Author Response: Rabies encephalitis presenting with new-onset refractory status epilepticus (NORSE)
Jonathan H.Smith, Neurologist, Mayo Clinic, Phoenix, AZ
Gerard J.Nuovo, Neurologist, Ohio State University, Columbus, OH
MauricioVillamar, Neurologist, Brigham and Women's Hospital, Boston, MA
Submitted September 05, 2018
We thank Drs. Jackson and Del Bigio for their comments on our case report.[1] The authors argue that there were insufficient data to support a diagnosis of rabies encephalitis, but do not offer an alternative, more cohesive explanation for the reported findings. The history of a fulminant and fatal course of new-onset refractory status epilepticus would be consistent, in our viewpoint, with what they feel does not qualify for a “rapid progressive neurologic deterioration.” It is certainly possible that the non-specific symptoms of personality change and declining academics in the preceding month were unrelated.
This case was diagnosed in 2003 in a patient from rural northeastern Kentucky who resided in an area where numerous caves are found. While no evidence of exposure to a rabid animal was confirmed, this is consistent with epidemiological data showing that, in the United States, up to 80% of indigenous cases of rabies are cryptic.[2]
The identified inclusions in our case were intracytoplasmic and highly consistent with Negri bodies. Drs. Jackson and Del Bigio correctly point out that inclusions resembling Negri bodies have been observed in other disorders.[3,4] However, none of the previously reported conditions associated with Negri-like bodies, such as developmental disorders and Reye syndrome, would account for the clinical presentation observed in this case.
With regards to the RT in situ PCR, it is important to stress that theinternalnegative and positive controls are built into every experiment and, indeed, every slide. This is in contrast to the external controls, which include the use of "irrelevant" primers (in place of the rabies primers, negative control) and omission of the DNase step (positive control) [5], which were done in this case.
By internal controls we mean the distribution of the signal among the different cell types as they relate to what is well-documented regarding rabies infection of the CNS. The signal for rabies RT in situ PCR was found in cells with the cytologic features of neurons. It was not found in cells with the cytologic features of endothelial cells, oligodendroglial cells, or astrocytes. Further, the cells with the intracytoplasmic inclusions had the cytologic features of neurons and it was these cells that showed a signal with RT in situ PCR for rabies. In sum, this is strong evidence for the specificity of the reaction.
Thus, in this sad and unusual case, the clinical, pathological, and molecular evaluation was most consistent with a diagnosis of rabies encephalitis.
1. Villamar MF, Smith JH, Wilson D, Smith VD. Rabies encephalitis presenting with new-onset refractory status epilepticus (NORSE). Neurol Clin Pract 2017;7:421-424.
2. Messenger SL, Smith JS, Rupprecht Ce. Emerging epidemiology of bat-associated cryptic cases of rabies in humans in the United States. Clin Infect Dis 2002;35:738-47.
3. Zherebitskiy V, Del Bigio MR. Eosinophilic intracytoplasmic inclusions in Purkinje neurons of children. Neuropathology 2009;29:9-12.
4. Derakhshan I. Is the Negri body specific for rabies? A light and electron microscopical study. Arch Neurol 1975;32:75-79.
5. Nuovo GJ, DeFaria DL, Chanona-Vilchi JG, Zhang Y. Molecular detection of rabies encephalitis and correlation with cytokine expression. Modern Pathology 2005;18:62-67.
We thank Drs. Jackson and Del Bigio for their comments on our case report.[1] The authors argue that there were insufficient data to support a diagnosis of rabies encephalitis, but do not offer an alternative, more cohesive explanation for the reported findings. The history of a fulminant and fatal course of new-onset refractory status epilepticus would be consistent, in our viewpoint, with what they feel does not qualify for a “rapid progressive neurologic deterioration.” It is certainly possible that the non-specific symptoms of personality change and declining academics in the preceding month were unrelated.
This case was diagnosed in 2003 in a patient from rural northeastern Kentucky who resided in an area where numerous caves are found. While no evidence of exposure to a rabid animal was confirmed, this is consistent with epidemiological data showing that, in the United States, up to 80% of indigenous cases of rabies are cryptic.[2]
The identified inclusions in our case were intracytoplasmic and highly consistent with Negri bodies. Drs. Jackson and Del Bigio correctly point out that inclusions resembling Negri bodies have been observed in other disorders.[3,4] However, none of the previously reported conditions associated with Negri-like bodies, such as developmental disorders and Reye syndrome, would account for the clinical presentation observed in this case.
With regards to the RT in situ PCR, it is important to stress that the internal negative and positive controls are built into every experiment and, indeed, every slide. This is in contrast to the external controls, which include the use of "irrelevant" primers (in place of the rabies primers, negative control) and omission of the DNase step (positive control) [5], which were done in this case.
By internal controls we mean the distribution of the signal among the different cell types as they relate to what is well-documented regarding rabies infection of the CNS. The signal for rabies RT in situ PCR was found in cells with the cytologic features of neurons. It was not found in cells with the cytologic features of endothelial cells, oligodendroglial cells, or astrocytes. Further, the cells with the intracytoplasmic inclusions had the cytologic features of neurons and it was these cells that showed a signal with RT in situ PCR for rabies. In sum, this is strong evidence for the specificity of the reaction.
Thus, in this sad and unusual case, the clinical, pathological, and molecular evaluation was most consistent with a diagnosis of rabies encephalitis.
1. Villamar MF, Smith JH, Wilson D, Smith VD. Rabies encephalitis presenting with new-onset refractory status epilepticus (NORSE). Neurol Clin Pract 2017;7:421-424.
2. Messenger SL, Smith JS, Rupprecht Ce. Emerging epidemiology of bat-associated cryptic cases of rabies in humans in the United States. Clin Infect Dis 2002;35:738-47.
3. Zherebitskiy V, Del Bigio MR. Eosinophilic intracytoplasmic inclusions in Purkinje neurons of children. Neuropathology 2009;29:9-12.
4. Derakhshan I. Is the Negri body specific for rabies? A light and electron microscopical study. Arch Neurol 1975;32:75-79.
5. Nuovo GJ, DeFaria DL, Chanona-Vilchi JG, Zhang Y. Molecular detection of rabies encephalitis and correlation with cytokine expression. Modern Pathology 2005;18:62-67.
For disclosures, please contact the editorial office at ncpjournal@neurology.org.