Clinically mild encephalitis/encephalopathy with a reversible splenial lesion

Patients and methods.

Possible encephalitis/encephalopathy patients with a reversible isolated lesion involving the central portion of the SCC on MRI were collected retrospectively by sending out a questionnaire to the members of the Annual Zao Conference on Pediatric Neurology and to some members of the Japanese Society of Pediatric Neurology and Japanese Society of Neuroradiology. We reviewed MR scans and charts of these patients, including information about symptoms, clinical diagnosis, medications, treatments, prognosis, results of CSF analysis, and EEG. The diagnosis of encephalitis has been defined as acute onset of brain dysfunction such as seizures and disorders of consciousness with inflammatory changes such as pleocytosis of CSF. When there was no evidence of inflammatory change, we used the term “encephalopathy.” A reversible isolated SCC lesion was defined, for the purposes of this study, as a lesion involving the central portion of the SCC without any accompanying lesions on the initial MRI, which disappeared on the follow-up study.

Results.

We identified 15 encephalitis/encephalopathy patients with a reversible isolated SCC lesion among the 22 patients whose clinical records and MRI examinations were referred for this study. Three patients were excluded because they had lesions in the white matter or cerebellum as well as in the SCC. Three were excluded because they had no follow-up MRI study. One patient, who was taking oral antiepileptic drugs, had another potential cause for the splenial lesions and was eliminated as well. The clinical records and radiologic examinations of the remaining 15 patients were reviewed by the authors and are the basis of this study. The findings of the 15 patients are summarized in tables 1 and 2⇓.

The 15 patients (8 male and 7 female; age 2 to 59 years) developed normally until the onset of neurologic symptoms. Fever preceded neurologic symptoms in all 15 patients. Directly causative agents were identified by rapid antigen-detection assay, PCR, positive IgM, or longitudinally increased IgG in 5 of 15 patients. The pathogens included influenza A, mumps virus (two patients), varicella-zoster virus, and adenovirus. The onset of neurologic symptoms ranged from day 1 to 7 of the illness. Eight of the 15 patients had seizures. Other neurologic symptoms included disorders of consciousness (12 patients), vertigo (2 patients), motor deterioration, blindness, ataxia, tremor, and hallucinations. No patient needed mechanical ventilation. Three patients had received antiepileptic drugs (phenobarbital for two patients and phenytoin for another) at the time of MR studies. Analysis of CSF revealed pleocytosis in 6 of 13 examined patients but normal glucose and protein levels. EEG showed slow basic activity characteristic of encephalitis/encephalopathy in 12 of 13 examined patients. Though their treatments were variable (e.g., corticosteroids for five patients and IV IgG administration for three patients), all 15 patients clinically recovered completely within 1 month (8 patients within 1 week after the onset of neurologic symptoms) without sequel.

In 14 of the 15 patients, the initial MR study was performed within 4 days of the onset of neurologic symptoms. On axial images, the lesion was ovoid and in the center of the SCC in six patients (Patients 3, 4, 7, 8, 13, 14) (figure 1) and extended irregularly into the lateral portion of SCC in the other eight patients (figure 2). In Patient 12, a lesion in the central portion of the SCC was detected on sagittal T1- and T2-weighted images (axial T2-weighted image being unavailable). There was no obvious correlation between the shape of SCC lesion and the scan date, neurologic symptoms (presence or absence of seizures, date of complete recovery), or laboratory findings. The SCC lesion was, compared with the surrounding splenium, homogeneously hyperintense on T2-weighted images and isointense to slightly hypointense on T1-weighted images. Homogeneously reduced diffusion (hyperintensity on diffusion-weighted images and low apparent diffusion coefficient [ADC] values) was seen in all seven patients examined by diffusion-weighted imaging. There was no enhancement of the SCC lesion after gadolinium administration in any of the five patients who received contrast material. MRI of Patient 7 showed normal findings at 2 days after the onset of neurologic symptoms but revealed an SCC lesion at 4 days (see figure 1). The SCC abnormalities of all 15 patients completely disappeared at follow-up MRI studies performed 3 days to 2 months after the first abnormal study (within 1 week in 8 of 15 patients). In at least six patients (Patients 1, 5, 8, 9, 13, 15), the SCC lesion disappeared before clinical recovery was complete.

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Figure 1. Case 7. MRI on day 5, showing an ovoid lesion in the mid-splenium of the corpus callosum on diffusion-weighted imaging (B) and apparent diffusion coefficient (ADC) map (C) with decreased ADC value and no enhancement on gadolinium-enhanced T1-weighted imaging (A). Follow-up study on day 20 showed no lesion on any sequence (D).

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Figure 2. Case 15. MRI on day 4, showing a lesion extending into the lateral portion of the splenium of the corpus callosum (SCC) on T2- and T1-weighted imaging (A, B) and diffusion-weighted imaging (C). The lesion in the SCC disappeared on all sequences on day 8 (D, E).

Discussion.

Despite different causative agents, the clinical features of the 15 patients with encephalitis/encephalopathy and an isolated reversible SCC lesion were nearly identical, consisting of relatively mild CNS manifestations and complete recovery within 1 month. Thus, we propose that this may represent a new clinicoradiologic syndrome with an excellent prognosis and that MRI is a key study in establishing the diagnosis.

As in any patient with encephalitis/encephalopathy and lesions in the white matter, acute disseminated encephalomyelitis (ADEM) should be considered in the differential diagnosis.9 ADEM is monophasic postinfectious or postvaccinial inflammatory disorder, which is pathologically characterized by an acute perivenous lymphocytic infiltration with confluent demyelination. ADEM presents with seizures, focal neurologic signs, and alteration of consciousness, which develop days to weeks after the onset of presumed viral infections. CSF analysis reveals mild pleocytosis. Corticosteroids are accepted as useful treatment for ADEM, and recovery occurs within weeks.9 In contrast, the patients in this report developed neurologic symptoms quickly after the onset of illness (day 1 to 7) and also recovered completely within 1 month (mostly within 1 week after neurologic manifestations). Directly causative agents were identified in 5 of the 15 patients, suggesting primarily infectious encephalitis/encephalopathy rather than postinfectious. Corticosteroids were not necessary in most of the patients.

MRI in ADEM usually shows multiple foci of T1 and T2 prolongation, typically bilateral and asymmetric, in the subcortical white matter.10 Although the corpus callosum may be involved in ADEM, these patients nearly always have asymmetric callosal lesions in addition to other white matter lesions.11 After contrast agent infusion, the lesions in ADEM will show variable enhancement depending on their acuity. The lesions usually evolve over weeks to months and disappear only after several months, as the imaging evolution of the disease lags behind the clinical evolution. Indeed, the white matter damage may be permanent. The SCC lesions in the patients in this report had no contrast enhancement, and most disappeared completely within 1 week before clinical recovery was complete. The splenial lesions in these patients, therefore, are clinically and radiologically unlikely to represent a manifestation of ADEM.

Other possible differential diagnoses of splenial lesions include ischemia, posterior reversible encephalopathy syndrome, diffuse axonal injury, multiple sclerosis, hydrocephalus, Marchiafava–Bignami disease, lymphoma, and extrapontine myelinolysis.11 These are excluded clinically and radiologically in our patients.

One of the most interesting MRI findings in the patients in this study is that the SCC lesion has reversible, homogeneous reduced diffusion. The reversibility suggests that this finding is distinct from cytotoxic edema seen in cellular energy failure, such as acute infarction, which is nearly always irreversible. We postulate two possible mechanisms for the transiently decreased ADC of the lesions: intramyelinic edema and inflammatory infiltrate. Recently, high signal on diffusion-weighted imaging and decreased ADC values of white matter lesions have been observed in patients with Canavan disease, metachromatic leukodystrophy, and phenylketonuria.12,13⇓ A possible explanation proposed for this phenomenon is intramyelinic edema due to separation of myelin layers.12,13⇓ Interestingly, periventricular T2 abnormalities in phenylketonuria have been shown to be reversible with improvement in metabolic control.13–15⇓⇓ Therefore, the transiently decreased ADC values of the SCC lesion suggest that reversible intramyelinic edema may be the operant factor. A diffusion-weighted imaging study of multiple sclerosis found decreased ADC values in 4 of 28 homogeneously enhancing multiple sclerosis lesions.16 The authors postulated that the influx of inflammatory cells and macromolecules, combined with related cytotoxic edema, might have caused decreased ADC. Thus, the decreased ADC in the splenium may be a result of inflammation. With either cause, intramyelinic edema or inflammation, ADC may return to normal if the cause resolves quickly.

Why is the splenium involved as an isolated site? Although the splenium is the only region where the vertebrobasilar system supplies blood to the corpus callosum (which is primarily supplied by the carotid system),17 the reversibility of the lesions and the absence of any other lesions in vascular distributions make it unlikely that the splenial abnormalities are the result of ischemia. Another possible pathogenesis of the splenial lesions might be related to the presence of elevated inflammatory cytokines, such as interleukin-6,18,19⇓ although the exact mechanism by which the splenium would be involved as an isolated site due to any of the causes is difficult to understand. One might propose that the viral antigens or receptors on the antibodies induced by the antigens have specific affinities for receptors on splenial axons or the myelin sheaths surrounding them, but this is pure speculation.

Recently, an ovoid-shaped reversible splenial lesion has been reported in approximately 20 patients with epilepsy receiving antiepileptic drugs.1–5⇓⇓⇓⇓ Homogeneously reduced diffusion was reported in some examined patients.3–5⇓⇓ Toxic levels or rapid withdrawal of antiepileptic drugs or frequent seizures are presumed to be the cause of the lesion in these patients. The imaging features of the lesions in these epileptic patients are very similar to those in our encephalitis/encephalopathy patients; however, the shape of the lesion is somewhat different. In reported patients and one patient referred to us who was receiving antiepileptic drugs, the SCC lesions were ovoid or round in shape1–5⇓⇓⇓⇓ except for one patient.3 In contrast, the lesions were ovoid in six of our patients and irregularly extended into the lateral portion of the SCC in eight patients with encephalitis/encephalopathy. Among 15 patients with encephalitis/encephalopathy in this study, 7 patients had no seizures, and only 3 of the 8 patients with seizures received antiepileptic drugs. We conclude, therefore, that the lesions in our patients with encephalitis/encephalopathy did not result from seizures or antiepileptic drugs per se, though these two conditions may share the same unknown pathogenesis or have same spectrum.

It is unclear how common this finding might be in patients with mild encephalitis/encephalopathy. Because of the relatively high incidence of influenza-associated encephalitis/encephalopathy in Japan,18,19⇓ we have had the opportunity to obtain brain MRI in 15 children with relatively mild CNS symptoms; however, MRI studies are not commonly obtained in such patients, making it difficult to know how often SCC lesions might be seen in this patient population.