-
ered warning signs of posterior circulation stroke and
warrant immediate imaging.
An important aspect of the physical examination in these
cases is deciding whether the ataxia is because of cerebellar
dysfunction. Speech can be affected in lesions of the cere-
bellum ipsilateral to the dominant hand,136 and is
commonly described as a “scanning speech” in which pa-
tients must carefully articulate individually spoken sylla-
bles. Finger-to-nose and heel-to-shin can be used to detect
dysmetria, a sign indicating ipsilateral cerebellar damage.
Reflex testing of the knees may demonstrate a “pendular”
response, in which the leg swings more than four times
after the tendon is struck. Finally, gait testing may reveal a
staggering, wide-based gait in which the patient appears to
be “drunk.” It is important to realize these tests may not be
possible to perform in younger children who may not yet
have highly developed speech or motor skills and may
instead present with a refusal to speak or walk.
An assessment of the child’s mental status is critical part
of the neurological examination for these patients. For
many emergency department visits, the chief complaint
may often be a change in behavior or personality, with
ataxia revealed as a major feature only after taking the
history or performing the physical examination. A formal
assessment of the mental status should include the level of
alertness, attention span, speech and language, and short-
term memory. As we have discussed, an altered mental
status is often the harbinger of urgent intracranial pathol-
ogy such as ADEM, cerebellitis with mass effect, or stroke.
Conversely, normal mentation is not normally seen with
ingestion of many toxic substances such as AEDs or ben-
zodiazepines.72,83 A patient with ataxia and an altered
mental status should be assumed to have intracranial pa-
thology until proven otherwise by MRI or unless there is an
unequivocal history of toxic ingestion.
Laboratory testing
The utility of obtaining a complete blood count and a
comprehensive metabolic profile has not been explicitly
studied in acute ataxia; however, these tests should be or-
dered as a first pass screening tooldany derangement in
electrolytes (with attention to magnesium and phosphate)
should be corrected accordingly and subsequently invoke
diagnostic algorithms themselves.137-139 Transaminitis may
hint toward an inborn error in metabolism.6 Vitamins B1,
B12, and E may be implicated in ataxia and should be
evaluated in a patient with a history of poor nutrition or
certain restrictive dietsdthese tests may be deferred until
after admission.140
Any suspicion of underlying metabolic disorder as sug-
gested by a positive family history or obstetric history of
spontaneous abortion, parental consanguinity, or that of
failure or delay in achieving milestones preceding the onset
of ataxia should be preliminarily investigated by obtaining
metabolic screening laboratories: ammonia, lactate can
screen for mitochondrial disorders such as Leigh syndrome,
pyruvate dehydrogenase deficiency,10,141 or errors in
catabolism. Abnormalities in these values or a suspicion for
26 M. Caffarelli et al. / Pediatric Neurology 65 (2016) 14e30
such a disorder may invoke follow-up levels of pyruvate,
urinary amino acids, organic acids, carnitine, and an acyl-
carnitine profile. However, these tests are better sent after
admission and are best interpreted under the guidance of a
geneticist or specialist in metabolic disorders.6
Imaging
The diagnostic yield of neuroimaging in children with
acute ataxia has previously been estimated to be low, esti-
mated by Whelan et al.4 in their review article to be
approximately 2.5% for CT and 5% for MRI. However, the
data they complied were largely from older retrospective
studies published from 1994 to, most recently, 2006.7,8,18,20
Since then there have been advances in the diagnostic
capability of MRI that have allowed for a greater ability to
resolve subtle areas of demyelination142,143 and cytotoxic
edema.144 Advances in angiography and the use of contrast
have also improved the ability to detect tissue edema and
neoplasms.144
Rudloe et al. reported clinically urgent neuroimaging
findings in 42 (12.5%) of 335 patients presenting with ataxia
for less than seven days. Twenty-two of these patients had a
tumor, and the remaining 20 had ADEM (12), infarct (three),
encephalitis (one), transverse myelitis (one), hemorrhage
(one), syrinx with hydrocephalus (one), and mastoiditis
with epidural abscess (one). CT was read as normal in 10
(26%) of 38 patients that subsequently showed pathology
on MRI. Of 273 patients with symptoms for less than
three days, 19 (7.0%) had significant imaging findings.9
Although Thakkar et al.10 did not explicitly report the total
rate of positive imaging results, they did report eight (6.7%)
of 120 patients as having been diagnosed with imaging-
dependent diagnoses: cerebellitis (three), cerebellar stroke
(two), ADEM (two), and cerebral vein thrombosis (one). The
diagnostic yield of imaging cannot truly be assessed in the
absence of prospective research.
MRI is superior to CT in detecting intracranial pathology.
Inflammatory diseases of the brain are unlikely to be
detected by CT. Rudloe et al.9 showed that of 10 patients
diagnosed with ADEM, only two had lesions detected with
CT, and the only patient with transverse myelitis had a
normal CT. Transverse myelitis can only be detected with
MRI and confirmed cases should be followed up with im-
aging of the optic nerves to evaluate for neuromyelitis
optica.145
CT is useful for quickly evaluating acute stroke and
determining if it is hemorrhagic or ischemic; however, MRI
may be superior in detecting small or very acute hemor-
rhagic lesions.29 Imaging of the posterior fossa with CT is
further limited by beam hardening artifacts from sur-
rounding bony structures.30 Although a study directly
comparing CT with MRI in imaging the posterior fossa has
not been done, Rudloe et al.9 demonstrated four children
with cerebrovascular lesions in the posterior fossa, one of
which was not detected with CT.
Imaging the brain with cranial CT may be critical in its
rapid evaluation for neurosurgical issues such as the evo-
lution of hemorrhage, mass effect, or obstruction of cerebral
CSF outflow. In centers where rapid MRI is available,
bypassing CT may save time, avoid unnecessary radiation
and save resources as negative CT findings will not
necessarily rule out clinically urgent pathology.146 On the
other hand, rapid MRI as previously discussed has only been
validated for assessing ventriculoperitoneal shunt mal-
function and not for emergent headaches, depression in
mental status, of focal neurological findings in the emer-
gency department.65,105,106
Lumbar puncture
Abnormalities in the CSF, namely pleocytosis, are not
unusual in the postinfectious ataxia disorders, APCA and
cerebellitis.7,8,19,20 Cerebellitis is inconsistently associated
with pleocytosis and cases with positive bacterial cultures
are very rare.27,28 Protein levels may be increased in patients
with GBS and MFS, but the sensitivity is 44% and 27%,
respectively, during the first week of presentation.44
Although increased protein levels in the setting of normal
cell counts can help confirm the diagnosis, a presumptive
diagnosis of the peripheral neuropathies is largely clinical
and has little dependence on LP.54,55 CSF protein levels are
mostly important for prognosticating GBS and monitoring
disease progression,44 and therefore can be reserved until
after admission to an inpatient unit.
Large studies on the presenting signs of meningitis focus
on fever, changes in mental status, hemorrhagic rash, and
septic features to heighten the urgency of performing an
LP.113,114,147 However, there is no evidence that ataxia with
or without the presence of these features is more or less
suggestive of bacterial meningitis. LP has been reported to
precipitate brain herniation in patients with bacterial
meningitis, and although CT may be helpful in finding
contraindications to LP, a normal CT scan does not preclude
the risk of herniation, which is best assessed clinically
(pupillary changes, irregular breathing, and so forth).148
LP can be diagnostic in the setting of subarachnoid
hemorrhage, especially several days into the presentation as
the sensitivity of CT drops over time.149,150 However, this
phenomenon is exceedingly rare in children, and no such
patients have presented with acute ataxia.9
The utility of obtaining CSF studies in the emergency
department when directing both diagnosis and manage-
ment of acute ataxia is uncertain and remains largely
unstudied.
Toxicology screening
Toxic causes of ataxia can generally be identified from
the clinical evaluation. Although the history is not always
afforded by caregivers, questioning on specific substances
or family members taking specific medications can be
useful. Gieron-Korthals et al.7 reported an a priori history of
ingestion in 61% of patients with positive toxicologic
findings.
Screening for substances has long been considered an
important test in the evaluation of acute ataxia,4,11 espe-
cially because many cases of ingestion will not necessarily
present with a history of ingestion. Benzodiazepines remain
a frequently ingested class of drugs, especially in toddlers
and young children, that are known to cause ataxia. Broad
screening will also help in detecting cases of cannabinoid
ingestions, which may become more frequent in the face of
liberalizing laws against the sale of marijuana and edibles.
 M. Caffarelli et al. / Pediatric Neurology 65 (2016) 14e30
Ethanol levels should be obtained as part of standard toxi-
cology panels, even in young children. Urine or blood
testing should be considered routine in cases where the
patient is demonstrating decreased level of consciousness,
acute confusional state, new onset of psychiatric symptoms,
or a panic attack.151 As rapid confirmation of a toxic inges-
tion will help to exclude more serious intracranial pathol-
ogy from the differential. AEDs known to cause ataxia are
less commonly prescribed as they were at the time Gieron-
Korthals et al. published their study of ataxia, with in-
gestions of these substances also less frequently reported.
Conclusions
The evaluation of a child with acute ataxia in the emer-
gency department is a challenge for the clinician in deter-
mining the extent and timing of initial screening tests. In
most studies, abnormalities detected by screening tests
were nondiagnostic except for in a minority of patients.
Therefore, careful analysis of the medical history should be
carried out as the differential is broad, including central and
peripheral causes of which some are life threatening. The
spectrum of the etiologic factors in acute ataxia appears to
have changed in the years since Gieron-Korthals et al.
published their landmark article in 1994. Some of the major
implicated changes are the use of new AEDs instead of
phenytoin and carbamazepine and the use of new vaccines
that may have reduced the incidence of classically post-
varicellar cerebellar ataxia. Prospective data are needed to
determine the relative incidence of different causes of acute
ataxia.
From the evaluations that could be performed in the
emergency room, toxicology screening should be consid-
ered in all children presenting with acute ataxia as it could
be positive up to 49% of the cases or higher if the potential
substance is known. Brain MRI is preferred over cranial CT
when structural lesions are suspected because it offers a
more complete evaluation of the posterior fossa. Head CT
should be avoided to prevent radiation unless time is of the
essence, as such is the case with hemorrhage, vascular
disorders, hydrocephalus, or impending herniation. Imag-
ing can be deferred for observation and follow-up in the
clinically improving child who is otherwise well appearing.
LP should be considered in patients with fever, meningeal
findings, or an abnormal or declining mental status, but
otherwise may be deferred until after admission. Other
evaluations for less common causes should be considered in
the context of the presenting symptoms, but evaluation in
the ER is unlikely to change management. Urine catechol-
amines in a child with OMS will not be reported until the
patient is already admitted and if it is negative will not rule
out this disorder. There is insufficient evidence at the pre-
sent time to establish a role for other tests in less frequent
conditions such as autoantibody testing or searching for
inborn errors of metabolism in children presenting with
acute ataxia. Testing for metabolitesdlactate, pyruvate,
ammonia, amino acids, organic acids, carnitine, and acyl-
carnitine profiledshould be done if there is any history of
developmental regression or a family history of early deaths
or pregnancy losses. Some tests could be normal in the first
few days of a disease process, as is the case with CSF protein
27
in GBSda high index of suspicion is required in the
appropriate clinical context.
Some institutions have protocols for the management of
acute ataxia in the emergency department and practitioners
should be familiar with these, but more research is needed
to answer several fundamental questions with regards to
the initial evaluation. Acute ataxia is a relatively common
presentation in children seen by pediatric acute services
and child neurologists as a whole, but the frequency of their
specific etiologies might be low. We are in need of multi-
center prospective research that is well enough powered to
understand the rates of different causes and how to reliably
test for them. Although a primary concern on initial
assessment is to exclude serious causes of this clinical
syndrome, one must also be able to quickly establish a
diagnosis that might require rapid intervention. A good
clinician should be able to keep an open mind when
recognizing the essentially benign nature of acute ataxia in
most children. The more confidence we have in evaluating
these patients, the better we can provide guidance and
reassurance to the families who may fear the worst.
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