Radiologic and Neurophysiologic Aspects of Stroke-like Episodes in Children
With Congenital Disorder of Glycosylation Type Ia
Argirios Dinopoulos, Ismail Mohamed, Blaise Jones, Sanjai Rao, David Franz and
Ton deGrauw
Pediatrics 2007;119;e768; originally published online February 16, 2007;
DOI: 10.1542/peds.2006-0763

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/119/3/e768.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2007 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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EXPERIENCE & REASON

Radiologic and Neurophysiologic Aspects of
Stroke-like Episodes in Children With Congenital
Disorder of Glycosylation Type Ia
Argirios Dinopoulos, MD, PhDa, Ismail Mohamed, MDa, Blaise Jones, MDb, Sanjai Rao, DOa, David Franz, MDa, Ton deGrauw, MD, PhDa
Divisions of aNeurology and bRadiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
The authors have indicated they have no financial relationships relevant to this article to disclose.

ABSTRACT
In an effort to shed light on the mechanism of hemiparetic stroke-like events experienced by patients with congenital
disorder of glycosylation type Ia, we evaluated 3 children with this disorder by brain imaging studies and continuous
electroencephalogram monitoring during such events. No evidence of ischemia or infarction was revealed on imaging
studies and electrographic seizures or intermittent epileptiform activity was demonstrated on electrographic recordings. All 3 patients showed clinical and electrographic improvement after administration of antiepileptic medication.
Epileptic phenomena can complicate the stroke-like events of patients with congenital disorder of glycosylation type
Ia, and the cause of the hemiparesis may indeed be an active epileptic inhibitory process. As such, electroencephalogram monitoring is warranted, and treatment with anticonvulsant agents is indicated.

C

ONGENITAL DISORDERS OF glycosylation (CDG) comprise a group of inherited multisystem diseases
characterized by defects in the glycosylation of glycoproteins. CDG type Ia (phosphomannomutase 2 deficiency) is, by far, the most frequently diagnosed Nglycosylation disease. It has a static clinical course that is
characterized by mental retardation, hypotonia, cerebellar dysfunction, polyneuropathy, seizures, and strokelike episodes of unknown origin. These episodes are
known to occur in 40% to 55% of cases and are thought
to be triggered by infection. They are associated with
irritability, mental status changes, and hemiparesis and
are sometimes accompanied by seizures. Their duration
varies, with recovery ranging from days to weeks.1,2
In an effort to shed light on the mechanism of these
hemiparetic stroke-like events, we evaluated 3 patients
with genetically confirmed CDG-Ia by continuous electroencephalogram (EEG) monitoring and brain imaging
studies during such events. We report our findings here
and propose a possible etiology.

CASE REPORTS

Treatment with intravenous lorazepam (0.2 mg/kg) was
followed by respiratory suppression, which required intubation. Continuous bedside EEG monitoring during
the hemiparesis revealed right parietal-occipital slowing
with frequent intermittent spikes and 6 electrographic
seizures arising from the right posterior quadrant. These
seizures varied in duration, with the longest lasting up to
15 minutes (Fig 1). With the exception of hemiparesis,
there were clinically no motor correlates to these seizures. Imaging studies (Table 1) performed during the
hemiparetic event showed no evidence of ischemia or
infarction. The patient was treated with intravenous fosphenytoin. Shortly after the initiation of treatment, her
EEG showed resolution of electrographic seizures, and
her mental status was steadily improved. Hemiparesis
completely resolved 96 hours after the onset of symptoms and 24 hours after the administration of intraveKey Words: hemiparesis, stroke-like, epilepsy, congenital disorder of glycosylation,
CDG
Abbreviations: CDG, congenital disorders of glycosylation; EEG,
electroencephalogram; ED, emergency department; DWI, diffusion-weighted imaging
www.pediatrics.org/cgi/doi/10.1542/peds.2006-0763

PATIENT 1. A 21⁄2-year-old girl with CDG-Ia presented at the

doi:10.1542/peds.2006-0763

emergency department (ED) 36 hours after acute onset
of left hemiparesis, irritability, and a diminished level of
consciousness after a febrile illness. At presentation, unresponsiveness and upward eye-rolling were observed.

Accepted for publication Sep 18, 2006.
Address correspondence to Argirios Dinopoulos, MD, PhD, Cincinnati Children’s Hospital Medical
Center, Division of Neurology, 3333 Burnet Ave, MLC11006, Cincinnati, OH 45229. E-mail: argidino@
yahoo.com
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2007 by the
American Academy of Pediatrics

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DINOPOULOS et al

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FIGURE 1
Patient 1: The tracings shown in A, B, and C (10-second epochs-bipolar montage) are segments of the EEG recording while the patient was hemiparetic. The tracing in A shows the
beginning, in B shows the evolution, and in C shows the end of an electrographic seizure. The seizure arose from the right posterior quadrant (T6-O2), spread over the parietal-occipital
head region (P4-O2), and lasted 15 minutes. The tracing in D (10-second epoch-bipolar montage) shows a segment of the recording 21⁄2 hours afterward, while the patient was clinically
improved and after administration (second dose) of intravenous fosphenytoin.

nous fosphenytoin. The patient was discharged on carbamazepine and has had no additional episodes over the
subsequent 4 years.
PATIENT 2. An 11-year-old girl with CDG-Ia presented at

spikes and sharp-wave activity (Fig 2) and complete
resolution of the hemiparesis 12 hours later. The patient
was discharged on oxcarbazepine and has had no additional hemiparetic episodes over the subsequent 31⁄2
years.

the ED 8 hours after acute onset of left-side hemiparesis,
irritability, and a diminished level of consciousness concurrent with a viral infection. She had had 3 previous
episodes of stroke-like events (at 3, 6, and 9 years of age)
that lasted up to 72 hours; because these events occurred
in conjunction with seizures, they were described by
previous clinicians as Todd’s paralysis. After admission,
continuous bedside EEG monitoring showed continuous
focal right frontal slowing with intermixed runs of semirhythmic spikes and sharp waves that lasted up to 8
seconds (Fig 2). Imaging studies (Table 1) performed
during the hemiparesis showed no evidence of ischemia
or infarction. Treatment with intravenous lorazepam
(0.1 mg/kg) resulted in disappearance of the rhythmic

PATIENT 3. A 14-year-old girl with CDG-Ia presented at the
ED 48 hours after developing agitation, right-arm weakness, and fever. After becoming increasingly lethargic,
she was admitted to the ICU. Bedside EEG monitoring
showed continuous rhythmic high-amplitude bifrontal
sharply contoured ␦ activity with higher amplitude on
the left frontocentral region. Shortly after the administration of intravenous lorazepam (0.1 mg/kg), rhythmic
frontal slowing disappeared and clinical improvement
was observed (Fig 3). Hemiparesis resolved 2 hours after
the administration of intravenous lorazepam and 72
hours after the onset of symptoms. Computer tomography of the head during the hemiparesis showed no acute

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TABLE 1 Patient Data
Case
No.

Mutations of PMM2 Gene and Coagulation
Deficiencies

Imaging Modalities and Timing in Relation to
Onset of Hemiparesis

Continuous EEG Monitoring

1

Mutations: I120T/V231M; coagulation deficiencies:
factor XI, antithrombin III, heparin cofactor II

HCT: 38 h after onset of hemiparesis; MRIa (sagittal
T1, axial T2, and FLAIR, DWI, ADC, coronal FSE);
1HMRS: 50 h after onset of hemiparesis and
while patient was hemiparetic

2

Mutations: R141H/F119L; coagulation deficiencies:
factor XI, antithrombin III, protein C, heparin
cofactor II

HCT: 10 h after onset of hemiparesis; MRIa (sagittal
T1, axial T2 and FLAIR, coronal FSE); 1HMRS: 28 h
after onset of hemiparesis and while patient was
hemiparetic

3

Mutations: R141H/F119L; coagulation deficiencies:
factor XI, antithrombin III, protein C and Sc

HCT: 48 h after onset of hemiparesis; MRIa (sagittal
T1, axial T2 and FLAIR, DWI, ADC, coronal FSE);
1HMRS, MRA, and MRV: 120 h after onset of
hemiparesis and 48 h after resolution

EEG recording (started 42 h after the onset of
the hemiparesis); right parietal-occipital
slowing with frequent intermittent spikes;
6 electrographic seizures arose from the
right posterior quadrant; resolution of the
electrographic seizures after treatment
with intravenous fosphenytoin
EEG recording (started 15 h after the onset of
the hemiparesis); continuous focal right
frontal slowing with intermittent
semirhythmic runs of spikes and sharps
waves lasting up to 8 sec; disappearance
of the spike and sharp-wave discharges
after 2 doses of intravenous lorazepam
EEG recording (started 50 h after the onset of
the hemiparesis); continuous rhythmic
high-amplitude bifrontal sharply
contoured ␦ activity with higher
amplitude on the left frontocentral region;
attenuation of the EEG pattern 7 min after
intravenous lorazepam

PMM2 indicates phosphomannomutase 2; HCT, head computer tomography; FLAIR, fluid-attenuated inversion recovery; FSE, fast-spin echo; ADC, apparent diffusion coefficient; 1HMRs, proton
magnetic resonance spectroscopy; MRA, magnetic resonance angiography; MRV, magnetic resonance venography.
a All MRI studies were performed on a 1.5-T magnetic resonance scanner (GE Medical Systems, Milwaukee, WI).

FIGURE 2
Patient 2: The tracings shown in A and B (10-second epochs-bipolar montage) are segments of the EEG recording during the stroke-like event. The tracing in A shows a segment of the
ongoing semirhythmic slowing with intermixed-spikes activity over the right frontocentral head region (F4-C4). The tracing in B shows a sample of the recording 2 hours afterward,
while the patient was clinically improved and after treatment with intravenous lorazepam.

changes, and both MRI and magnetic resonance angiography performed after the resolution of the hemiparesis
showed no evidence of ischemia. The patient was discharged on topiramate and has had no additional hemiparetic episodes over the subsequent 21⁄2 years.
DISCUSSION
Here we report the electrographic and imaging findings
of 3 patients with CDG-Ia during a hemiparetic strokelike event. Signs of neuronal hyperexcitability were
demonstrated on the electrographic recordings of all 3
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DINOPOULOS et al

patients, with no evidence of ischemia revealed by the
imaging studies. To our knowledge, ours is the first study
to document electrographic and imaging findings during
hemiparetic stroke-like events.
Several studies have described the neurologic manifestations of CDG-Ia1–3; however, because detailed evaluation during hemiparetic stroke-like episodes is lacking, the pathophysiology and specific mechanism of
these episodes remain unknown. Ischemia has been proposed as a possible etiology of these stroke-like events,
because both procoagulant (factor XI) and anticoagulant

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FIGURE 3
Patient 3: The tracing shown in A (30-second epoch-bipolar montage) is a segment of the EEG recording during the hemiparetic stroke-like event and shows continuous rhythmic
high-voltage slow waves (⬃1 Hz) over the frontal head region bilaterally, but it is better seen on the left (F3-C3). The tracing in B (30-second epoch-bipolar montage) is a segment of
the EEG.

(protein C, antithrombin III, and protein V) proteins are
reported to be deficient in most patients with CDG-Ia.4,5
Other factors that support ischemia as the cause of the
events include platelet hyperaggregability and transient
decrease of endogenous anticoagulants during catabolic
stress.6 Nevertheless, there has been no report that provided clear neuroradiologic or pathologic evidence of
ischemic stroke, and there have been very few reports of
other thrombotic accidents in patients with CDG-Ia.7,8
The above-described coagulation deficiencies were also
observed in all 3 of our patients (Table 1); however, no
evidence suggestive of ischemia was seen in the neuroimaging studies performed during the hemiparetic
events. Moreover, for 2 patients, no restricted diffusion
was observed on diffusion-weighted imaging (DWI) or
apparent diffusion coefficient maps. Signal-intensity
changes can be detected within minutes of arterial occlusion with DWI, and increased signal intensity detected with T2-weighted sequences is usually observed
after 8 hours.9 Regardless of the fact that MRI modalities
have been shown to miss transient ischemic events, DWI
and apparent diffusion coefficient mapping, in particular, usually detect events associated with prolonged duration and disturbances of higher brain function.10 If the
prolonged hemiparesis (lasting ⬎48 hours) in our cases
was caused by a cortical ischemic infarction, this infarction would have likely been detected on standard MRI.
The cytotoxic edema caused by the infarction would be
even more likely to exhibit a restricted diffusion on DWI.
Epileptic seizures are not uncommon in patients with
CDG-Ia and often are observed in association with
stroke-like events. A transient focal neurologic deficit
known as postictal paralysis (Todd’s paralysis) can follow
a convulsive motor seizure. Our data are insufficient to
prove that the paralysis in our patients was ictal; however, the phenomenon cannot be considered a simple

Todd’s paralysis, because the hemiparesis persisted beyond 24 hours, ictal discharges were present on EEG,
and clinical motor seizures were absent before hemiparesis.11 The EEG recording during the hemiparesis
showed clear electrographic seizures in patient 1. No
electrographic seizures were captured for patients 2 and
3. However, EEG recording showed a continuous semirhythmic slowing with intermittent runs of spikes and
sharp-waves activity in patient 2 (Fig 2) and a continuous sharply contoured rhythmic ␦ activity in patient 3
(Fig 3). Both patterns resolved after the administration
of lorazepam. Continuous rhythmic sharp waves and
frequent rhythmic spikes and sharp waves are commonly seen in comatose patients but also can be seen in
patients with nonconvulsive status epilepticus.12 The significance of such patterns is unclear and reflects the
difficulty of differentiating ongoing epileptic discharges
from abnormalities caused by diffuse metabolic neuronal
dysfunction. The rapid electrographic response and,
more importantly, the clinical response observed after
treatment with antiepileptic drugs favor an epileptic etiology in our patients.
During the events, electrographic seizures in patient 1
and epileptiform discharges in patients 2 and 3 lateralized with the hemiparesis and, specifically for patients 2
and 3, the maximal activity was observed on the premotor cortex. Inhibitory motor seizures with ictal hemiparesis of variable duration, and even inhibitory motor
status epilepticus with hemiparesis lasting from 14 hours
to 6 weeks, have been described in the literature.13–15
Penfield and Jasper16 and, more recently, Luders et al17
have reported a negative motor response elicited by
stimulation of the human premotor cortex. Despite the
inherent limitations of EEG surface recordings, we postulate that the clinical hemiparesis was the result of
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subclinical electrographic seizures that actively inhibited
motor function.
The pathogenesis of the observed neuronal hyperexcitability in patients with CDG-Ia is unclear, but it is
presumably related to a deficient glycosylation at the
neuronal level.18 Transient disease-related noncytotoxic
edema is also a possibility; Pearl and Krasnewich2 described a patient with CDG-Ia who demonstrated neuroradiologic evidence of transient edema during a
stroke-like event. Transient cortical hypoperfusion, induced by the coagulation defects, that was severe
enough to cause neuronal dysfunction but mild enough
to be undetected by the MRI modalities cannot, however, be excluded. Focal neuronal hyperexcitability has
been documented also in patients with mitochondrial
encephalopathy lactic acidosis and stroke syndrome and
has been proposed as the triggering mechanism of
stroke-like events.19
CONCLUSIONS
On the basis of our clinical observations, EEG recordings,
and neuroimaging findings, the diffuse and focal neuronal dysfunction that is evident during stroke-like events
in patients with CDG-Ia cannot be explained solely by
ischemia. Clinical and subclinical seizure activity may
complicate the stroke-like events, and the cause of the
hemiparesis may indeed be an active epileptic inhibitory
process. As such, EEG or, ideally, video-EEG monitoring
is warranted, and treatment with anticonvulsant agents
is indicated.
ACKNOWLEDGMENTS
We thank Dr G. Matthijs from the Center for Human
Genetics in Leuven, Belgium, for the mutation screening
in the PMM2 gene; Dr M. Privitera for thoughtful comments; and A. P. Cohen, medical writer, for assistance in
writing this manuscript.
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Radiologic and Neurophysiologic Aspects of Stroke-like Episodes in Children
With Congenital Disorder of Glycosylation Type Ia
Argirios Dinopoulos, Ismail Mohamed, Blaise Jones, Sanjai Rao, David Franz and
Ton deGrauw
Pediatrics 2007;119;e768; originally published online February 16, 2007;
DOI: 10.1542/peds.2006-0763
Updated Information &
Services

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References

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2007 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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