Psychiatric Manifestations Caused by Mycoplasma pneumoniae Encephalitis Mimicking Autoimmune Encephalitis

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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.][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
2][3] The most prevalent complication is encephalitis. 6Approximately 20% of individuals exhibiting central nervous system (CNS) abnormalities do not have any prior or concurrent respiratory infection. 2,3cute 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. 9Our 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. 4,10he 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 immunemediated 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. 11,12he 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. 13The 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. 14erological 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. 15Seroconversion 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. 6According 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. 17,18The 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. 18,19It 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. 12Practically, 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. 20A singlecenter 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 recent multicenter study included a total of 87 patients with MPE, where 55 individuals (63.2%) among these patients received immunomodulating medication. 20Out 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. 18Various 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 longlasting impairments in cognitive, physical, or visual abilities.

Table 1
Laboratory and imaging profile of the patient in this report 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.