Case description
Case 1
A previously healthy 14-year-old boy with a 4-day history of fever and cough was referred to our hospital due to clinical deterioration despite clarithromycin treatment. He had no remarkable medical or drug history. On admission (day 1), he was alert without any neurological abnormalities. Laboratory investigations revealed normal WBC count (7,680/μL; normal range; 3,400-10,000/μL), normal blood urea nitrogen (11 mg/dL, normal range; ≤21 mg/dL), slightly elevated serum creatinine (1.03 mg/dL, normal range 0.6-1 mg/dL), hyponatremia (134 mEq/L; normal range; 135–145 mEq/L), and positive CRP (3.4 mg/dL; normal range; <0.3 mg/dL). Serum levels of calcium, magnesium, glucose and the liver function test were normal. Serum anti-M.pneumoniae IgM antibody using a rapid enzyme immunoassay (EIA, Immunocard® Mycoplasma, Meridian Bioscience Inc., OH, USA) was negative. Antigens of influenza virus and adenovirus in the throat swab specimens were negative. Urinalysis was normal. Analysis of CSF was not performed.
A chest X-ray revealed dense infiltration in the bilateral lower lobes, indicative of pneumonia. Intravenous minocycline (100 mg/day) was administered for the treatment of M.pneumoniae pneumonia. In the following evening, he became afebrile but developed abnormal speech and hallucinations. In the morning on day 3, he suddenly developed delirious behavior followed by drowsiness. Glasgow Coma Scale (GCS) score was 8 (E3, V1, M4). The brain MRI revealed hyperintensity lesions in the SCC on diffusion- and T2-weighted images (Fig. 1a and b). Intravenous dexamethasone and acyclovir were administered. He rapidly improved and was fully conscious in the evening on day 3. Neuroimaging on day 7 revealed disappearance of hyperintensity lesions in the SCC (Fig. 1c and d). Laboratory investigations revealed negative CRP, while seroconversion of serum anti-M.pneumoniae IgM antibody was noted. He was discharged without neurological sequelae on day 7.
Case 2
A previously healthy 8-year-old girl with 1-day history of cough, headache, fever, lethargy, vomiting and diarrhea followed by drowsiness and seizures for ~20 s was referred to our hospital. She had no remarkable medical or drug history. On the same day, her younger brother was admitted to our hospital because of pneumonia due to M.pneumoniae diagnosed by pulmonary manifestation, chest X-ray finding, and positive M.pneumoniae-specific IgM. On admission (day 1), she was drowsy; GCS score was 8 (E3, V1, M5). Her body temperature was 38.3 °C, and the blood pressure was normal (108/68 mmHg). Physical examination revealed neither nuchal rigidity nor neurological abnormalities. Laboratory investigations revealed that WBC count (6,480/μL), serum levels of CRP, calcium, magnesium, glucose, the liver function test and urinalysis were within the normal range. However, hyponatremia (132 mEq/L) and positive serum anti-M.pneumoniae IgM antibody were noted. Serum IgM antibody against Epstein-Barr virus capsid antigen was negative but IgG antibody was positive, indicative of previous infection. Antigens of influenza virus and adenovirus in the throat swab specimens, and those of rotavirus, norovirus and adenovirus in the stool specimens were negative. Stool culture revealed no pathogenic bacteria. Analysis of CSF was not performed.
A chest X-ray revealed increased bronchial markings in the right lower lobe. The brain computed tomography (CT) and the EEG revealed no abnormalities. Intravenous fluid therapy was immediately given, followed by administration of an anticonvulsant, diazepam suppository (6 mg), for prophylaxis of further convulsions. Six hours later, her consciousness was fully recovered. On the following day, she started receiving oral minocycline (2 mg/kg/day). On day 5, she suddenly developed headache, drowsiness, ataxia and intension tremor. The brain MRI revealed hyperintensity lesions in the SCC (Fig. 2a) and the left cerebellum (Fig. 2b) on diffusion-weighted images. Similar signal characteristics were noted in the SCC and the left cerebellum on T2-weighted images.
Oral minocycline was switched to intravenous administration for additional 3 days. On day 6, she became afebrile, rapidly improved, and was fully conscious without disturbance of gait, cognition, speech, swallowing and vision. However, she still had intension tremor, slight muscle weakness and disabled fine motor incoordination of the left hand. Neuroimaging on day 12 revealed disappearance of the hyperintensity lesions in the SCC and the left cerebellum (Fig. 2c and d). She was discharged on day 14 with slight disability of fine motor incoordination of the left hand, which completely recovered 2 months after the onset of the disease.
Litterature review
The literature search found 13 cases, including 4 English-language full reports (7 cases) [5, 12–14], 1 Japanese-language full report (1 case) [15] and 5 Japanese-language abstract-only reports (5 cases) [16–20]. Our recent 2 cases described above were added for a total of 15 cases with M.pneumoniae-associated MERS. Of the 15 patients, 5 and 10 patients were “probable” and “possible” cases, respectively, while none was “confirmed” case. Demographic, clinical characteristics, laboratory data, neuroimaging findings, and outcome of these patients are summarized in Table 1. Mean age, male/female ratio, and mean duration of prodromal illness before the onset of neurological symptoms were 8.3 years (range 2–14 years), 1.5 (9/6), and 3.5 days (range 1–8 days), respectively. Of note, mean period of prodromal illness before the onset of neurological symptoms was shorter in the patients with type II MERS (1 day) than in those with type I MERS (3.8 days, range 1–8 days).
Table 1 Pediatric cases of MERS associated with Mycoplasma pneumoniae infection As neurological symptoms, drowsiness (12/15, 80 %) was the most common, followed by abnormal speech (5/15, 33 %), ataxia (4/15,27 %), seizure (4/15,27 %), delirium (3/15, 20 %), abnormal behavior (2/15,13 %), confusion (2/15,13 %), tremor (2/15, 13 %), irritability (2/15,13 %), hallucination (1/15,7 %), muscle weakness (1/15, 7 %), motor deterioration (1/15, 7 %), and peripheral facial nerve paralysis (1/15, 7 %). Among non-neurological symptoms, fever (14/15, 93 %) was the most common, followed by cough (8/15, 53 %), headache (7/15, 47 %), gastrointestinal symptoms (abdominal pain, vomiting and diarrhea, 6/15, 40 %), lethargy (5/15, 33 %), and dizziness (1/15, 7 %). Prolonged fever (≥6 days) developed in 58 % (7/12) of the patients, in whom the information of duration of fever was available. Seven (47 %) of the 15 patients had no respiratory symptoms.
All patients were diagnosed by serologic tests. Eight (53 %) of the 15 patients were diagnosed by a single measurement of M.pneumoniae-specific antibody; there were 4 and 2 cases with positive IgM antibody as measured by EIA and enzyme-linked immunosorbent assay (ELISA), respectively, and in the remaining 2 patients, M.pneumoniae-specific antibody as measured by ELISA was positive but what type of antibody was unknown. Of these 8 patients with positive M.pneumoniae-specific antibody, 2 patients simultaneously showed positive M.pneumoniae DNA in the throat swab specimens by PCR. There was a 4-fold or more rise in serum anti-M.pneumoniae antibody titer as measured by complement fixation test (CFT) in 1 case and by particle agglutination assay (PA) in 4 cases. Information of the method for serologic tests was not available in the remaining 2 cases. None of the patients underwent culture analysis.
Three patients showed clarithromycin resistance. Chest X-ray or CT of the 7 patients examined revealed infiltration of the lobes (n = 5) or increased bronchial markings (n = 2). Leukocytosis (>10,000 WBCs/μL), positive CRP (>0.3 mg/dL) and hyponatremia (<135 mEq/L) were noted in 42 % (5/12), 75 % (9/12) and 44 % (4/9) of the patients, respectively. CSF pleocytosis (>10WBCs/μL) was found in 3 (33 %) of the 9 patients, three of whom showed negative M.pneumoniae in CSF as measured by PCR. The levels of interleukin (IL)-6 in CSF were elevated in a patient with type I MERS. EEG revealed slow wave in 63 % (5/8) of the patients examined.
On neuroimaging, all except 2 patients showed type I MERS. Two patients were type II MERS; our case 2 with hyperintensity lesions in the SCC and the left cerebellar lesions, and other case with those in the SCC, center semiovale and parietal white matter bilaterally [5]. Hyperintensity lesions in the SCC and other brain areas on neuroimaging disappeared within 18 days in all except 4 patients including 3 with type I and 1 with type II MERS, in whom the lesions on the follow-up MRI disappeared 2–4 months after the initial MRI.
Antibiotic treatment included azithromycin (4/10), ciprofloxacin (3/10), and minocycline (3/10), while none received clarithromycin after the onset of MERS. Intravenous steroids were given to 42 % (5/12) of the patients. All patients with type I MERS completely recovered within 19 days, while 2 patients with type II MERS developed neurological sequelae, which recovered 2 and 6 months, respectively, after the onset of the disease.