Child Neurology: Rocky Mountain spotted fever encephalitis

Neurologic manifestations.

Neurologic manifestations are common in patients with RMSF and range from headache, behavioral abnormalities, meningismus, and photophonophobia to more serious neurologic manifestations such as amnesia, aphasia, hearing loss, ataxia, seizures, and encephalitis/coma.^4,5 Neurologic involvement including encephalitis is associated with higher mortality rates, which can be as high as 88% for comatose patients.³ Encephalitis is associated with infiltration of the perivascular spaces in the brain (Virchow-Robin spaces) by lymphocytes, macrophages, and polymorphonuclear lymphocytes at autopsy.⁶

Diagnosis of RMSF.

Diagnosis of RMSF is challenging as the presentation is nonspecific, and serologic testing may be negative at the time of treatment. Failure to consider the diagnosis leads to delays in treatment, with resultant increased mortality.² Therefore, any clues to the diagnosis are important for prompt recognition of this potentially fatal infection. Antibodies usually do not develop until roughly a week after exposure, which limits the clinical utility of serologic testing early in the course of the infection. PCR or immunohistochemistry performed on skin biopsy specimens may provide a diagnosis during the acute illness, and may be indicated when serologic testing is negative.⁷ The current gold standard test is the indirect fluorescent antibody test, which is highly sensitive and specific for rickettsioses but does not distinguish among the rickettsiae. Therefore, in the early phase of illness, a high clinical suspicion, appropriate historical and examination findings, and supportive laboratory values are important. Nonspecific but helpful laboratory findings include thrombocytopenia, elevated aminotransferases, creatinine kinase, and hyponatremia.¹ CSF typically demonstrates a moderate polymorphonuclear or lymphocytic pleocytosis with <100 cells/μL, moderately elevated protein (100–200), and normal glucose.⁵ The differential diagnosis for a patient with rash and encephalomeningitis is broad (table).

MRI findings in RMSF encephalitis.

There is very little literature on the MRI findings in RMSF.⁸ Bonawitz et al.⁹ reported the largest series to date with 34 patients, among whom only 6 had MRI studies. Four of these were abnormal: 1 patient had “prominent perivascular spaces,” 1 had focal arterial infarctions, 1 had diffuse edema, and 1 had meningeal enhancement. Baganz et al.⁶ reported a single case of RMSF with neurologic manifestations wherein a 45-year-old woman with encephalitis was noted to have punctate T2 hyperintense lesions disseminated throughout the white matter on MRI that resolved with treatment and resolution of neurologic signs and symptoms. White matter infarctions and leptomeningitis have also been described.

The starry sky pattern on MRI.

We previously reported a case of a 32-month-old boy with RMSF encephalitis with MRI findings resembling a starry sky pattern on T1, T2, and diffusion-weighted imaging.¹⁰ Since then, at least 2 other cases with the starry sky pattern on MRI have been reported. Autopsy of patients who died of RMSF encephalitis has demonstrated gliosis, demyelination, and necrosis in affected areas.⁹ It has been suggested that this pattern represents perivenular vasculitis; however, the precise underlying mechanisms are not clear and the absence of parenchymal enhancement indicates that the blood–brain barrier is intact.

While the starry sky pattern is highly suggestive of RMSF in the proper clinical context, it is not entirely specific to this entity. A similar-appearing pattern on diffusion-weighted imaging (DWI) can be seen in the setting of Nipah virus encephalitis, diffuse axonal injury, fat embolism, or other thromboembolic phenomenon. Similarly, multiple T2 hyperintense foci in similar distribution without associated DWI changes can be seen in such etiologies as Lyme disease, cryptococcus, neurocysticercosis, viral encephalitis, tuberculous meningitis, air embolism, and rarely mucopolysaccharidoses.⁸ We suggest that in cases of encephalitis with MRI consistent with the starry sky pattern on DWI, empiric treatment with doxycycline should be considered. This is especially prudent in the presence of supportive laboratory studies (described above) even while the specific diagnostic evaluation for RMSF is underway, given the high case-fatality rate among untreated patients.

Treatment.

When there is high clinical concern for RMSF, treatment should not await laboratory confirmation. Tetracyclines and chloramphenicol are the only antibiotics with definite efficacy for RMSF.¹ Doxycycline is the preferred first-line agent, even in children. The dosing in children is 2.2 mg/kg divided into twice daily dosing up to 100 mg BID for a minimum of 5–7 days or until the patient is afebrile for at least 2–3 days. IV therapy is recommended in cases with neurologic involvement.

RMSF is a tick-borne infection caused by R rickettsii that leads to multiorgan vasculitis and can progress rapidly to death if not recognized and treated. Encephalitis and other neurologic manifestations are associated with severe illness and worse outcomes. The starry sky pattern, which consists of multifocal, punctate areas of diffusion restriction predominantly distributed in the white matter, is common in RMSF encephalitis in children, but the sensitivity and specificity is unknown. This finding should serve as a clue to the diagnosis in the right clinical context, which includes rash, headache, fever, elevated aminotransferases, anemia, and thrombocytopenia. In patients with encephalitis who have the starry sky pattern on MRI, consideration should be given to empirical treatment with doxycycline while the diagnostic evaluation is underway.