Brainstem and Striatal Encephalitis Complicating Mycoplasma Pneumoniae Pneumonia: Possible Benefit of Intravenous Immunoglobulin

Encephalitides of the brainstem and the striatum associated with Mycoplasma pneumoniae infection are believed to be mediated by an autoimmune process triggered by the organism, a toxin or direct invasion by the organism itself. Inability to identify M. pneumoniae from cerebrospinal fluid by culture or polymerase chain reaction suggested a possible immunologic process. A trial of intravenous immunoglobulin in a critically ill patient with encephalitis that developed in parallel to M. pneumoniae pneumonia was associated with neurologic improvement within 48 h of treatment. Central nervous system complications occur in ∼1 per 1000 patients with Mycoplasma pneumoniae respiratory infections but occur in as many as 7% of patients who are hospitalized for such infections. 1 Complications include various forms of encephalitis, meningitis, acute disseminated encephalomyelitis and cranial neuropathies. 1 A restricted encephalitis of the caudate and putamen, collectively referred to as the striatum, has been reported in parainfectious and postinfectious settings with mumps, echoviruses and recently M. pneumoniae. 2–8 I report the case of a 6-year-old girl with concomitant striatal and brainstem encephalitis in the setting of M. pneumoniae pneumonia who demonstrated clinical improvement after the administration of intravenous immunoglobulin (IVIg). Case report. A previously healthy 6-year-old girl presented to the emergency room with a 4-day history of nausea, vomiting, cough and high fevers. She appeared ill and dehydrated. Vital signs were temperature 97.6°F, pulse 116/min, blood pressure 115/71 mm Hg and respiratory rate 24/min. Chest auscultation revealed crackles in the right axilla and right posterior lower chest. There were no murmurs and the neurologic examination was unremarkable. The white blood cell count was 12 500/l with 62% polymorphonuclear leukocytes, 22% lymphocytes, 12% monocytes, hematocrit 47.1%, platelets 594 000/μl and positive serum M. pneumoniae IgM. No cold agglutinins were detected in serum. Chest roentgenogram revealed opacification in the lower and middle lobes of the right lung. Azithromycin was begun at 5 mg/kg/day iv and was administered for a total of 14 days. On Hospital Day 2 the patient was intubated for respiratory distress secondary to aspiration that occurred after postprandial vomiting. She was extubated the following day but required reintubation because of apnea leading to cardiac arrest. Magnetic resonance imaging of the brain revealed inflammation in the brainstem, particularly at the pontine-medullary junction, as well as in the caudate and putamen bilaterally, indicative of encephalitis (Fig. 1). Biparietal edema was present in a watershed distribution, consistent with ischemia from the cardiac arrest.Fig. 1: Fluid-attenuated inversion-recovery sequence magnetic resonance images demonstrating high signal in the brainstem (right) and in the caudate and putamen bilaterally (left). With fluid-attenuated inversion-recovery sequencing magnetic resonance imaging, inflammation and edema demonstrate high signal but unlike the T2 sequence, CSF does not appear bright.PCR of a throat swab specimen was strongly positive for M. pneumoniae and serology showed IgM 1.96 (negative, <0.77), confirming acute respiratory infection. Cerebrospinal fluid (CSF) obtained on Hospital Days 6 and 13 had normal cell counts, glucose and protein content and was negative for M. pneumoniae by PCR and culture on both occasions (Table 1). CSF viral culture was negative. Opening pressure documented only on the first CSF sample was 21 cm H2O.Table 1: Reported cases of striatal necrosis complicating Mycoplasma pneumoniae infectionThe remainder of the evaluation was negative for other infectious etiologies including serologic assays for Epstein-Barr virus, cytomegalovirus and enteroviruses; stool culture for enteroviruses; nasopharyngeal aspirate for common respiratory viruses including respiratory syncytial virus, influenza and parainfluenza by immunofluorescence staining and culture; induced sputum for bacterial culture, acid-fast staining and immunofluorescence staining for Pneumocystis carinii. After the episode of apnea, the patient was able to open her eyes to voice and make attempts to follow simple commands. However, during subsequent days her neurologic status deteriorated to Stage IV encephalopathy and generalized seizures. IVIg 0.5 g/kg was administered once daily on Hospital Days 10 to 12. By Hospital Day 13 the patient was awake, following commands and able to respond appropriately to questions. The neurologic examination stabilized to increased tone, hyperreflexia, left arm > left leg weakness, absent gag reflex and difficulty swallowing and handling of oropharyngeal secretions. However, the patient was initiating ventilations on her own without apnea. On Hospital Day 29 the patient was transferred to a rehabilitation facility where she remained for 6 weeks during which she improved neurologically, including regaining the ability to eat on her own and ambulate. Three months after the onset of the illness, the patient was at her cognitive and behavioral preillness baseline. She had chorea and coordination difficulties. She returned to school 4 months after the onset of her illness. Discussion. In published reports of M. pneumoniae-associated striatal encephalitis 2–8 including this case (Table 1), patient ages ranged from 5 to 11 years. There were four girls and three boys. Patient race was not commented on by most authors but two of the six children were of Asian descent and a third case, which did not comment on race, was from Japan. My patient was Caucasian. Neurologic symptoms developed between 4 days and 4 weeks after the onset of respiratory symptoms. 2–8 In the report in which the neurologic symptoms were noted at 4 weeks, the child had continued fevers and vomiting requiring parenteral nutrition from the onset of respiratory infection, suggesting that neurologic symptoms may have developed earlier. 8 Striatal encephalitis and necrosis manifests clinically with encephalopathy and extrapyramidal symptoms including rigidity, bradykinesia and tremor. These symptoms were prominent in my patient. In addition this patient demonstrated symptoms consistent with brainstem dysfunction, including aspiration and apnea. CSF glucose and protein values was normal in all the reported cases. White blood cell count in the CSF ranged from 0 to 33 cells/μl; and when a differential was reported, it consisted predominantly of lymphocytes (62 to 100%). 2–8 Antibiotics (macrolides, tetracyclines, quinolones) used for treatment of the concomitant respiratory infection had no discernable effect on the central nervous system disease. All patients were receiving appropriate antibiotic therapy when neurologic disease developed. Therapy for M. pneumoniae-mediated neurologic disease is supportive. Some have used levodopa in cases of striatal necrosis to help with the extrapyramidal symptoms with some success. 4 I report this case because of the possible success with use of IVIg. The mechanisms by which encephalitis develops as a consequence of M. pneumoniae respiratory infection is unknown but probably heterogeneous, mediated by direct invasion of brain tissue by the organism, production of a neurotoxin or an autoimmune phenomenon induced by the immune system response to the organism. 1, 9 Although some Mycoplasma species such as Mycoplasma gallisepticum and Mycoplasma neurolyticum, which infect birds and mice, respectively, produce neurotoxins, this phenomenon has not been demonstrated with M. pneumoniae. 9 Current evidence supports autoimmunity and direct organism invasion as mechanisms for central nervous system injury in M. pneumoniae infections. 1, 9, 10 Although some cases, particularly those with abnormal CSF cell counts, provide evidence for the presence of the organism in the central nervous system using PCR or culture on CSF, other cases in which the process appears to be encephalitic without meningeal involvement, including the case described here, do not. 1, 9, 10 The organism has never been cultured from brain parenchymal tissue. 1, 9 Autoantibodies to brain are detected in as many as 75% of patients with M. pneumoniae infection but do not correlate with neurologic complications. 10 Circulating immune complexes are detected in 41% of patients with M. pneumoniae respiratory infections. 10 Because M. pneumoniae DNA was not detected in CSF, speculation arose that an immune-mediated process might respond to the immunomodulatory effects of IVIg. One patient with M. pneumoniae brainstem encephalitis associated with anti-GQ1b ganglioside IgG was successfully treated with immunoadsorption therapy. 11 Some case reports suggest possible benefit of plasma exchange in M. pneumoniae-associated myelitis and polyradiculitis. 1 These facts superimposed on the gravity of the patient’s neurologic state provided the basis of IVIg therapy in this case. The improvement in this child’s encephalopathy and seizures occurred within 48 h after initiation of IVIg therapy. Apnea resolved a few days later. Although this suggests benefit, it by no means provides definitive proof. Because all previously reported patients with striatal encephalitis survived and improved neurologically, one can speculate that the observed improvement in this child would have occurred despite IVIg. However, the previously reported patients had a gradual improvement during many months to 2 years, and none had prompt, pronounced improvement as in this case. IVIg probably hastened short term recovery in this case rather than improved the eventual outcome. Because M. pneumoniae-mediated encephalitis is rare, it is unlikely that a randomized control trial could answer the question of benefit of IVIg in this setting. A positive clinical response to IVIg would not prove that the disease is immunologically mediated because IVIg has the ability to neutralize pathogens and toxins.