Diverse Seizure Presentation of Acute Mycoplasma Pneumoniae Encephalitis Resolving With Immunotherapy

Case 1

A 7-year-old previously healthy left-handed female presented with new onset right distal upper extremity tonic clonic motor seizure and expressive aphasia. Postictally she demonstrated slow recovery with transient right upper extremity paresis. Review of systems did not reveal any symptoms consistent with infection. On admission her initial examination was consistent with postictal paresis and aphasia that normalized within 2 hours. Head computed tomography was normal for age, and her electroencephalogram demonstrated focal slowing as well as frequent epileptifrom activity emanating from the left frontocentral area. Patient was initially treated with levetiracetam, but she developed intractable simple focal motor seizures, up to 25 per day, of the right upper extremity associated with aphasia, with incomplete recovery of the right upper strength, in between seizures. Electrographic seizures emanated from the left frontocentral area. These seizures persisted despite sequential trials achieving therapeutic levels of levetiracetam, valproate, phenobarbital, lacosamide, and fosphenytoin over a period of 2 days. Brain magnetic resonance imaging showed a 4 × 3 cm area within the posterior left frontal lobe demonstrating abnormal subcortical restricted diffusion, as well as subtle associated T2 prolongation/fluid-attenuated inversion recovery hyperintensity without associated abnormal enhancement or susceptibility. Because of this finding, patient had a conventional brain angiogram that was normal and cerebrospinal fluid analysis that showed 12 nucleated cells and 39 red blood cells per microliter, normal protein, and normal glucose. The patient also had an extensive metabolic and infectious evaluation that revealed a positive Mycoplasma pneumonia immunoglobulin M. Because of the increasing seizure frequency without recovery of motor function, the patient was placed on intravenous pentobarbital for 5 days, intravenous immunoglobulin, intravenous corticosteroids, and azithromycin. After these interventions she had a virtually full recovery, with no further seizures in 3 months of follow-up, with near complete recovery of strength of her right upper extremity without aphasia.

Case 2

A 15-year-old previously healthy right-handed female presented with generalized nonconvulsive seizure, associated with decreased muscle tone followed by a generalized tonic clonic seizure. Review of systems did not reveal any immediate preceding symptoms consistent with infection. Her initial examination was consistent with encephalopathy, associated with variable levels of alertness. Admission electroencephalogram was abnormal with focal slowing as well as frequent epileptiform activity emanating from the left frontotemporal area. Patient was treated with levetiracetam, but rapidly progressed to intractable focal seizures intermittently generalizing to tonic clonic seizures. These seizures occurred up to 35 times per day and were associated with mental status change followed by euphoric laughing, loss of motor tone, and then subsequently loss of consciousness. During the interictal period, clinically she was confused and agitated, with intermittent expressive aphasia. Electrographic seizures emanated from the left frontocentral area. The seizures failed to respond to sequential trials achieving therapeutic levels of levetiracetam, oxcarbamazepine, clonazepam, valproate, and fosphenytoin over a 2-week period. Brain magnetic resonance imaging and magnetic resonance spectroscopy were normal. Her cerebrospinal fluid analysis showed 6 nucleated cells and 1 red blood cell per microliter, normal protein, and normal glucose. The patient also had an extensive metabolic and infectious evaluation that revealed a positive Mycoplasma pneumoniae immunoglobulin M. Because of the worsening of her clinical status, patient was treated intravenous immunoglobulin, intravenous corticosteroids, and azithromycin. After these interventions she had a steady recovery, with no further seizures in 2 years of follow-up and resolution of her neuropsychiatric symptoms.

Case 3

An 11-year-old previously healthy right-handed male presented with generalized tonic clonic seizure from sleep, associated with intermittent hallucinations. Review of systems did not reveal any symptoms consistent with infection. Initial examination was normal. Head computed tomography was normal, and his electroencephalogram demonstrated mild generalized slowing without epileptiform activity. Patient was treated with levetiracetam, with good control of his seizures. Brain magnetic resonance imaging showed patchy bilateral, but asymmetric foci of T2/fluid-attenuated inversion recovery hyperintensity in the centrum semiovale and periatrial white matter without associated restricted diffusion or abnormal enhancement, consistent with a parainfectious demyelinating process. His cerebrospinal fluid analysis showed no nucleated cells and 1775 red blood cells per microliter, normal protein, and normal glucose. The patient also had an extensive metabolic and infectious evaluation that revealed a positive Mycoplasma pneumoniae immunoglobulin M. On admission day, patient had worsening of his hallucinations. Because of the imaging findings and the worsening of his psychiatric symptoms, patient received intravenous corticosteroids and azithromycin. After these interventions he had a complete recovery, with no further seizures or hallucinations in 3 months of follow-up.

Discussion

Mycoplasma pneumoniae is a very small bacterium in the class of mollicutes and is a common pathogen in pediatric patients. Extrapulmonary manifestations are common in patients with Mycoplasma pneumoniae infections, with encephalitis being the most common extrapulmonary manifestation. ² The presence of Mycoplasma pneumoniae encephalitis in the absence of pulmonary manifestations is very unusual.

Encephalitis commonly presents with encephalopathy, fever, pleocytosis, and/or increased protein content in cerebrospinal fluid with negative culture, abnormal electroencephalogram findings consistent with encephalitis-like diffuse or focal slow activity, or periodic lateralized epileptiform discharges and abnormal results of neuroimaging, including computed tomography and magnetic resonance imaging. ^{3 –6}

The diagnosis of Mycoplasma pneumonia encephalitis is difficult to attain as it usually requires multiple diagnostic modalities, including cultures, polymerase chain reactions and serological tests from various specimens, including serum, cerebrospinal fluid, and throat swabs. ^7,8 Furthermore, clinicians should be cautioned as the sensitivity of Mycoplasma pneumoniae polymerase chain reaction using cerebrospinal fluid and serum immunoglobulin M is not high, so its negativity should not rule out Mycoplasma pneumoniae meningoencephalitis. ⁷

Seizures are a common manifestation of Mycoplasma pneumonia encephalitis. In a study by Lin et al, it was shown that during the acute phase, 53 patients (53.5%) had seizures, the most common type of which was primary focal with secondary generalized tonic-clonic seizure (39.6%). ³

All 3 of our patients presented in our epilepsy monitoring unit with recurrent seizures and neuropsychiatric presentation, including hallucinations as the initial presentation of their illness, without any preceding symptoms consistent with infection. Seizure types were diverse and included generalized tonic clonic seizures, generalized nonconvulsive seizures, focal seizures with secondary generalization, focal seizures with neuropsychiatric symptoms, and focal motor seizures with expressive aphasia. Two out of 3 patients had worsening of their clinical symptoms developing refractory seizures to antiepileptic medication that were controlled only after intravenous corticosteroids and intravenous immunoglobulin was initiated. Our third patient appeared to have good seizure control but abnormal mental status and was treated with intravenous corticosteroids and 1 intravenous antiepileptic agent. The brain magnetic resonance imaging findings were also very variable, including normal scan, cortical and subcortical changes, and white matter changes. Serologic evidence of acute Mycoplasma pneumoniae (immunoglobulin M) was found after infectious evaluation in all 3 of the patients, and all patients were treated with azythromycin.

Despite the severity of their clinical course, recovery was virtually complete, with full functional recovery and cessation of seizures. In previous studies it has been reported that the rate of intractable epilepsy after mycoplasma related encephalitis is high, approximately 40%. ³ Even though the number of our cases is small, we believe that clinical suspicion for Mycoplasma pneumonia encephalitis should be raised in previously healthy patients with an initial presentation of acute refractory seizures without systemic symptoms. Furthermore, once diagnosed, aggressive management of seizures in patients with Mycoplasma pneumonia encephalitis including intravenous corticosteroids and intravenous immunoglobulin could potentially aid in improving functional recovery and future seizure control in this group.