ILLUSTRATIVE CASE

Cerebrovascular Complications of Pediatric
Pneumococcal Meningitis in the PCV13 Era
Miya E. Bernson-Leung, MD, Laura L. Lehman, MD

WHEN IT’S MORE THAN MENINGITIS
Case 1
A previously healthy, full-term 5-month-old girl presented to the emergency department with a 1-day history of
fever to 103°F, emesis, poor feeding, and progressive lethargy. She had recently started day care. The patient had
received her routine 2- and 4-month childhood vaccines on schedule, including the 13-valent pneumococcal
conjugate vaccine (PCV13). Initial examination revealed decreased responsiveness, rightward gaze preference,
decreased movement of the left side, and positive Brudzinski sign. Laboratory testing is as in Table 1. Ceftriaxone
and vancomycin were started at meningitic dosing. Cerebrospinal fluid grew Streptococcus pneumoniae serotype
33F, a nonvaccine serotype.

Case 2
A previously healthy 21-month-old boy presented to the emergency department with a 1-day history of fever to 103°F,
emesis, cough, and lethargy. Rapid influenza testing was positive for influenza A, and oseltamivir was started.
History was notable for day care attendance and multiple sick contacts. He was fully immunized, including PCV13.
The next morning, he had a brief seizure with eye deviation and generalized convulsions, and became obtunded.
Simultaneously, blood culture grew gram-positive cocci in pairs and chains. He returned to the emergency
department, where he had right-sided weakness, posturing, rightward eye deviation, and meningismus as well
as further seizures requiring lorazepam and fosphenytoin. Laboratory testing is as in Table 1. Ceftriaxone and
vancomycin were started at meningitic dosing. Cerebrospinal fluid grew S pneumoniae serotype 15B, a
nonvaccine serotype.

Question
What are possible causes of altered mental status, seizures, and focal neurologic deficits in a febrile child, and what
further evaluation should be performed?
Discussion
Lethargy, seizures, and focal neurologic deficits immediately raise concern for bacterial meningitis or meningoencephalitis,
even in immunized children; lumbar puncture is confirmatory.1 Transient altered mental status and focal
neurologic deficits can be postictal phenomena in the right clinical context. However, it is important to recognize

www.hospitalpediatrics.org
DOI:10.1542/hpeds.2015-0236
Copyright © 2016 by the American Academy of Pediatrics
Address correspondence to Miya Bernson-Leung, MD, Department of Neurology, Boston Children’s Hospital, 300 Longwood Ave, Boston,
MA 02115. E-mail: miya.bernson-leung@childrens.harvard.edu
HOSPITAL PEDIATRICS (ISSN Numbers: Print, 2154-1663; Online, 2154-1671).
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
Dr Bernson-Leung acquired the clinical data, and drafted the initial manuscript; Dr Lehman analyzed and interpreted the clinical data,
and reviewed and revised the manuscript; and both authors approved the final manuscript as submitted.

374

Department of Neurology,
Boston Children’s
Hospital, Boston,
Massachusetts

BERNSON-LEUNG and LEHMAN

TABLE 1 Laboratory Testing
Case One

Case Two

WBC at presentation, serum

2.8 K cells/mL

6.3 K cells/mL

ANC at presentation, serum

1.22 K cells/mL

5.2 K cells/mL

Peak WBC, serum

28.98 K cells/mL

15.47 K cells/mL

Peak ANC, serum

15.12 K cells/mL

9.21 K cells/mL

C-reactive protein, serum

28.55 mg/dL

8.77 mg/dL

Erythrocyte sedimentation rate, serum

75 mm/h

62 mm/h

342%

Not tested

Von Willebrand factor antigen

36 cells/mm3 (64% neutrophils/bands)

WBC, CSF

3

RBC, CSF

22 cells/mm

Protein, CSF

346.5 mg/dL

825 cells/mm3
200 cells/mm3
421 mg/dL

Glucose, CSF

Below threshold of detection

Below threshold of detection

Bacterial culture, CSF

Streptococcus pneumoniae
- serotype 33F
- sensitive to ceftriaxone (MIC by Etest 0.12)

Streptococcus pneumoniae
- serotype 15B
- sensitive to ceftriaxone (MIC by Etest 0,0.03)

Immunodeficiency evaluation

Normal immune globulins, complement, T- and B-cell
subsets, peripheral blood smear review for
functional asplenia, and Toll-like receptor function.

Normal IgG. Pneumococcal IgG panel during
hospitalization showed humoral immunity to all
PCV13 serotypes but not to 15B.

ANC, absolute neutrophil count; CSF, cerebrospinal fluid; Ig, immunoglobulin; MIC, minimum inhibitory concentration; RBC, red blood cell count; WBC, white blood
cell count.

that altered mental status, seizures, and
focal deficits are also presenting features
of stroke in children. In non-neonates
with acute arterial stroke, 11.8% presented
with altered mental status, 15.8% with
seizures, and 72.4% with focal weakness.2
Urgent neuroimaging is therefore
warranted to establish the diagnosis of
acute stroke. By expert consensus, the
modality of choice is MRI with T1, T2,
fluid-attenuated inversion recovery, T2*
(gradient-echo or susceptibility-weighted),
diffusion-weighted, and contrast sequences,
and consideration of magnetic resonance
angiography (MRA) and magnetic resonance
venography. Imaging will help to identify
stroke subtype (arterial ischemic versus
cerebral sinovenous thrombosis [CSVT]
versus hemorrhagic) and therefore guide
further management. Computed tomography
is suboptimal for the detection of CSVT and
early ischemic stroke.3
The inclusion of pneumococcal conjugate
vaccines in the standard pediatric
immunization series since 2000 has
significantly lowered the overall incidence
of invasive pneumococcal disease and
specifically pneumococcal meningitis.4
However, the introduction of 7-valent
pneumococcal conjugate vaccine (PCV7) in
2000 and PCV13 in 2010 has also changed
HOSPITAL PEDIATRICS Volume 6, Issue 6, June 2016

the landscape of pneumococcal disease,
reflecting the rise of “replacement”
serotypes not covered by existing vaccines.5,6
A recent study compared the period after
PCV7 introduction but before PCV13 with the
period after PCV13, and found a further
reduction in the number of cases of invasive
pneumococcal disease at 8 children’s
hospitals, but no reduction in cases of
pneumococcal meningitis.7
Even healthy, vaccinated children develop
invasive pneumococcal disease. In 1 study,
.95% of children with invasive
pneumococcal disease had received at least
1 dose of PCV7, and immunodeficiency
was present in fewer than 10%.6 One
possible explanation is an increased
frequency of nonvaccine serotypes, some of
which may be more virulent or invasive.5,6
Patient 1 had serotype 33F and patient
2 had serotype 15B. Serogroups 15 and
33 have been noted to be increasing causes
of invasive disease after the introduction
of PCV7.8 In 2003 to 2009, serotype 33F
comprised 5.3% of all cases of invasive
disease but comprised only 0.74% of
nasopharyngeal samples from asymptomatic
colonized children. Its invasive capacity is
up to 50-fold higher than less-invasive
serotypes, and higher than any other
nonvaccine serotype in this sample.

Serotype 15B/C comprised 3.8% of invasive
serotypes and 9% of colonization samples,
with low invasive capacity. Serotype 19A,
by comparison, was the most common
cause of invasive disease (39%) but also of
colonization (14%), with an intermediate
invasive capacity; it is now included in
PCV13.6 Serotype 33F is included in a
15-valent conjugate vaccine currently in
trial.9 Both 15B and 33F are included in
the 23-valent pneumococcal polysaccharide
vaccine but this vaccine is not currently
recommended for children without
underlying medical conditions and is not
intended to replace conjugate vaccines.10
The large number of pneumococcal
serotypes, and the possibility for even lessinvasive serotypes such as 15B to produce
invasive disease as in patient 2, also provide
support for alternative vaccination
strategies that are not serotype-specific.11,12
Stroke and meningitis are frequently
comorbid; before the introduction of
PCV7, strokes were discovered in 10% to
27% of children with acute bacterial
meningitis.13–15 Some small studies suggest
S pneumoniae infection is more commonly
associated with stroke relative to other
pathogens,13,15 although others found no
association.14 In a population-based series
conducted in the United Kingdom after the
375

introduction of PCV7, 10 (42%) of 24 children
with pneumococcal meningitis specifically
were found to have stroke, including 8 with
arterial ischemic stroke and 3 with CSVT;
1 child had both. Children with stroke were
more likely to have seizures at presentation,
focal signs, or anemia, and more likely to
have serotypes not covered by PCV7. They
were also more likely to have a poor
outcome at follow-up than those without
strokes, with an adjusted odds ratio of 40.16
A study of 173 cases of pneumococcal
meningitis in US children in the 3 years
before and 3 years after PCV13 introduction
(2007–2009 vs 2011–2013) found that
infarcts and CSVT were common and,
surprisingly, had increased (albeit not
significantly). In 2011 to 2013, 26% of

children with pneumococcal meningitis had
infarcts and 7% had CSVT versus 16% and
4%, respectively, in 2007 to 2009.7
Proposed mechanisms for stroke due to
bacterial meningitis include vasculitis,
thrombosis, and vasospasm.1,15,17 In one
series of mostly unvaccinated adults with
pneumococcal meningitis, arterial stroke
occurred in 21.8% of cases, of which 11 of
17 had evidence of vasculitis on computed
tomography, MRI, conventional angiography,
or transcranial Doppler ultrasound.
Criteria for vasculitis included vessel wall
irregularity, arterial narrowing, focal
dilatation, and occlusion of distal middle
cerebral artery branches.18 In another adult
series, 48.1% of those who underwent

conventional angiography showed a
spectrum of abnormalities, including
vasculitis affecting small, medium, and
large arteries and obstruction of cortical
veins and venous sinuses.17 There are
reports of adults undergoing new or
recurrent stroke both with and without
evidence of vasculitis even weeks after
initial recovery from pneumococcal
meningitis, suggesting that inflammatory or
vasculopathic processes can be ongoing.19,20

Cases Continued
In both patients, MRI performed on day 1 to
2 of hospitalization showed multifocal
infarction (Figs 1 and 2). In patient 1,
imaging findings progressed over time to
include additional ischemic and hemorrhagic

FIGURE 1 Case One serial imaging. A, Diffusion-weighted MRI on HD1 showed acute infarction in the right posterior cerebral artery territory, and
multiple punctate foci of infarction throughout the bilateral cerebral hemispheres. B, Susceptibility-weighted MRI on HD2 showed
cortical vein thrombosis (white arrow) and small hemorrhages in the subcortical white matter (black arrows). C, Magnetizationprepared rapid gradient-echo (MPRAGE) on HD2 showed nonocclusive thrombus of the left transverse sinus. D, MRA on HD7 showed new
stenosis of the A1 segment of the right anterior cerebral artery and the right cavernous-clinoid internal carotid artery (right) compared
with initial imaging (left). E, T2-weighted MRI at discharge (HD37) demonstrating diffuse cerebral atrophy and subdural hygromas.

376

BERNSON-LEUNG and LEHMAN

FIGURE 2 Case Two serial imaging. A, Diffusion-weighted MRI on HD2 showed multiple foci of infarction throughout the cortex, white matter, and
basal ganglia. B, Susceptibility-weighted MRI on HD5 demonstrating a deep vein thrombosis along the left frontal horn. C, MRA on
HD5 showed irregular stenoses of the cavernous segments of the internal carotid arteries (arrows) and V4 segments of the vertebral
arteries (not shown). D, T2-weighted MRI showed new hydrocephalus on HD22.

strokes, arterial stenosis, and CSVT. Steroid
therapy with methylprednisolone 1 mg/kg
per day for 3 days was given on hospital day
(HD) 3 and again on HD 8 out of concern for
a vasculitis–like process. Anticoagulation
was initiated on HD 5 given the progression
of cerebral sinovenous thromboses on serial
imaging, first with heparin drip then with
low-molecular-weight heparin. In patient 2,
imaging progressed to multifocal vasculitis,
new ischemic strokes, and CSVT. Steroid
therapy with dexamethasone 0.6 mg/kg per
day was started on HD 6 and continued
through HD 19. Aspirin 81 mg (5 mg/kg per
day) was started on HD 6 for secondary
stroke prevention.

Question
What is the role for additional therapies
besides antibiotics in bacterial meningitis
with stroke?

Discussion
The role of steroid treatment in bacterial
meningitis remains controversial, and no
literature specifically addresses stroke
prevention in this setting.21,22 A Cochrane
review across all ages found evidence that
HOSPITAL PEDIATRICS Volume 6, Issue 6, June 2016

steroid treatment is associated with
decreases in hearing loss and short-term
neurologic sequelae, and no effect on
nonhearing long-term sequelae. Subgroup
analysis for S pneumoniae showed reduced
mortality with steroid treatment.21 In both
our cases, clinical worsening prompted the
initiation of steroid therapy in accordance
with published recommendations for the
treatment of central nervous system
vasculitis, although the evidence supporting
specific treatments of vasculitis especially
secondary to infection is limited.23
Current guidelines for the management of
stroke in children have been developed by
the American Heart Association/American
Stroke Association,3 the American College of
Chest Physicians,24 and the Royal College
of Physicians, 25 all based on expert
consensus rather than trial data.
Recommendations vary for acute treatment
immediately following first stroke, with
1 recommending aspirin,25 1 recommending
anticoagulation,3 and 1 recommending
either24 while etiologic workup is ongoing.
All support the chronic use of aspirin for
secondary stroke prevention after first

arterial ischemic stroke in children in cases
in which there is not an arterial dissection,
cardioembolic cause, or hypercoagulable
state.3,24,25
For acute CSVT with or without associated
venous infarction, there is agreement that
anticoagulation is reasonable.3,24,25
Anticoagulation has not been extensively
studied in children with CSVT specifically
secondary to meningitis, but head and neck
infections including meningitis are frequent
causes of CSVT in children and therefore
anticoagulation recommendations apply.15,26
Based on recent series of CSVT in children,
this recommendation stands even in cases
with intracranial hemorrhage, as the benefit
of preventing further thrombosis outweighs
the risk of hemorrhagic complications.27,28

CASE RESOLUTION
For patient 1, examination progressed to
anisocoria, absent corneals, and absent
oculocephalic reflex. On HD 3, seizures arose
from the right posterior quadrant,
progressing to status epilepticus requiring
pentobarbital burst suppression for 12 days
followed by levetiracetam, phenobarbital,
377

and lacosamide. She remained afebrile
after admission. She received 21 days of
ceftriaxone; vancomycin was stopped after
48 hours when speciation and susceptibility
results returned. She spent a total of
39 days in the hospital. She passed a
hearing test before discharge, but aspirated
on swallow study and eventually required
a gastrostomy tube. Anticoagulation was
discontinued after 3 months. The patient
developed infantile spasms at 10 months
of age. She continues to receive physical,
speech, and occupational therapy. Her motor
asymmetry has improved. At 17 months of
age, she can crawl and babble.
Patient 2 remained seizure free after
admission on phenytoin and then switched
to levetiracetam. He was intermittently
febrile for 7 days. He received 21 days of
ceftriaxone and 5 days of oseltamivir;
vancomycin was stopped after 48 hours
when speciation and susceptibility results
returned. Hydrocephalus developed with an
acute decompensation on HD 30 with apnea,
desaturation, and emesis, for which an
endoscopic ventricular drain was placed.
He later underwent endoscopic third
ventriculostomy with choroid plexus
cauterization on HD 35. He spent a total of
42 days in the hospital. He passed a hearing
test before discharge. Five months after
discharge, at 27 months of age, the patient
was meeting developmental milestones
with a normal neurologic examination.
There was no seizure recurrence and repeat
EEG was normal, so levetiracetam was
discontinued.

CONCLUSIONS
Arterial ischemic stroke, CSVT, and
intracranial hemorrhage are all known
complications of pneumococcal meningitis
in children1,13–15 and in adults,18 and portend
a worse prognosis.16,17 Our 2 cases of
vaccinated children with pneumococcal
meningitis due to non-PCV13 serotypes
highlight its spectrum of cerebrovascular
disease and morbidity. Clinical signs
indicating the presence of stroke, including
focal deficits, altered mental status, and
seizures, may be obscured by or attributed
to the meningitis itself. The clinician’s index
of suspicion for stroke in the setting of
meningitis must therefore remain high,
378

even in the postvaccine era: despite overall
declines in invasive pneumococcal disease,
pneumococcal meningitis continues to
occur with devastating consequences.7

Acknowledgments
Thank you to Dr Amy Danehy for assistance
with the neuroimaging and to Dr Jonathan
Finkelstein for expert infectious disease
input.

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