Keywords
Mycoplasma pneumoniae
- encephalopathy - behavioral changes - children
Introduction
A significant etiological factor for upper respiratory tract infections and community-acquired
pneumonia is Mycoplasma pneumoniae. The incidence of extrapulmonary neurological problems in infected patients has been
shown to range from 0.1 to 7%, often manifesting within a timeframe of 2 to 14 days
following the onset of respiratory symptoms. The syndrome encompasses various conditions,
including aseptic meningitis, encephalitis, meningoencephalitis, acute bilateral striatal
necrosis, cerebellar ataxia, and immune-mediated disorders such as optic neuritis,
acute disseminated encephalomyelitis, postinfectious hemorrhagic leukoencephalitis,
transverse myelitis, and Guillain–Barré syndrome.[1]
[2]
[3]
[4]
[5]
Case Report
A previously healthy 3-year-old boy presented to a tertiary care center in the Riyadh
region of Saudi Arabia with acute onset of irritability, sleep disturbance, slurred
speech, increased appetite, episodes of unresponsiveness, moving in circles, and staring
alternating with laughing episodes, each lasting for up to 15 to 30 minutes, over
a week. He lost his previous toilet training during this period. Abnormal jerks were
noted while awake and asleep. Symptoms were preceded by low-grade fever and flu-like
illness 3 weeks before presentation. Multiple family members had a recent vague febrile
illness and were treated as outpatients. There was no history of trauma or drug ingestion.
There was no history of previous similar episodes, loss of consciousness, seizures,
headache, visual problems, or hallucinations. He was a product of a nonconsanguineous
marriage with unremarkable perinatal and birth history. He was fully vaccinated. There
was no family history of early infantile deaths or neurological, metabolic, or psychiatric
disorders.
Clinical Findings
On examination, he had normal vital signs, including an oxygen saturation level of
95% on room air, and a normal level of consciousness. The patient's cranial nerves,
as well as his motor, sensory, and cerebellar examinations, were normal without any
signs of neurological deficits. The fundoscopic examination was normal. He had a mild
cough with clear ears, a congested throat, and a normal chest examination.
Diagnostic Assessment
Basic hemogram, biochemistry, renal, and liver profiles were normal. Brain magnetic
resonance imaging (MRI) was unremarkable. Electroencephalography (EEG) showed a slow
background with no epileptiform discharges. Cerebrospinal fluid (CSF) analysis revealed
normal protein and glucose levels and an absence of white blood cells. CSF bacterial
cultures and polymerase chain reaction (PCR) results for herpes simplex virus 1 (HSV-1)
and other viruses were negative. Complete metabolic panels, including tandem mass
spectrometry and urinary organic acid data, were unremarkable. The workup for autoimmune
encephalitis, which included myelin oligodendrocyte glycoprotein antibody, anti-N-methyl-d-aspartate
receptor, and voltage-gated potassium channel antibodies, was negative. Mycoplasma
serology IgM was detected ([Table 1] summaries all investigations).
Therapeutic Intervention
Based on the clinical findings, EEG results, negative CSF viral panel, and bacterial
cultures, the impression was M. pneumoniae-induced encephalopathy. Marked improvement was noted after methylprednisolone pulse
therapy (30 mg/kg/d) for three consecutive days, followed by intravenous immunoglobulin
(IVIG; 1 g/kg/d) for two consecutive days, valproic acid (VPA) twice per day, and
azithromycin (10 mg/kg/d) once per day for 7 consecutive days.
Follow-up and Outcomes
At the 6-week follow-up visit, the patient exhibited normal cognitive function and
behavior, and he regained previous toilet training but had some irritability and sleep
disturbance. The seizures were well controlled. He had a normal examination. VPA was
discounted at the 3-month follow-up visit after normalization of the EEG, as the child
returned to his usual normal state of health. Interestingly, the Mycoplasma IgM antibody
test was positive three times during the first 3 months of follow-up.
Discussion
The pediatric age group has been extensively documented to experience extrapulmonary
neurological complications caused by M. pneumoniae.[1]
[2]
[3] The most prevalent complication is encephalitis.[6] Approximately 20% of individuals exhibiting central nervous system (CNS) abnormalities
do not have any prior or concurrent respiratory infection.[2]
[3] Acute encephalopathy/encephalitis is characterized by altered mental status, regression
of developmental milestones, seizure or focal neurological signs (motor weakness or
ataxia), and altered personality/behavior.[7]
[8] Enterovirus and HSV are the most common causes of infection among individuals in
the pediatric age group.[9] Our patient presented with a vague clinical picture that included acute encephalopathy,
behavioral disturbance, and seizure-like episodes where multiple differential diagnoses
were entertained, including infectious/postinfectious autoimmune process, metabolic
disorders, drug intoxication, focal (temporal lobe), hypothalamic hamartoma, paraneoplastic
syndrome, pediatric acute onset neuropsychiatric syndrome (PANS), and childhood psychosis.
Autism was ruled out by the psychiatrist in the emergency room due to the acute onset
and characteristic clinical course of the disease. Further evaluation revealed evidence
of acute M. pneumoniae infection. The constellation of clinical presentation, lack of CSF inflammatory findings,
slow background on EEG, and the presence of normal brain MRI suggested that our patient
had M. pneumoniae encephalopathy despite the absence of respiratory symptoms. His clinical status did
not match the characteristic criteria for PANS caused by M. pneumoniae.[4]
[10]
The precise pathogenesis by which M. pneumoniae causes neurological complications has not been definitively established. However,
it has been proposed that the underlying mechanism may involve either direct invasion
into the CSF with positive PCR for mycoplasma or a systemic immune-mediated response
triggered by molecular mimicry (antibodies or a cell-mediated response to the pathogen
cross-react with the myelin autoantigens or specific epitopes of target in CNS) approximately
2 to 3 weeks after the respiratory disease subsides with positive mycoplasma antibodies.[11]
[12]
The diagnostic criteria for M. pneumoniae infection, which can lead to CNS complications, encompass the identification of M. pneumoniae using culture or PCR in respiratory or CSF samples, as well as the presence of positive
serological test results.[1] Microbial culture is seldom used in routine medical practice. The most sensitive
and specific method for detecting M. pneumoniae infection is a PCR test, but its sensitivity is limited. PCR is less sensitive for
diagnosis than serum specimens at acute and convalescent periods.[13] The diagnosis depends on the existence of a consistent clinical presentation that
aligns with positive serological test results (IgM and IgG titers), as determined
by techniques such as enzyme-linked immunosorbent assay and indirect immunofluorescence.
Mycoplasma pneumoniae-specific IgM-positive results support acute infection.[14] Serological tests are limited by the reliance on convalescent sera for confirmation.
IgM antibodies exhibit age-related variations and typically manifest as a positive
result during acute infection. However, it is possible for these antibodies to remain
negative during the duration of acute infection or to remain positive for several
months.[15] Seroconversion is defined as a 4-fold increase in the titer between acute and convalescent
serum[16] or a single high anti-M. pneumoniae complement fixation antibody titer >1:128 confirms the diagnosis. In the past, cold
agglutinins were utilized due to their production occurring 1 to 2 weeks after infection
in 50% of patients and their potential persistence for several weeks. However, their
sensitivity and specificity are limited. Persistent positivity of the repeated serum
M. pneumoniae IgM antibody test was observed in our patient. CSF analysis was unremarkable for
our patient, which was the same as the findings of several case series reported in
the literature on encephalitis secondary to M. pneumoniae.
The absence of controlled clinical trials and recommendations has resulted in the
unavailability of standard therapy for the management of encephalitis or meningoencephalitis
caused by M. pneumoniae. Spontaneous recovery has been reported in the literature.[6] According to several case series studies, the administration of immune-modulating
therapy with intravenous pulse methylprednisolone at a dose of 20 mg/kg/d intravenously
for 3 to 5 days, either as a standalone treatment or in combination with oral prednisone
at a dose of 1 mg/kg/d for 10 to 14 days, with a gradual withdrawal for 4 to 6 weeks,
has a beneficial effect.[17]
[18] The role of antimicrobial treatment remains controversial because it depends on
the associated mechanism. Azithromycin (10 mg/kg of body weight once per day for 5
to 7 days orally or intravenously) is the first-line agent due to its good CNS penetration
and anti-inflammatory effect, which prevents immune system activation with fewer side
effects.[18]
[19] It is indicated in the direct invasion, while if an immune-mediated mechanism is
suspected, the appropriateness of antimicrobial therapy, particularly after the resolution
of the acute disease, remains uncertain,[1]
[4] but recent studies support its early use with reported significant clinical improvement.
Despite the lack of established information regarding the optimal antibiotic, dosage,
and length of therapy.[12] Practically, it is given alongside steroids when other potential causes have been
ruled out and should be continued regardless of prodromal or neurological symptoms
till more evidence is obtained. The selection of other treatments, such as IVIG at
a dose of 400 mg/kg/d for 5 days or 1 g/kg/d for 2 days, or plasmapheresis, depends
on the complexity of the patient's symptoms and the response rate to steroid therapy.[20] A single-center cohort study suggested early IVIG therapy for patients with suspected
mycoplasma pneumoniae encephalitis (MPE) who do not react to alternative therapy, especially those who
experience prodromal signs of infection for a week or more.[20] A recent multicenter study included a total of 87 patients with MPE, where 55 individuals
(63.2%) among these patients received immunomodulating medication.[20] Out of the 55 patients, 37 (42.5%) received IVIG, 13.8% received corticosteroids,
and 6.9% of the participants received both IVIG and corticosteroids. The study found
that giving azithromycin along with IVIG or corticosteroid therapy led to shorter
stays in the hospital and faster management of symptoms compared with giving azithromycin
alone.[18] Various clinical reports have reported that the rare use of immunomodulatory medication,
based on potential immune-related mechanisms, effectively reduces illness severity
and improves outcomes. However, further studies on the efficacy of immunomodulatory
treatment are necessary in the pediatric age group. Our patient responded dramatically
to intravenous steroid therapy and IVIG, and his behavioral disturbances subsided
over 3 weeks.
Conclusion
Our report serves as a reminder that M. pneumoniae infection is a possible cause of encephalopathy and behavioral disturbance in children.
Early recognition and promotion of immunomodulatory and antimicrobial treatment can
prevent the affected child from experiencing different levels of long-lasting impairments
in cognitive, physical, or visual abilities.
Table 1
Laboratory and imaging profile of the patient in this report
|
Variables
|
Results
|
|
Total WBC per 10 g/L
|
8
|
|
Hemoglobin level g/dL
|
11.5
|
|
Platelet per 10 g/L
|
220
|
|
ESR mm/h
|
30
|
|
Electrolytes
|
Normal
|
|
Liver profile
|
Normal
|
|
Urea, creatinine
|
Normal
|
|
Hepatitis, Epstein–Barr virus, cytomegalovirus, herpes virus I, serology
|
Unremarkable
|
|
Mycoplasma serology
|
IgM positive, IgG negative
|
|
Nasopharyngeal swab/Mycoplasma culture
|
Not done
|
|
CSF analysis
|
Total WBC 0 per mm3, glucose 60 mg/dL (NR: 50–75), protein 0.25 mg/mL (NR: 0.15–0.6)
|
|
CSF oligoclonal bands
|
Negative
|
|
CSF culture
|
Negative
|
|
CSF viral multiplex
|
Negative
|
|
Electroencephalography
|
Slow background for age, with no epileptiform discharges
|
|
Metabolic workup[a]
|
Unremarkable
|
|
Autoimmune encephalitis workup[a]
|
Unremarkable
|
Abbreviations: CSF, cerebrospinal fluid; NR, normal range; WBC, white blood cell.
a Metabolic workup; serum ammonia, lactate, venous blood gas, tandem mass spectrometry,
and urinary organic acid. Autoimmune encephalitis workup; myelin oligodendrocyte glycoprotein,
anti-N-methyl-d-aspartate receptor, and neuronal voltage-gated potassium channel antibodies.
