Multiple Sclerosis and Related Disorders 46 (2020) 102471

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Multiple Sclerosis and Related Disorders

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Correspondence

Acute disseminated encephalomyelitis following Tdap vaccination and bacterial T

meningoencephalitis

ARTICLE INFO ABSTRACT

Keywords: Introduction: Association of Acute Disseminated Encephalomyelitis (ADEM) with both recent vaccination and
Acute disseminated encephalomyelitis viral infections is well described in current literature. However, the coincidence of ADEM and bacterial infec-
Bacterial meningitis tions has been rarely documented. In this report, we present a case of ADEM which occurred after bacterial
Vaccination meningoencephalitis and prior vaccination against tetanus, diphtheria, and pertussis (Tdap).
Tdap
Case presentation: A 62-year old woman was hospitalized with an upper respiratory tract infection three weeks
after Tdap triple vaccination. A few days after admission, she became somnolent and developed meningism.
Cerebrospinal fluid (CSF) analysis revealed pleocytosis and increased protein/lactate levels compatible with
bacterial meningoencephalitis. The patient was treated with intravenous antibacterial triple therapy in combi-
nation with dexamethasone leading to a significant improvement of clinical symptoms and improvement of CSF
parameters. Five days later, the patient's condition worsened again, and she developed aphasia and right-sided
hemiparesis. A magnetic resonance imaging (MRI) scan revealed distinct fluid-attenuated inversion recovery
sequence (FLAIR)-hyperintense lesions in both hemispheres. Following brain biopsy, the diagnosis of ADEM was
made and methylprednisolone pulse therapy was initiated for five days leading to a nearly complete remission of
symptoms.
Conclusion: ADEM is a neurological syndrome which may be associated with bacterial infection of the central
nervous system (CNS). We hypothesize that the preceding Tdap triple vaccination may have contributed to the
development of ADEM.

List of abbreviations 2. Case presentation

ADEM: acute disseminated encephalomyelitis A 62-year old woman was hospitalized in reduced general condition
Tdap: tetanus, diphtheria and acellular pertussis vaccine due to upper respiratory tract infection and suspected pneumonia with
CSF: cerebrospinal fluid fever (38.8°C) general. She had been vaccinated with a Tdap vaccine
CNS: central nervous system three weeks before. Therapy with azithromycin and ampicillin/sul-
MRI: magnetic resonance imaging bactam was started on day of admission. Two days later, the patient's
HSV: herpes simplex virus condition worsened with reduction of consciousness and meningism.
VZV: varicella zoster virus An immediate CT scan showed no notable pathology. The lumbar
EBV: Epstein Barr Virus puncture revealed increased leucocyte count (635/μL), increased total
JCV: John Cunningham virus protein (2220 mg/L) and lactate (4 mmol/L), an albumin CSF / serum
MoCA: Montreal cognitive assessment ratio of 36.1 × 10−3 as well as intrathecal IgM synthesis of 9.9 %.
Cytological differentiation showed mainly neutrophilic granulocytes,
1. Introduction along with some macrophages and lymphocytes, in line with the di-
agnosis of bacterial meningitis. No pathogen was identified in the initial
Association between recent vaccination and Acute Disseminated Cerebrospinal fluid (CSF) analysis, and the patient was thus placed on
Encephalomyelitis (ADEM) is a well-established phenomenon. In par- empirical therapy with acyclovir, ceftriaxone, and ampicillin in com-
ticular, vaccinations against human papilloma virus (HPV), seasonal bination with dexamethasone, according to current guidelines of the
influenza, hepatitis, measles/mumps/rubella (MMR) as well as tetanus/ German Society of Neurology. This resulted in rapid improvement of
diphtheria/pertussis (Tdap) have been reported to increase the risk for the patient's consciousness and CSF parameters (30 leucocytes/µL, total
ADEM (Huynh et al., 2008; Pellegrino et al., 2013), even if the overall protein 1010 mg/L, lactate 2.7 mmol/l, reduced number of granulo-
odds are relatively small. Although we have a good understanding of cytes in the cytological differentiation) two days after onset of treat-
the connection between viral infections and ADEM, our knowledge of ment. Acyclovir treatment was discontinued following negative PCRs
the relationship between bacterial infections and ADEM is still frag- for HSV and VZV.
mentary (Okada and Yoshioka, 2010; Kato et al., 2015). Here, we On day 5 after the start of empirical therapy, the patient's condition
present the case of a female patient who developed ADEM subsequently rapidly deteriorated, and she developed aphasia and incomplete right-
to bacterial meningitis and further had received Tdap vaccination in sided hemiparesis. An MRI scan revealed distinct FLAIR-hyperintense,
close temporal context. contrast-enhanced lesions in both hemispheres, with left and frontal

https://doi.org/10.1016/j.msard.2020.102471
Received 10 June 2020; Received in revised form 25 August 2020; Accepted 26 August 2020
2211-0348/ © 2020 Elsevier B.V. All rights reserved.
Correspondence Multiple Sclerosis and Related Disorders 46 (2020) 102471

Fig. 1. (A) Time course of clinical features, CSF parameters and therapeutic interventions demonstrating initial improvement of bacterial meningoencephalitis and a
secondary deterioration due to development of ADEM. Numbers in squares indicate days when MRI imaging was performed. Histology of biopsies shows a mild
hypercellularity in haematoxylin and eosin (HE) stain (a, scale bar 20 μm). No clear demyelination is noted in the retrieved material in luxol fast-blue-periodic acid-
Schiff (LFB-PAS) stain (b, scale bar 20 μm). Immunohistochemistry reveals perivascularly accentuated infiltration of CD3-positive lymphocytes (c, scale bar 10 μm)
and CD68-positive macrophages (d, scale bar 10 μm). Sequences of MRI scans showing progression and subsequent reduction of diffuse white matter lesions over a
period of 80 days. (B) Coronal section, FLAIR image, day 6 after onset of symptoms showing widespread white matter lesions. (C–E) Axial section, FLAIR, day 9 (C),
12 (D) and 24 (E) after onset of symptoms showing widespread, diffuse white matter lesions. Ventricle width increases over time. (F) Axial section, FLAIR, day 80
after onset of symptoms showing marked regression of white matter lesion load and reduced parenchymal swelling. (G–I) Axial section, gadolinium-enhanced T1, day
6 (G), day 9 (H) and day 12 (I) after onset of symptoms showing a gradual decrease of the initial contrast-enhancement.

dominance (Fig. 1B and G). Although acyclovir was reinstated and
antibiotic therapy continued, the patient did not improve and was thus
transferred to our tertiary hospital.
A follow-up CSF examination on day 7 after onset of treatment re-
vealed persistently increased leucocyte count (75/μL), combined with
increased total protein (1860 mg/l) and lactate (4 mmol/L) and an
albumin CSF / serum ratio of 42.9 × 10−3. A repeated diagnostic work-
up for viral and bacterial pathogens (meningococci, pneumococci,
cryptococci, haemophilus influenzae, type B streptococci, borrelia
burgdorferi, E. coli, listeria spec., HSV, VZV, EBV, adenovirus, en-
terovirus, JCV) yielded no further insights. The follow-up cranial MRI
scan showed further increase of the hyperintense lesions, whereas
contrast accumulation was weaker than previously observed (Fig. 1C
and H) and CSF findings improved (7 leucocytes/μL, total protein 475
mg/L, lactate 2 mmol/L, albumin CSF / serum ratio of 10.7 × 10−3).
Nevertheless, the patient's condition remained unchanged with persis-
tent aphasia and hemiparesis.
As a further diagnostic measure, a stereotactic needle brain biopsy
was performed and showed perivascular CD3-positive lymphocytes in-
dicative of inflammatory reaction. There were CD68-positive macro-
phages, but a clear demyelination was not detected in the retrieved
material (Fig. 1A). Neither signs of viral or bacterial infection, nor for
CNS vasculitis or lymphoma were revealed.
Under working hypothesis of parainfectious ADEM, we initiated
methylprednisolone pulse therapy (1000 mg daily IV) for five days,
which resulted in a rapid regression of neurological symptoms. On
second day of methylprednisolone therapy, the patient regained speech,
and hemiparesis improved markedly. In the MRI scans, supratentorial

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Correspondence
parenchymal swelling decreased although extensive T2 white matter
hyperintensities persisted (Fig. 1D). No contrast-enhancement was de-
tected at this point (Fig. 1I).
When the patient was transferred to a rehabilitation clinic, she no
longer presented any focal neurologic signs, except for mild instability
of gait and latent paresis of her right arm. Eight weeks after initial
admission, she was re-admitted to our department for a clinical re-
evaluation. The latent paresis of the right arm had improved further
and no other sequelae were observed. There were no signs of overt
cognitive deficits (MoCA test: 28 of 30 possible points), and the patient
was able to resume her professional life as nurse in a psychosomatic
clinic. MRI scans showed marked reduction of the lesion load (Fig. 1E
and F).
3. Discussion
In the present case, the initial disease course and CSF findings were
consistent with bacterial meningitis subsequent to respiratory tract in-
fection and pneumonia, even if no pathogen could be identified, which
occurs in up to 20% of community-acquired bacterial meningitis cases
(Van de Beek et al., 2006). Moreover, differential diagnoses such as
viral meningitis or an earlier onset of ADEM than suspected are ren-
dered relatively implausible in view of the patient's clinical presenta-
tion combined with her CSF parameters: leucocyte count, lactate, and
total protein were all well above the expected levels for either viral CNS
infections or ADEM (Koelman et al., 2016). Despite sporadic reports of
significantly higher numbers in some cases of ADEM, they were still
well below anything we have measured in our patient (Schwarz et al.,
2001).
After initial improvement, a secondary deterioration occurred with
development of left-hemispheric syndrome and corresponding FLAIR-
hyperintensities in the MRI scans. These lesions showed multiple
characteristics of ADEM, such as large confluent bihemispheric lesions
with deep gray matter and cortical involvement, combined with marked
contrast-enhancement (Pohl et al., 2016). Brain biopsy excluded other
infectious pathologies, and there was no indication of a vasculitic or
neoplastic origin of the MRI abnormalities. Although the biopsied tissue
fragment did not show any explicit demyelination, the findings were in
line with a possible diagnosis of ADEM: brain biopsy shows a demye-
lination in around 90 % of adult ADEM cases (Young et al., 2010), but
the limited amount of tissue from a needle biopsy may diminish diag-
nostic yield. The patient showed a striking response to methylpredni-
solone therapy, which further supports ADEM as the most probable
differential diagnosis.
ADEM is defined as demyelinating disease of the CNS, typically
monophasic and associated with focal neurologic signs and en-
cephalopathy. Although ADEM is most frequently observed in child-
hood or adolescence, several reports also describe ADEM or ADEM-like
illnesses in adults (Schwarz et al., 2001; Kaunzner et al., 2018). In
about 5% of all ADEM cases, a recent immunization can be identified,
but there is controversy about their causal relationship (Huynh et al.,
2008). Pathogenetically, myelin autoantigens likely share antigenic
determinants with those of an infecting pathogen, and ADEM thus
probably results from molecular mimicry in the way of a transient au-
toimmune response against myelin or other autoantigens by non-spe-
cific activation of an autoreactive T-cell clone. Peptides from infectious
proteins or vaccines share structural similarities to the host's own
peptides and are thought to activate autoreactive T-cells.
The association of ADEM with both recent vaccinations and pre-
ceding viral or (less established) bacterial infections – involving the
upper respiratory tract in up to 77% of all known cases – has been
reported (Huynh et al., 2008; Okada and Yoshioka, 2010;
Pellegrino et al., 2013; Kato et al., 2015 ). However, to our knowledge,
this is the first case of bacterial meningitis and Tdap vaccination both
preceding the development of ADEM. While a causal relation between
the recent vaccination, the bacterial meningitis and the subsequent
3
Multiple Sclerosis and Related Disorders 46 (2020) 102471
diagnosis of ADEM must remain conjectural to some degree, the co-
incidence of all three in such a short interval of time as well as the
unique sequence of events in the case of our patient justifies the hy-
pothesis that this potential two-fold activation of the immune system
may have resulted in an overshooting autoimmune response.
4. Conclusion
Our case adds to the spectrum of adult ADEM cases and suggests
that a double activation of the immune system by a preceding vacci-
nation as well as bacterial meningitis may trigger this acute CNS dis-
order. Secondary deterioration after initial improvement of bacterial
meningitis may thus be caused by ADEM and should be considered as a
differential diagnosis, particularly because it represents a treatable
pathology with potentially beneficial outcome.
Funding
No funds were received in support of this study.
Authors' contributions
JN, ML and PL analysed the patient data and wrote the manuscript.
JN, KS, SH, AB and PL were treating neurologists of this patient, con-
tributed to the interpretation of this case and revised the manuscript.
CM interpreted the neuroradiological data. FL interpreted the brain
biopsy. All authors read and approved the final manuscript.
Ethics approval and consent to publish
Written informed consent was obtained from the patient for pub-
lication of this case report and accompanying images. A copy of written
consent is available for review by the Editor-in-Chief of this journal.
Availability of data and material
Data sharing is not applicable to this article as no datasets were
generated or analysed during the current study.
Declaration of Competing Interest
The authors declare that they have no competing interests.
Acknowledgements
We thank B Hemmer, the director of the Department of Neurology,
Technical University of Munich, for his remarkable support during
treatment and diagnostics and for revising the manuscript. We thank
the patient and her family for allowing us to report this case.
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a
Department of Neurology, Technical University of Munich, School of

⁎
Corresponding author at: Klinikum rechts der Isar, Department of
Neurology, Ismaninger Str. 22, 81675 München, Germany.