JENNIFER L. McGUIRE
HISTORY OF PRESENT ILLNESS
The patient is a previously healthy 9-year-old boy who presented to his pediatrician 3 days prior to admission with complaints of headache and malaise. Crackles were noted in the right lung and he was treated with azithromycin for suspected community-acquired pneumonia. The next day he developed low grade fevers with decreased oral intake, emesis, lethargy, and weakness. His mother described him as “being out of it.” His symptoms worsened over the next 2 days and he was admitted to an outside hospital with disorientation, slurred speech, diffuse weakness, drooling, and brady-kinesia. A noncontrast cranial computed tomography (CT) was normal, but magnetic resonance imaging (MRI) of the brain revealed bilateral basal ganglia T2-hyperintensities without restricted diffusion. He was transferred to a regional Children’s Hospital for further evaluation and management. There was no history of trauma, drug or toxin exposure, ill contacts, or any chronic changes in his behavior or school performance.
The medical history was remarkable for bronchiolitis requiring hospitalization at 3 months of age. He had a history of primary enuresis that had improved over the past 6 months. He was a third grader who did well in school. His older half-brother had attention-deficit and hyperactivity disorder, but there was no other family history of neurologic or developmental disorders. The boy had been placed in foster care at age 5; however, he had returned to live with his mother, stepfather, stepbrother, and stepsister 2 years ago.
T 39°C; HR 60 bpm; RR 28/min; BP 114/64 mmHg; Oxygen saturation 94% in room air
Weight 50th percentile; Height 50th percentile
General examination revealed a pale boy with masked facies who was occasionally tearful sitting up in bed. He was oriented to person and place, but was confused regarding the date and reason for his hospitalization. He had minimal spontaneous movement. Pupils were equally round and reactive to light. There were no Kaiser-Fleischer rings and optic disc margins on undilated fundoscopic examination were sharp. Extraocular movements were full without nystagmus. Facial sensation was full and symmetric bilaterally. Facial strength was full and symmetric, but he had diminished voluntary facial movement throughout. His tongue, uvula, and palate were midline. Motor examination revealed a resting tremor in bilateral hands. He had normal tone but diminished strength throughout. Sensory examination was intact and symmetric in all four extremities to light touch, temperature, and proprioception. He had coordinated but slow movement with finger-nose-finger. Deep tendon reflexes were normal. Babinski reflexes were downgoing bilaterally. There were no murmurs on cardiac examination. Crackles were appreciated bilaterally with diminished breath sounds at the left lung base.
Laboratory results from the outside hospital were as follows: A complete blood count (CBC) revealed a WBC count of 4600/mm3 (57% segmented neutrophils, 33% lymphocytes, 8% monocytes, and 2% eosinophils). Serum electrolytes, blood urea nitrogen, creatinine, and calcium were normal. The serum glucose was 124 mg/dL. Liver function tests were significant for an elevated lactic dehydrogenase level 228 U/L. Ammonia level was 19 mcg/dL. Serum ceruloplasmin and lead levels were normal. Carboxyhemoglobin level was normal. Urinalysis and urine tests for heavy metals were negative. Lumbar puncture revealed clear cerebrospinal fluid with a glucose of 65 mg/dL and protein of 40 mg/dL. There were 20 CSF WBC/mm3 and no red blood cells (RBC). Viral and bacterial cultures of blood, urine, and CSF were negative. CSF herpes simplex virus (HSV) and enteroviral polymerase chain reaction (PCR) were also negative. Plasma and cerebrospinal fluid (CSF) amino acids, pyruvate, and lactate were normal. The initial chest radiograph was abnormal (Figures 8-3A and 8-3B).
Figure 8-3. A. Chest radiograph, anterior-posterior view. B. Chest radiograph, lateral view. C. Chest CT.
COURSE OF ILLNESS
The child was hospitalized. His medications on arrival included acyclovir, vancomycin, cefotaxime, and eythromycin. He was started on nasogastric feeds due to the profound weakness of his oropharyngeal muscles and difficulty swallowing. He showed no evidence of respiratory or cardiovascular compromise, although the bradykinesia and tremor worsened during the 48 hours following admission and his ability to communicate verbally deteriorated. A Parkinsonian-like clinical picture prompted initiation of amantadine. A chest CT was also abnormal and suggested a potential cause (Figure 8-3C). The results from a CSF PCR confirmed the diagnosis.
DISCUSSION CASE 8-3
This child presented with encephalopathy, weakness, and bradykinesia, in the context of a CSF pleocytosis and MRI demonstrating focal bilateral basal ganglia T2 hyperintensities. Encephalopathy can be defined as a depressed or altered level of consciousness, lethargy, or a change in personality for more than 24 hours; this child demonstrated progressive lethargy and disorientation over 5 days. Encephalopathy in children is broadly categorized into acute and chronic forms, with toxic, metabolic, or infectious etiologies. The most notorious of the toxins causing encephalopathy are carbon monoxide and lead; however, toxic etiologies do not typically demonstrate a fever and pleocytosis, and ideally an exposure history is present. Multiple metabolic disorders that involve the basal ganglia may cause encephalopathy, including Wilson disease (copper accumulation in the brain, liver, and cornea) and pantothenate kinase-associated neurogeneration (deposition of iron-containing material in the substantia nigra); however, these are rare disorders that usually present as chronic encephalopathy, and are unlikely in children with a normal metabolic and hepatic evaluation.
Encephalitis, or inflammation of the brain associated with clinical neurologic dysfunction, is a common cause of encephalopathy in children. Encephalitis may be related to a primary infection, or may be a postinfectious immunologically mediated phenomenon. Primary infectious encephalitis is most commonly caused by viruses, including herpes simplex virus, enterovirus, or arboviruses, but may also be caused by nonviral pathogens such as Borrelia burgdorferi and Rickettsia species. The clinical diagnosis of encephalitis rests on the presence of encephalopathy requiring hospitalization, in conjunction with fever, seizures, focal neurologic findings (such as bradykinesia in this case), or other objective measures of central nervous system (CNS) inflammation (such as a CSF pleocytosis or the appropriate MRI changes). Identification of a causative organism in primary infectious cases rests on specific microbial testing in the CSF and periphery using organism-appropriate PCR and serologies. No causative agent is found in up to 65% of clinical encephalitis cases.
Mycoplasma pneumoniae, varicella, and influenza are among the few infectious agents causing pneumonia concurrently with encephalitis. Central nervous system findings in varicella more classically cause a postinfectious cerebellitis.
The chest radiograph (Figures 8-3A and 8-3B) revealed a moderate-size left pleural effusion and left lower lobe consolidation. The chest CT (Figure 8-3C) confirmed poorly enhancing left lower lobe consolidation with a left plueral effusion with compressive atelectasis of the left upper lobe as well as a small right pleural effusion. The child’s pneumonia raised the possibility of a common etiology for both his respiratory disease and CNS disease. Mycoplasma pneumoniae PCR assay of the CSF and nasopharyngeal aspirate were positive. The diagnosis of Mycoplasma pneumoniae encephalitis was confirmed.
INCIDENCE AND EPIDEMIOLOGY
Mycoplasma pneumoniae, the smallest free-living organism, accounts for one-third of all pneumonias in children 5-9 years old and 70% of all pneumonias in children aged 9-15 years. Less than 0.1% of these cases have central nervous system complications. In one Toronto series of 159 children with encephalitis, M. pneumoniae was implicated as the etiology in 7% of children. In the California Encephalitis project, 111 (5.6%) of 1988 patients enrolled had evidence of recent or current M. pneumoniae infection. The median age of children with M. pneumoniae-associated encephalitis is about 11 years old; there does not appear to be a seasonal or gender predominance.
Mycoplasma pneumoniae pneumonia most commonly presents as a gradual onset of headache, malaise, fever, and rhinorrhea and progresses to cough, dyspnea, and bronchpneumonia. Extrapulmonary manifestations are commonly reported. Systemic manifestations of infection include a maculopapular rash, erythema multiforme, and/or Stevens-Johnson syndrome. Central nervous system involvement may be related to direct CNS viral invasion (aseptic meningitis, meningoencephalitis, or encephalitis), vascular occlusion (systemic or focal cerebral vasculitis), and/or immune-mediated injury (Guillain-Barré, transverse myelitis). CNS manifestations are protean and vary according to pathogenesis. In M. pneumoniae-related encephalitis, symptoms commonly include encephalopathy, meningeal signs (headache, stiff neck, fever >39°C), and/or seizures. Encephalitis may occur without respiratory symptoms, or may follow onset of respiratory symptoms by up to a week. Immune mediated M. pneumoniae white matter injury may follow respiratory symptoms by several weeks.
Detection of M. pneumoniae. Diagnosis of M. pneumoniae infection is typically based on one of three possible findings: (1) fourfold change in serum complement fixing IgG antibodies to M. pneumonia; (2) positive serum IgM antibodies in combination with a positive respiratory sample PCR; or (3) positive M. pneumoniae CSF PCR. However, the subsequent diagnosis of M. pneumoniae as the definitive cause of a case of clinical encephalitis is significantly more complicated and fraught with potential difficulties. First, M. pneumoniae is widely prevalent in the respiratory tract in healthy patients. Therefore, when serologies are positive or an organism is isolated from the periphery in a clinical case of encephalitis, it is unclear whether that is a definitively causative source of CNS infection, or an incidental finding related to baseline population prevalence. Among the 111 patients in the California Encephalitis Project with evidence of recent or current M. pneumoniae infection, 85% were positive by serology alone (Mycoplasma IgM-positive), 11% were positive by respiratory PCR alone, and 2% had positive CSF PCR for M. pneumoniae. Second, if an older child or adult who has been exposed to M. pneumoniae in the past is rein-fected, they may not mount a typical IgM response to infection. Therefore, infection may be present in the absence of IgM antibodies. This problem is one reason why acute and convalescent serologies are helpful. Third, IgM titers may persist for months after a primary infection, therefore an elevated IgM may not indicate a concurrent infection that is causative for the clinical presentation of encephalitis. Finally, the actual pathophysiologic role of M. pneumoniae in the CNS is unclear. Hence, some have argued that when the organism is isolated from the CSF it may be a contaminant, and may not be clinically important. Therefore, diagnosis should be made with caution, in the context of a combination of positive tests and exclusion of alternate diagnoses.
Lumbar puncture. Cerebral spinal fluid is normal in 45%-70% of patients with M. pneumoniae encephalitis. Abnormalities, when present, include a mild-to-moderate mononuclear CSF pleocytosis (<100 WBCs). The CSF protein may be normal or mildly elevated, and the glucose is normal.
Neuroimaging. Cranial CT is often normal in M. pneumoniae-related encephalitis. However, cranial MRI is abnormal in up to 49% of cases, typically demonstrating nonspecific focal, multifocal, or diffuse edema or ischemia, enhancing lesions, or white matter lesions. MRI is most helpful to exclude other causes of encephalopathy and fever.
Electroencephalogram (EEG). EEG findings are abnormal in up to 79% of children with M. pneumoniae-related encephalitis. Most cases demonstrate nonspecific diffuse slowing; fewer cases demonstrate focal dysfunction or epilepti-form activity.
There are no clear-cut guidelines to the treatment of M. pneumoniae encephalitis. M. pneumoniae does not have a cell wall; therefore, it is resistant to penicillins and cephalosporins. Macrolide antibiotics (erythromycin, clarithromycin, azithromycin), tetracyclines, and fluoroquinolones effectively eradicate the organism in vitro, but have limited ability to cross the blood-brain barrier, and have not been demonstrated to clinically alter the course of the neurologic illness. There is anecdotal evidence that corticosteroids and intravenous immunoglobulin may be beneficial in treating CNS infection with M. pneumoniae, particularly in cases with prominent white matter disease, when a postinfectious immune-mediated mechanism is suspected.
Mortality rates of 8% and morbidity rates of 23% have been reported in M. pneumoniae-related encephalitis. Common long-term neurologic sequelae include cognitive problems, movement disorders, and seizures.
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