Keywords
encephalitis - mycoplasma pneumoniae - galactocerebroside
A 9-year-old boy presented at our emergency department with complaints of fever, vomiting,
and generalized weakness since 2 days. His mother witnessed an episode with twitches
of the mouth, right arm and right leg with deviation of the eyes to the right, lasting
for less than a minute, followed by confusional behavior. A similar event was seen
at our emergency department. The boy had no relevant medical history, no previous
seizures during fever, and used no medications. Parents were of mixed Caucasian-far
east Asian descent, and also had no relevant medical history. At neurological examination,
the child was cardiopulmonary stable with a temperature of 38.6°C. After waking him
from sleep, he was well orientated and alert, without meningeal signs. Further neurological
examination revealed no abnormal signs. Symptoms and physical examination were not
suggestive of a pneumonia. A third seizure was observed after the examination. Laboratory
tests revealed a leukocytosis of 17.0 × 107/L (predominantly elevated neutrophils and monocytes) and elevated C reactive protein
of 23 mg/L with a normal blood glucose level of 5.9 mM. Cerebrospinal fluid (CSF)
examination showed 166 × 106/L leukocytes, elevated lactate of 2.3 mM with normal total protein and glucose levels
(0.3 g/L and 2.4 mM, respectively). Microscopic examination of CSF revealed no bacteriae
for Gram staining. With an initial differential diagnosis of epileptic seizures as
a possible sign of a bacterial meningitis/encephalitis, the patient was treated with
ceftriaxone, dexamethasone and levetiracetam, and subsequently admitted to our pediatric
ward. Observation during the next 3 days revealed transgressive behavior: in contrast
to known personality by parents, the patient uttered frequently very rude language/cursed,
was obstinate and tired, with a remarkably large appetite. Initially, motor seizures
with deviation of the eyes to the right were observed. EEG (electro encephalogram)
examinations revealed a slow background rhythm of 7–8 Hz with prominent delta activity
in the frontocentral regions ([Fig. S1A]; supplementary figure is available only in the online version) and a paroxysmal
build-up of rhythmic epileptic activity ([Fig. S2]: supplementary figure is available only in the online version).
Fig. 1 FLAIR-weighted MRI-image of our patient 3 days (A, B) and 14 days (C, D) after presentation. Please not the hyperintense aspect of bilateral basal ganglia
(A) and left-frontal cortex (B) at presentation, with complete normalization during follow-up (C, D). FLAIR, fluid attenuated inversion recovery; MRI, magnetic resonance imaging.
Fig. 2 Quantification of GalC IgG and IgM antibodies in serum (A) and CSF (B) in control samples (black dots) and our patient (grey square). GalC, galactocerebroside.
CSF cultures for bacteriae remained negative and CSF polymerase chain reaction (PCR)
for Herpes Simplex virus type 1 and 2, Varicella Zoster Virus, and enterovirus were
negative. A brain magnetic resonance imaging (MRI) scan showed a remarkable T2 and
FLAIR (fluid attenuated inversion recovery) hyperintense signal of basal ganglia and
focal cortical regions ([Fig. 1A] and [B]). Paraneoplastic antineuronal and autoantibodies were absent in blood and CSF, including
anti-contactin-associated protein-like 2 (CASPR2), anti-leucine-rich glioma inactivated-1
(LGI1), anti-N-methyl-d-aspartate receptor (NMDAR) and, anti-myelin oligodendrocyte
glycoprotein (MOG). Serologic examination revealed no current infection with Rickettsia, Borrelia burgdorferi, Tick-borne encephalitis, Cytomegalovirus or Epstein-Barr Virus. An agglutination assay showed a very high serum IgM/IgG response
against Mycoplasma pneumoniae (titer 1280, 3 days after presentation; titer 640, 18 days after presentation; cut-off
for positive ≥ 80). M. pneumoniae PCR in serum and CSF was negative, a PCR on respiratory samples was not performed.
We tested the presence of antigalactocerebroside (anti-GalC) antibodies in the serum
of our patient and found a marked elevation of both IgG and IgM levels (+ 7.5 and + 11.7
SD [standard deviation] above mean, respectively; [Fig. 2A]). Only a small amount of CSF was available for the GalC assays, no clear elevation
of anti-GalC IgG or IgM was found (+ 2.1 and −0.2 SD from mean, respectively, [Fig. 2B]). With the working diagnosis M. pneumoniae-associated parainfectious encephalitis, the patient was treated with methylprednisolone
20 mg/kg/day for 3 days. Complaints resolved quickly, no seizures were observed, and
our patient could leave our ward 10 days after presentation at the emergency department.
A repeated brain MRI scan 14 days after presentation was completely normal ([Fig. 1C] and [D]), as well as the EEG registration ([Fig. S1B]; supplementary figure is available only in the online version). Our patient does
well at home and school, and levetiracetam was discontinued in the absence of seizures.
M. pneumoniae carriage is prevalent. Genetic material can be encountered in the airways of 21–56%
of children without respiratory symptoms but may vary substantially with season and
year.[1]
[2] In a case series of children presenting with acute encephalitis, 50/159 cases demonstrated
evidence of a (previous) M. pneumoniae infection but this was only judged to be probably causally related in 11/159 cases
and possibly in 9/159 cases.[3] Only in 6/159 cases, CSF PCR for M. pneumoniae was positive. Interestingly, edema of the basal ganglia was described as MRI finding
in one of the cases.[3] A M. pneumoniae-associated acute onset bilateral striatal necrosis has previously been described
in a girl with neutropenic fever also lacking intrathecal molecular of serological
positive tests.[4] Besides direct infection, M. pneumoniae is associated with postinfectious autoimmune-sequelae in children, including neurological
disorders as the Guillain–Barré syndrome (GBS). Recently, in a Dutch cohort of children
with GBS, 21% showed IgM positivity for M. pneumoniae, indicating a recent immune response to the microorganism possibly by infection.[5] Interestingly, 25% of children with GBS has elevated serum antibodies to the glycolipid
GalC that resides in both the central and peripheral nervous system.[5] These anti-GalC antibodies show various neurotoxic effects in animal models and
may contribute to the development of postinfectious encephalitis or GBS, respectively.
M. pneumoniae may trigger the production of these anti-GalC antibodies that were shown
to cross-react with unidentified structures of the M. pneumoniae.[6] In a Japanese patient series, elevated GalC antibodies were described in patients
with an M. pneumoniae-associated encephalitis.[7] In an earlier case of a 9-year-old boy with Birkenstaf brainstem encephalitis and
M. pneumoniae antibodies, elevated GalC IgG and IgM levels were found both in serum and CSF.[8] Remarkably, GalC antibodies in the CSF of our patient were not elevated. This could
be a technical issue with a limited sensitivity of the Enzyme-Linked Immuno Sorbent
Assay for detecting GalC antibodies in CSF. The acute and monophasic clinical course
of our patient are also compatible with a postinfectious encephalitis following M. pneumoniae infection. In previous cases, a short prodrome of 2 days has been argued to be more
supportive of an infectious instead of a parainfectious autoimmune etiology.[9] However, the symptoms of our patient at presentation were likely due to his intracranial
disease, a prolonged subclinical prodrome was not recorded. The complete and swift
response to treatment with steroids can also be regarded as indication for a parainfectious
mechanism.
Our case description supports an association between acute encephalitis with pleiocytosis
in children and a M. pneumoniae infect but suggests that besides a primary infect of the CNS, a parainfectious autoimmune
phenomenon can be the underlying mechanism. In analogy with GBS, anti-GalC antibodies
may be mediators of this postinfectious immune-mediated disease.[10]
