Clinical and Radiological Features of Rotavirus Cerebellitis

Discussion

The most important finding in this series is that the clinical and radiologic features of the 11 patients with rotavirus cerebellitis were similar—consciousness disturbance after gastroenteric symptoms of fever, vomiting, and diarrhea, followed by mutism (10 of the 11 patients). MR imaging revealed a reversible splenial lesion in the acute stage, abnormal signal intensity in the cerebellar white matter/nuclei in the acute-to-subacute stages, followed by increased signal intensity in the cerebellar cortex and finally cerebellar atrophy.

Acute cerebellitis is considered an inflammatory syndrome and is clinically defined as fever, nausea, headache, and an altered mental status in conjunction with acute onset of cerebellar symptoms.^8,9 Although pathologic investigation has been restricted to critically ill patients, it has been suggested that direct invasion by an etiologic pathogen is the main mechanism.^8,10 Inflammatory swelling of the cerebellum is apt to compress the brain stem and may induce alterations of consciousness, which can mask the initial stage of cerebellar symptoms.⁸ This mechanism was, however, unlikely in our patients with rotavirus cerebellitis because severe cerebellar swelling was not seen in the acute phase; instead, the disease seemed to progress from cerebellar white matter/nuclear involvement to cerebellar cortical involvement. EEG revealed slow basic activity, and MR imaging showed a reversible splenial lesion in 8 and 6 of the 11 patients, respectively, suggesting that concurrent encephalitis may have been the cause of the disturbance of consciousness. Thus, we believe the more correct diagnosis was acute rotavirus cerebellitis concurrent with encephalitis.

Mutism with subsequent dysarthria following a disturbance of consciousness is the most interesting clinical finding in this series. Cerebellar mutism is most commonly described after cerebellar surgery in children; it is typically reversible within days to months, with recovery proceeding through a stage of ataxic dysarthria.^11–13 It has been postulated that this mutism may represent an extreme form of dysarthria or anarthria, resulting from impaired coordination of the articulatory muscles due to the cerebellar injury.^11,12

Severe speech disturbances, such as mutism, are unusual clinical symptoms in acute cerebellitis in children¹³; only 6 such patients have been reported.^2,7,13–15 Two of those 6 patients were diagnosed as having rotavirus cerebellitis,^2,7 and another one, as having cerebellitis following acute gastroenteritis due to an unknown pathogen (with no findings on rotavirus examination).¹² On the basis of the present series and previously reported patients, it is reasonable to postulate that rotavirus cerebellitis has distinct clinical features, being characterized by disturbance of consciousness a few days after gastroenteric symptoms, followed by cerebellar mutism. Pediatric neurologists should be aware of this clinical sequence for prompt diagnosis and management of such patients

In 6 of our 11 patients with rotavirus cerebellitis, MR imaging revealed transient lesions in the cerebellar white matter/nuclei with reduced diffusion between days 5 and 7. These lesions disappeared afterward, being followed in some patients by T2/FLAIR hyperintensity in the cerebellar cortex and, finally, cerebellar atrophy. Other reports of acute cerebellitis describe edema of the cerebellar cortex, usually bilateral, followed by cerebellar atrophy,^2,8,13,14 rather than involvement of the cerebellar white matter or nuclei. Even the prior reports of MR imaging in patients with rotavirus cerebellitis² have not described white matter or nuclear involvement; however, those MR imaging studies were performed in the chronic stage of the illness (days 29 and 180), which may explain why the earlier deep lesions were not seen. Stereotactic ablation of the dentate nucleus and superior cerebellar peduncle has been reported to cause reversible mutism, as has trauma to the dentate nucleus and/or its outflow tract.^9,16,17 These findings suggest that bilateral involvement of the dentatorubrothalamic tract from the dentate nucleus to the brain stem may cause transient cerebellar mutism. It is, therefore, possible that the lesions in the cerebellar white matter/nuclei observed on MR imaging in the present series may be the cause of their cerebellar mutism. It is not clear why the lesions in the cerebellar white matter/nuclei (seen between days 5 and 7) disappear by the time mutism is observed. It is possible that the mutism is masked by the disturbance of consciousness (encephalitis) in the acute stage and that the functional abnormalities, perhaps biochemical in nature, last longer than the imaging abnormalities.

The pathophysiology of CNS involvement in patients with rotavirus gastroenteritis is not fully understood. It is often explained as direct CNS invasion by the rotavirus.² Supporting this explanation, rotavirus ribonucleic acid or antigen has been detected in the blood and CSF of patients with rotavirus gastroenteritis, with or without neurologic manifestations,^1,2,18 and extraintestinal rotavirus replication has been detected in mice.¹⁹ However, neither rotavirus antigen nor PCR of the CSF is always positive in patients with the encephalitis/encephalopathy that is associated with rotavirus gastroenteritis; rotavirus PCR was positive in only 3 of 8 patients reported by Nagatomi and Nakagomi²⁰ and in neither of the 2 patients so examined in the present series (patients 1 and 2).

It is not clear how rotavirus would affect the CNS without direct invasion. Rotavirus could damage enterocytes through toxinlike activity, such as viral nonstructural protein 4.²¹ Nonstructural protein 4 alone or with rotavirus infection induces nitric oxide metabolites, which are highly reactive free radicals. Serum and CSF nitric metabolites have been reported to be elevated in patients with rotavirus gastroenteritis-induced convulsions.²² Marked elevation of interleukin-6 was reported in the CSF of a patient with rotavirus cerebellitis,² suggesting CNS inflammation with or without rotavirus direct invasion. There have been, however, no reports explaining why rotavirus might affect the cerebellum more than the cerebrum.

The MR imaging finding of reversible splenial lesions with homogeneously reduced diffusion in the acute stage between days 4 and 6 in this series was also interesting. An isolated splenial lesion with homogeneously reduced diffusion (sometimes associated with symmetric white matter lesions) is a key finding for the diagnosis of MERS.^3,4 The clinical symptoms of MERS consist of delirious behavior, disturbance of consciousness, and seizures, all of which completely resolve within a month.^3,4 Although several patients have been reported having MERS associated with rotavirus gastroenteritis,⁵ there has been no report of patients presenting with both acute cerebellitis and a reversible splenial lesion. Splenial lesions were recognized between days 4 and 6 in 6 of the 11 patients in this series; these were identical to those reported in MERS in location, signal intensity, and complete reversibility. Three of the 6 patients had an isolated splenial lesion that, in patients with MERS, would suggest probable clinical and radiologic reversibility. Although there was complete resolution of the splenial lesion in all 6 patients, follow-up MR imaging showed cerebellar involvement, and the 6 patients developed disturbance of consciousness, mutism, and finally neurologic sequelae. It is, therefore, important to recognize that an isolated splenial lesion with homogeneously reduced diffusion is not always a benign sign predicting complete clinical and radiologic recovery, especially in pediatric patients with rotavirus gastroenteritis.

This study has some limitations. Patients were selected retrospectively on the basis of a diagnosis of rotavirus cerebellitis and associated MR imaging abnormalities. Some patients with rotavirus cerebellitis may not have any MR imaging abnormality, or some patients with other types of viral infections may develop this type of cerebellitis. PCR or antigens of rotavirus in the CNS, and cytokines of blood and CSF were not examined in most patients enrolled in this study. Such evaluations in the future, in addition to pathologic investigations, may lead to a better understanding of the pathophysiology of rotavirus cerebellitis.