Reply
=====

* James L. Fleckenstein

In our August 1999 article in the *AJNR,* we reported that in two of seven patients with St. Louis encephalitis (SLE), T2-weighted images showed hyperintensity in the substantia nigra (1). In one of the patients, the hyperintensity was asymmetrical. In both patients, the infusion of contrast material did not cause abnormal enhancement. There were no other MR alterations in these patients. We searched the literature to find instances of such selective involvement of the substantia nigra and could find none. Our bibliography included four papers on Japanese encephalitis (JE), three by Shoji et al and one by Misra et al. Although there was evidence of involvement of the substantia nigra in an occasional patient in these series, it always occurred in the setting of diffuse, widespread, radiologic evidence of injury. A 1997 article presenting seven cases of JE by Misra et al described “nonspecific signal change” in two cases of midbrain involvement, and an image of a third case exemplified the midbrain abnormality. One midbrain lesion was hemorrhagic, as were thalamic lesions in five of the seven cases (2).

That JE can cause selective predominant involvement of the substantia nigra, however, is evidenced in an article that appeared in *Neurology* in November, 1999 (3). Investigators in Lucknow, India studied 52 patients with JE over a 6-year period, and found five patients with predominant involvement of the substantia nigra. They wrote that “predominant involvement of the substantia nigra in JE has not been previously reported.” Because Kalita and Misra are from the same institute in Lucknow, we do not know whether the image in their letter-to-the-editor comes from one of these cases, from their similar article in press (4), or if it represents a different patient. The clinical manifestations of illness in these five patients closely resemble those of the two patients reported in our article, although overall it is generally difficult to compare patients with these diseases because of their variable features.

An underlying assumption in the letter by Kalita and Misra is that because SLE is caused by an arbovirus, and particularly a flavivirus, it should cause disease closely resembling JE. Their implication is that if more severely ill patients with SLE had been studied, the same radiologic findings should have been seen as have been reported in JE. In view of this implication, it may be worth reviewing the differences between SLE and JE. The patients studied in Dallas in 1995 were similar to those seen in two other Dallas SLE epidemics in 1966 and 1976. The overall fatality rate in these three epidemics was 10%; in JE, it is approximately 25%. In 1966, of 49 patients followed prospectively, 67% had tremors; in JE, the percent is less (5). Neurologic sequelae in survivors of SLE are infrequent, whereas in JE they are common. Thalamic hemorrhages are never seen in SLE; they are common in JE. In SLE there is diffuse encephalitis, but a paucity of findings radiologically. The radiologic manifestations in the two patients we reported were seen only in the substantia nigra. We reported another case in which the CT scan showed two large areas of decreased attenuation in the brain stem, which was cited in our *AJNR* article (1). The critical study is that of Reyes et al, in which they measured quantitatively the pathologic changes in the brains of patients with SLE, and which duplicated earlier qualitative studies (6–8). They found that, excluding midbrain measurements, the substantia nigra had at least eight times the quantity of brain involved than did the next most severely affected segment of the CNS (spinal gray matter).

We have also become aware of a case report of a 33-year-old woman from Singapore with encephalitis lethargica, who had bilateral substantia nigra changes on MR images. The authors made the diagnosis on clinical grounds, reported the case in *Neurology* in November 1999, and stated that this is “the first case of a patient showing bilateral substantia nigra changes on MRI” (9).

Since tremors can be seen in adults with Western equine encephalitis, we cannot exclude involvement of the substantia nigra in that disease. In view of the recent report in *Neurology* concerning JE, the letter by Kalita and Misra, and the rarity of encephalitis lethargica, our concluding statement should be changed to: Severely ill and tremulous patients presenting with encephalitis in North American cities, who show isolated T2-weighted hyperintensity of the substantia nigra, should be examined for SLE.

It is important to note that there are missing references in the reference list of our original article (1), and that some of the references are not numbered correctly. Revisions were made in order to bring the total number of references down to eight, but were not incorporated into the final article. Reference 5 (of this reply) was included in the text citations of our original article, but was not included in the reference list. References 3–6 in the reference list of our article were cited as 5–8 in the text. References cited as 10–12 in the text were numbered 7 and 8 in the reference list (one reference was deleted), and correspond to references 6, 7, and 8 of this reply.

## References

1.  Cerna F, Mehrad B, Luby IP, Bums D, Fleckenstein JL. **St. Louis encephalitis and the substantia nigra: MR imaging evaluation.** AJNR Am J Neuroradiol 1999;20:1281-1283
    
    [Abstract/FREE Full Text](http://www.ajnr.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiYWpuciI7czo1OiJyZXNpZCI7czo5OiIyMC83LzEyODEiO3M6NDoiYXRvbSI7czoyMToiL2FqbnIvMjEvMTAvMTk3OS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

2.  Kumar S, Msra UK, Kalita J, Salwani V, Gupta RK, Gujral R. **MRI in Japanese encephalitis.** Neuroradiology 1997;39:180-184
    
    [CrossRef](http://www.ajnr.org/lookup/external-ref?access_num=10.1007/s002340050388&link_type=DOI) 
    
    [PubMed](http://www.ajnr.org/lookup/external-ref?access_num=9106289&link_type=MED&atom=%2Fajnr%2F21%2F10%2F1979.atom) 
    
    [Web of Science](http://www.ajnr.org/lookup/external-ref?access_num=A1997WR87500005&link_type=ISI) 

3.  Pradhan S, Pandey N, Shashank S, Gupta RK, Mathur A. **Parkinsonism due to predominant involvement of substantia nigra in Japanese encephalitis.** Neurology 1999;53:1781-1786
    
    [Abstract/FREE Full Text](http://www.ajnr.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6OToibmV1cm9sb2d5IjtzOjU6InJlc2lkIjtzOjk6IjUzLzgvMTc4MSI7czo0OiJhdG9tIjtzOjIxOiIvYWpuci8yMS8xMC8xOTc5LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

4.  Kalita J, Misra UK. **Comparison of CT scan and MRI findings in the diagnosis of Japanese encephalitis.** J Neurol Sci 1999; (in press) 
    
    

5.  Southern P Jr. Smith JW, Luby JP, Barnett JA, Sanford JP. **Clinical and laboratory features of epidemic St. Louis encephalitis.** Ann Int Med 1969;71:681-689
    
    

6.  Reyes MG, Gardner JJ, Poland JD, Monath TP. **St. Louis encephalitis. Quantitative histologic and immunofluorescent studies.** Arch Neurol 1981;38:329-334
    
    [CrossRef](http://www.ajnr.org/lookup/external-ref?access_num=10.1001/archneur.1981.00510060031002&link_type=DOI) 
    
    [PubMed](http://www.ajnr.org/lookup/external-ref?access_num=7016088&link_type=MED&atom=%2Fajnr%2F21%2F10%2F1979.atom) 
    
    [Web of Science](http://www.ajnr.org/lookup/external-ref?access_num=A1981LT42000001&link_type=ISI) 

7.  Weil A. **Histopathology of the central nervous system in epidemic encephalitis (St. Louis epidemic).** Arch Neurol Psychiatry 1934;31:1139-1152
    
    [CrossRef](http://www.ajnr.org/lookup/external-ref?access_num=10.1001/archneurpsyc.1934.02250060025002&link_type=DOI) 
    
    [Web of Science](http://www.ajnr.org/lookup/external-ref?access_num=000201612500002&link_type=ISI) 

8.  Suzuki M, Phillips CA. **St. Louis encephalitis: a histopathologic study of fatal cases from the Houston epidemic in 1964.** Arch Path 1966;81:47-54
    
    [PubMed](http://www.ajnr.org/lookup/external-ref?access_num=5900447&link_type=MED&atom=%2Fajnr%2F21%2F10%2F1979.atom) 
    
    [Web of Science](http://www.ajnr.org/lookup/external-ref?access_num=A19667159000006&link_type=ISI) 

9.  Kun LN, Yian SY, Haur LS, Tjia H. **Bilateral substantia nigra changes on NM in a patient with encephalitis lethargica.** Neurology 1999;53:1860-1862
    
    [Abstract/FREE Full Text](http://www.ajnr.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6OToibmV1cm9sb2d5IjtzOjU6InJlc2lkIjtzOjk6IjUzLzgvMTg2MCI7czo0OiJhdG9tIjtzOjIxOiIvYWpuci8yMS8xMC8xOTc5LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

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