Atypical herpes Simplex encephalitis: clinical, virologic, and neuropathologic evaluation
Article abstract-An atypical form of herpes simplex encephalitis produced by HSV-1 documented in the present article demonstrates that (1) prominent EEG abnormality may correlate with subtle increase in signal intensity on MRI; (2) the disease may start with prominent involvement of the cingulate gyri; and (3) viral infection of the brainstem may cause early onset of severe neurologic dysfunction and coma.
NEUROLOGY 1992;42:1~09-1~12
John W. Rose, MD; William G. Stroop, PhD; Fumisuke Matsuo, MD; and Jenny Henkel, BS
Herpes simplex encephalitis (HSE) is the most common cause of sporadic encephalitis i n the United States.' The clinical presentation frequently includes a syndrome of rapid onset characterized by fever, headache, seizures with focal neurologic signs, and impaired consciousness.2A recent report demonstrates the clinical use of the MRI in the diagnosis of HSE.3MRI appears to be superior to CT, especially in the early course of the encephalitis. The diagnostic accuracy of MRI in HSE has yet to be compared with that of the EEG or with polymerase chain reaction (PCR) of CSF.4Interestingly, EEG is more sensitive for early diagnosis than nuclear brain scan or CT.5 We describe HSE i n which t h e initial MRI revealed only subtle abnormalities. I n contrast, EEG was strikingly abnormal at the onset of the disease. Neuropathologic examination revealed severe inflammation i n t h e cingulate gyrus. Significant inflammation and viral nucleic acid in the brainstem correlated with early clinical signs of brainstem dysfunction. Case report. A 47-year-old woman in good health experienced malaise and urinary frequency. The following day the patient was found a t home having intermittent seizures. These seizures were characterized as generalized toniclclonic associated with intermittent head turning to the right. Intervention with anticonvulsants reduced the seizures to focal motor seizures involving the right lower extremity. A contrast-enhanced CT was normal. CSF revealed 356 RBC/mm3,but no WBC/mm3.The
patient remained comatose and required intubation. Treatment with acyclovir was initiated. The next day, the patient was comatose with no spontaneous respirations. Corneal reflexes, oculocephalic reflexes, and response to caloric stimulation were absent. Pupils were midposition and poorly responsive to light. Clonic jerks of the right lower extremity continued. There was no response to deep pain. The following day the examination revealed 2-mm slightly reactive pupils, a present left corneal reflex, and decerebration to deep pain. EEG was abnormal, demonstrating continuous periodic 0.5 to Usec discharges in the left parasagittal region. Acyclovir therapy was discontinued after 6 days of treatment. The patient remained stuporous and expired from pneumonia and gastrointestinal hemorrhage. Magnetic resonance i m a g i n g . Cranial MRI was obtained 72 hours after onset of seizures. TI sagittal and two echo T,-weighted axial and coronal images were obtained and were initially considered normal (figure 1A). Follow-up MRI obtained 6 days later revealed increased signal intensity in cingulate gyri, the insular cortex, and, to a lesser extent, the temporal lobes on the T,-weighted images (figure 1B). Pathology. Examination of the brain revealed petechiae with softening in the left superior frontal and left cingulate gyri and left insular cortex. Coronal sections demonstrated obscuration of the graylwhite junction in these regions and the right cingulate gyrus. There was no evidence of uncal herniation. Microscopic examination of involved regions showed mononuclear inflammation with perivascular cuffs and focal infiltrates of inflammatory cells. Glial nodules, neuronophagia, and intense lymphocytic infiltrates with regions of necrosis and macrophages were observed. Sections of midbrain, pons, and medulla
Figure 1. (A) MRI 72 hours after onset of seizures and coma. Coronal image (TR 2,700, TE 201, which was initially interpreted as normal, demonstrates increased signal intensity in the cingulate gyri and insular cortex. (B) MRI 6 days later. Coronal image (TR 2,700, TE 20) demonstrates prominent increase in signal intensity in the cingulate gyri and the insular cortex.
A
B September 1992 NEUROLOGY 42 1809
Figure 2. I n situ hybridization was used to localize HSV-1 nucleic acids within nervous system tissues obtained at autopsy. HSV-1 nucleic acids were found in the cingulate gyrus, pons, medulla, and trigeminal ganglion. (A) HSV-1 nucleic acids in a neuron (arrow) adjacent to the highly necrotic left cingulate gyrus (H-E, X470 before 51% reduction). In. the opposite corner of this field, infiltrating lymphocytes can be seen adjacent to a blood vessel. (€3) Localization of HSV-1 nucleic acids in cells (arrows) of the pons (H-E, X336 before 51% reduction), (C) Within the medulla, the majority of positive cells were Located in the trigeminal nerve tract, although positive cells were also located in the deeper parenchyma adjacent to small white matter tracts (H-E, X200 before 5196 reduction).
demonstrated glial nodules and perivascular infiltrates. Intranuclear or intracytoplasmic inclusions were not observed in sections of cortex or brainstem. Virus isolation. Cultures were established from the cingulate gyrus, temporal lobe, frontal cortex, olfactory bulb, and CSF. On day 8 of culture, cytopathic effect (CPE) characteristic of HSV was seen in cultures of the cingulate gyrus, temporal lobe, and frontal cortex, which were co-cultivated with VERO cells. Filtrates of positive cultures passed onto fresh VERO cells produced CPE within 24 hours. CPE was observed in the culture inoculated with CSF (day 15). Intranuclear viral particles characteristic of herpesviruses with an average diameter of 95 nm (range, 77 to 103 nm) were observed in the nuclei of these cells by electron microscopy. Virus was not isolated from the eyes, nostrils, or vagina. Restriction endonuclease digestion analysis. DNAs of HSV strains of a specific type (eg, HSV-1) digested with a given restriction endonuclease produce DNA fragments of similar size.6 In contrast, considerable differences in the pattern of the DNA fragments are produced by cleavage with a given enzyme between strains of HSV-1 and HSV-2.6 We utilized restriction endonuclease polymorphisms between HSV-1 and HSV-2 to unambiguously classify the virus isolated from the patient because the virus could not be classified with HSV-specific monoclonal antibodies due to cross-reactivity. The electrophoretic profile of EcoRI a n d BamHI restriction digests of the patient’s viral DNA identify a 1810 NEUROLOGY 42 September 1992
type 1 HSV strain (figure 3A). However, not all of the patient’s viral DNA fragments produced by cleavage with either enzyme migrated identically with their counterparts in the reference HSV strain +GC (figure 3). I n situ hybridization. At autopsy, blocks of left cingulate gyrus and temporal lobe were fixed in PLP fixative,I and coronal slices of brainstem were prepared and fixed in formalin. All tissue blocks were embedded in paraffin, cut into three to five 5-pm sections at each of two to three levels separated by 60 to 80 pm, and pretreated for t h e d e t e c t i o n of HSV-1 RNA a n d DNA by i n s i t u hybridizati0n.I Sections were hybridized, washed, developed, and stained as previously described.I Viral nucleic acids were present in the cingulate gyrus, pons, medulla, and trigeminal ganglion by in situ hybridization (figure 2).
Discussion. The clinical presentation and course of this p a t i e n t raise issues concerning the diagnosis and pathogenesis of HSE. The localization of the encephalitis was atypical in that the most severe a b n o r m a l i t i e s w e r e observed in the left cingulate gyrus. The EEGs d e m o n s t r a t e d periodic discharges l o c a l i z e d t o the left a n t e r i o r parasagittal area. Subtle increased signal i n t e n s i t y i n the cingulate gyri o n the initial MRI concurs w i t h a parasagittal localization. The appearance of the initial MRI m a y have been less d r a m a t i c due t o early institution of
Figure 3. Restriction endonuclease digestion analysis of the DNA isolated from the patient’s virus. (A)Purified DNA from the +GC reference strain of HSV-1 (lanes 1 and 3) and from the patient’s virus (lanes 2 and 4) were digested with restriction enzymes EcoRI (lanes 1 and 2) and BamHI (lanes 3 and 4). HindIII digested A D N A was used to provide kb-size markers (not shown). Only DNA fragments between 23 and 1.2 kb are shown. Although the pattern of fragments in the patient’s virus is consistent with its identification as a strain of HSV-1, a few differences are apparent between the patient’s DNA and the +GC reference strain. (B) Diagrams of the EcoRI and BamHI restriction sites in the genomes of the reference strain and the patient’s virus with reference to the HSV-1 genome. The structure of the genome is shown with the unique long (U,) and unique short (Us) regions of the D N A bounded by the reiterated flanking sequences (TR,, TR,, IR,, IR,) at the ends of the U, and Ussegments. Each map unit equals approximately 15.2 Kb. The fragments produced by EcoRI and BamHI in +GC and the patient’s virus are indicated above the line and below the line, respectively, for each enzyme. The EcoRI and BamHI letter designations correspond to the published maps of the HSV-1 F strain.6 The stippled boxes at the bottom of the figure indicate where the major differences between the reference strain and the patient’s virus are located. I n particular, patient virus BamHI DNA fragments e, c, a, a‘ (located at EcoRI boundaries d l j and d, g), 1, d (located at EcoRI boundary ile), x, y, and z (located with EcoRI fragments K l and K2) were of different kb than in the HSV-1 reference strain (figure 3B).
antiviral therapy. More prominent abnormalities were demonstrated by follow-up MRI performed 9 days after the onset of seizures. Findings at autopsy further demonstrated the predominance of the pathologic process in the left cingulate and superior frontal gyri in this patient. Prominent involvement of the cingulate gyrus relative to the temporal lobe is unusual in HSE. Viral infection of the brainstem was suspected from the clinical course and confirmed by histopathology and in situ hybridization. Inflammatory response in the brainstem of patients with HSE was previously described post mortem, but was not correlated with the clinical status of the patient or the presence of viral nucleic a ~ i d .The ~ , ~dramatic early loss of brainstem functions in the present patient appears to be
due to direct involvement of the brainstem with viral infection and associated inflammation. The unusual location of the most intense lesions obligated us to conclusively determine the type of HSV. Restriction endonuclease analysis was performed t o determine that the infection was HSV type 1. The minor differences noted in the mobility of some of the DNA fragments in the patient’s virus relative to the HSV-1 reference strain are consistent with the previously described differences among HSV strains of a given type.’* The decision to perform a brain biopsy may have to rest on clinical presentation in conjunction with EEG findings rather than the appearance of the MRI or a n inflammatory response in the CSF. Findings in the present case would suggest that September 1992 NEUROLOGY 42 1811
brain biopsy of the temporal lobe might have been less productive than biopsy of the superior frontal or cingulate gyri. The relative merits of MRI, gadolinium-enhanced MRI, and EEG have yet to be evaluated. The PCR of CSF in early untreated HSE4 has significant diagnostic potential and may replace brain biopsy for t h e vast majority of patients in the very near future.
Acknowledgments We wish to thank Douglas C. Schaefer, Emma-Jean Battles, Alex Kogan, and M. Careene Banks for expert technical assistance, and Drs. Jennette J. Townsend and J. Richard Baringer for their critical review of the manuscript. From the Neurovirology Research Laboratory (Dr. Rose), Veterans Affairs Medical Center, Salt Lake City, UT; the Department of Neurology (Drs. Rose and Matsuo), University of Utah Medical School, Salt Lake City, UT; the Ophthalmology Research Laboratory (Dr. Stroop), Veteran Affairs Medical C e n t e r , a n d D e p a r t m e n t s of Ophthalmology a n d Neurology, Baylor College of Medicine, Houston, TX;and the Division of Molecular Virology (Dr. Stroop and Ms. Henkel), Baylor College of Medicine, Houston, 'TX. Supported by the Medical Research Service of the Department of Veterans M a i m and Research Grant 1929-A-1from the National Multiple Sclerosis Society. W.G.S. i s supported i n p a r t by a J u l e s a n d Doris S t e i n Professorship awarded by Research to Prevent Blindness, Inc. Received November 6 , 1991. Accepted for publication i n final form February 11,1992. Address correspondence and reprint requests to Dr. John W. Rose, Neurovirology Research Laboratory (15 lB), VA Medical Center, 500 Foothill Drive, Salt Lake City, UT 84148.
1812 NEUROLOGY 42 September 1992
References 1. Whitley RJ, Soong S-J, Dolin R, Galasso GJ, Ch'ien LT, Alford CA, The Collaborative Study Group. Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis. N Engl J Med 1977;297:289-294. 2. Baringer JR, Stroop WG. Problems and promise in management of Herpes virus infections of t h e nervous system. Antiviral chemotherapy: new directions for clinical application and research. Amsterdam: Elsevier Science Publishing Co., Inc., 1986:270-273. 3. Schroth G, Gawehn J , Thron A, Vallbracht A, Voigt K. Early diagnosis of herpes simplex encephalitis by MRI. Neurology 1987;37:179-183. 4. Puchhammer-Stock1 E, Popow-Kraupp T, Heinz F, Mandl C, Kunz C. Establishment of PCR for the early diagnosis of herpes simplex encephalitis. J Med Virol 1990;32:7782. 5 . K a u f m a n DM, Zimmerman RD, Leeds NE. Computed tomography i n herpes simplex encephalitis. Neurology 1979;29:1392-1396. 6. Roizman B. The structure and isomerization of herpes simplex virus genomes. Cell 1979;16:481-494. 7. Stroop W, Rock D, Fraser N. Localization of herpes simplex i n the trigeminal and olfactory systems of the mouse central nervous system during acute and latent infections by in situ hybridization. Lab Invest 1984;51:27-38. 8. Lach B, Atack E . Disseminated hemorrhagic leukoencephalomyelitis with localized herpes simplex brainstem infection. Acta NeuroDathol (Berl) 1988:75:354-361. 9. Esiri MM. Herpes simplex encephalitis: a n immunohistological study of t h e distribution of viral antigen within the brain. J Neurol Sci 1982;54:209-226. 10. Hayward GS, Frenkel N, Roizman B. Anatomy of herpes simplex virus DNA: strain differences and heterogeneity in the locations of restriction endonuclease cleavage sites. Proc Natl Acad Sci USA 1975;72:1768-1772.
Atypical herpes simplex encephalitis: Clinical, virologic, and neuropathologic evaluation John W. Rose, William G. Stroop, Fumisuke Matsuo, et al. Neurology 1992;42;1809 DOI 10.1212/WNL.42.9.1809 This information is current as of September 1, 1992 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/42/9/1809.full.html
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This article has been cited by 3 HighWire-hosted articles: http://www.neurology.org/content/42/9/1809.full.html##otherarticl es
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1992 by AAN Enterprises, Inc.. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Article abstract-An atypical form of herpes simplex encephalitis produced by HSV-1 documented in the present article demonstrates that (1) prominent EEG abnormality may correlate with subtle increase in signal intensity on MRI; (2) the disease may start with prominent involvement of the cingulate gyri; and (3) viral infection of the brainstem may cause early onset of severe neurologic dysfunction and coma.
NEUROLOGY 1992;42:1~09-1~12
John W. Rose, MD; William G. Stroop, PhD; Fumisuke Matsuo, MD; and Jenny Henkel, BS
Herpes simplex encephalitis (HSE) is the most common cause of sporadic encephalitis i n the United States.' The clinical presentation frequently includes a syndrome of rapid onset characterized by fever, headache, seizures with focal neurologic signs, and impaired consciousness.2A recent report demonstrates the clinical use of the MRI in the diagnosis of HSE.3MRI appears to be superior to CT, especially in the early course of the encephalitis. The diagnostic accuracy of MRI in HSE has yet to be compared with that of the EEG or with polymerase chain reaction (PCR) of CSF.4Interestingly, EEG is more sensitive for early diagnosis than nuclear brain scan or CT.5 We describe HSE i n which t h e initial MRI revealed only subtle abnormalities. I n contrast, EEG was strikingly abnormal at the onset of the disease. Neuropathologic examination revealed severe inflammation i n t h e cingulate gyrus. Significant inflammation and viral nucleic acid in the brainstem correlated with early clinical signs of brainstem dysfunction. Case report. A 47-year-old woman in good health experienced malaise and urinary frequency. The following day the patient was found a t home having intermittent seizures. These seizures were characterized as generalized toniclclonic associated with intermittent head turning to the right. Intervention with anticonvulsants reduced the seizures to focal motor seizures involving the right lower extremity. A contrast-enhanced CT was normal. CSF revealed 356 RBC/mm3,but no WBC/mm3.The
patient remained comatose and required intubation. Treatment with acyclovir was initiated. The next day, the patient was comatose with no spontaneous respirations. Corneal reflexes, oculocephalic reflexes, and response to caloric stimulation were absent. Pupils were midposition and poorly responsive to light. Clonic jerks of the right lower extremity continued. There was no response to deep pain. The following day the examination revealed 2-mm slightly reactive pupils, a present left corneal reflex, and decerebration to deep pain. EEG was abnormal, demonstrating continuous periodic 0.5 to Usec discharges in the left parasagittal region. Acyclovir therapy was discontinued after 6 days of treatment. The patient remained stuporous and expired from pneumonia and gastrointestinal hemorrhage. Magnetic resonance i m a g i n g . Cranial MRI was obtained 72 hours after onset of seizures. TI sagittal and two echo T,-weighted axial and coronal images were obtained and were initially considered normal (figure 1A). Follow-up MRI obtained 6 days later revealed increased signal intensity in cingulate gyri, the insular cortex, and, to a lesser extent, the temporal lobes on the T,-weighted images (figure 1B). Pathology. Examination of the brain revealed petechiae with softening in the left superior frontal and left cingulate gyri and left insular cortex. Coronal sections demonstrated obscuration of the graylwhite junction in these regions and the right cingulate gyrus. There was no evidence of uncal herniation. Microscopic examination of involved regions showed mononuclear inflammation with perivascular cuffs and focal infiltrates of inflammatory cells. Glial nodules, neuronophagia, and intense lymphocytic infiltrates with regions of necrosis and macrophages were observed. Sections of midbrain, pons, and medulla
Figure 1. (A) MRI 72 hours after onset of seizures and coma. Coronal image (TR 2,700, TE 201, which was initially interpreted as normal, demonstrates increased signal intensity in the cingulate gyri and insular cortex. (B) MRI 6 days later. Coronal image (TR 2,700, TE 20) demonstrates prominent increase in signal intensity in the cingulate gyri and the insular cortex.
A
B September 1992 NEUROLOGY 42 1809
Figure 2. I n situ hybridization was used to localize HSV-1 nucleic acids within nervous system tissues obtained at autopsy. HSV-1 nucleic acids were found in the cingulate gyrus, pons, medulla, and trigeminal ganglion. (A) HSV-1 nucleic acids in a neuron (arrow) adjacent to the highly necrotic left cingulate gyrus (H-E, X470 before 51% reduction). In. the opposite corner of this field, infiltrating lymphocytes can be seen adjacent to a blood vessel. (€3) Localization of HSV-1 nucleic acids in cells (arrows) of the pons (H-E, X336 before 51% reduction), (C) Within the medulla, the majority of positive cells were Located in the trigeminal nerve tract, although positive cells were also located in the deeper parenchyma adjacent to small white matter tracts (H-E, X200 before 5196 reduction).
demonstrated glial nodules and perivascular infiltrates. Intranuclear or intracytoplasmic inclusions were not observed in sections of cortex or brainstem. Virus isolation. Cultures were established from the cingulate gyrus, temporal lobe, frontal cortex, olfactory bulb, and CSF. On day 8 of culture, cytopathic effect (CPE) characteristic of HSV was seen in cultures of the cingulate gyrus, temporal lobe, and frontal cortex, which were co-cultivated with VERO cells. Filtrates of positive cultures passed onto fresh VERO cells produced CPE within 24 hours. CPE was observed in the culture inoculated with CSF (day 15). Intranuclear viral particles characteristic of herpesviruses with an average diameter of 95 nm (range, 77 to 103 nm) were observed in the nuclei of these cells by electron microscopy. Virus was not isolated from the eyes, nostrils, or vagina. Restriction endonuclease digestion analysis. DNAs of HSV strains of a specific type (eg, HSV-1) digested with a given restriction endonuclease produce DNA fragments of similar size.6 In contrast, considerable differences in the pattern of the DNA fragments are produced by cleavage with a given enzyme between strains of HSV-1 and HSV-2.6 We utilized restriction endonuclease polymorphisms between HSV-1 and HSV-2 to unambiguously classify the virus isolated from the patient because the virus could not be classified with HSV-specific monoclonal antibodies due to cross-reactivity. The electrophoretic profile of EcoRI a n d BamHI restriction digests of the patient’s viral DNA identify a 1810 NEUROLOGY 42 September 1992
type 1 HSV strain (figure 3A). However, not all of the patient’s viral DNA fragments produced by cleavage with either enzyme migrated identically with their counterparts in the reference HSV strain +GC (figure 3). I n situ hybridization. At autopsy, blocks of left cingulate gyrus and temporal lobe were fixed in PLP fixative,I and coronal slices of brainstem were prepared and fixed in formalin. All tissue blocks were embedded in paraffin, cut into three to five 5-pm sections at each of two to three levels separated by 60 to 80 pm, and pretreated for t h e d e t e c t i o n of HSV-1 RNA a n d DNA by i n s i t u hybridizati0n.I Sections were hybridized, washed, developed, and stained as previously described.I Viral nucleic acids were present in the cingulate gyrus, pons, medulla, and trigeminal ganglion by in situ hybridization (figure 2).
Discussion. The clinical presentation and course of this p a t i e n t raise issues concerning the diagnosis and pathogenesis of HSE. The localization of the encephalitis was atypical in that the most severe a b n o r m a l i t i e s w e r e observed in the left cingulate gyrus. The EEGs d e m o n s t r a t e d periodic discharges l o c a l i z e d t o the left a n t e r i o r parasagittal area. Subtle increased signal i n t e n s i t y i n the cingulate gyri o n the initial MRI concurs w i t h a parasagittal localization. The appearance of the initial MRI m a y have been less d r a m a t i c due t o early institution of
Figure 3. Restriction endonuclease digestion analysis of the DNA isolated from the patient’s virus. (A)Purified DNA from the +GC reference strain of HSV-1 (lanes 1 and 3) and from the patient’s virus (lanes 2 and 4) were digested with restriction enzymes EcoRI (lanes 1 and 2) and BamHI (lanes 3 and 4). HindIII digested A D N A was used to provide kb-size markers (not shown). Only DNA fragments between 23 and 1.2 kb are shown. Although the pattern of fragments in the patient’s virus is consistent with its identification as a strain of HSV-1, a few differences are apparent between the patient’s DNA and the +GC reference strain. (B) Diagrams of the EcoRI and BamHI restriction sites in the genomes of the reference strain and the patient’s virus with reference to the HSV-1 genome. The structure of the genome is shown with the unique long (U,) and unique short (Us) regions of the D N A bounded by the reiterated flanking sequences (TR,, TR,, IR,, IR,) at the ends of the U, and Ussegments. Each map unit equals approximately 15.2 Kb. The fragments produced by EcoRI and BamHI in +GC and the patient’s virus are indicated above the line and below the line, respectively, for each enzyme. The EcoRI and BamHI letter designations correspond to the published maps of the HSV-1 F strain.6 The stippled boxes at the bottom of the figure indicate where the major differences between the reference strain and the patient’s virus are located. I n particular, patient virus BamHI DNA fragments e, c, a, a‘ (located at EcoRI boundaries d l j and d, g), 1, d (located at EcoRI boundary ile), x, y, and z (located with EcoRI fragments K l and K2) were of different kb than in the HSV-1 reference strain (figure 3B).
antiviral therapy. More prominent abnormalities were demonstrated by follow-up MRI performed 9 days after the onset of seizures. Findings at autopsy further demonstrated the predominance of the pathologic process in the left cingulate and superior frontal gyri in this patient. Prominent involvement of the cingulate gyrus relative to the temporal lobe is unusual in HSE. Viral infection of the brainstem was suspected from the clinical course and confirmed by histopathology and in situ hybridization. Inflammatory response in the brainstem of patients with HSE was previously described post mortem, but was not correlated with the clinical status of the patient or the presence of viral nucleic a ~ i d .The ~ , ~dramatic early loss of brainstem functions in the present patient appears to be
due to direct involvement of the brainstem with viral infection and associated inflammation. The unusual location of the most intense lesions obligated us to conclusively determine the type of HSV. Restriction endonuclease analysis was performed t o determine that the infection was HSV type 1. The minor differences noted in the mobility of some of the DNA fragments in the patient’s virus relative to the HSV-1 reference strain are consistent with the previously described differences among HSV strains of a given type.’* The decision to perform a brain biopsy may have to rest on clinical presentation in conjunction with EEG findings rather than the appearance of the MRI or a n inflammatory response in the CSF. Findings in the present case would suggest that September 1992 NEUROLOGY 42 1811
brain biopsy of the temporal lobe might have been less productive than biopsy of the superior frontal or cingulate gyri. The relative merits of MRI, gadolinium-enhanced MRI, and EEG have yet to be evaluated. The PCR of CSF in early untreated HSE4 has significant diagnostic potential and may replace brain biopsy for t h e vast majority of patients in the very near future.
Acknowledgments We wish to thank Douglas C. Schaefer, Emma-Jean Battles, Alex Kogan, and M. Careene Banks for expert technical assistance, and Drs. Jennette J. Townsend and J. Richard Baringer for their critical review of the manuscript. From the Neurovirology Research Laboratory (Dr. Rose), Veterans Affairs Medical Center, Salt Lake City, UT; the Department of Neurology (Drs. Rose and Matsuo), University of Utah Medical School, Salt Lake City, UT; the Ophthalmology Research Laboratory (Dr. Stroop), Veteran Affairs Medical C e n t e r , a n d D e p a r t m e n t s of Ophthalmology a n d Neurology, Baylor College of Medicine, Houston, TX;and the Division of Molecular Virology (Dr. Stroop and Ms. Henkel), Baylor College of Medicine, Houston, 'TX. Supported by the Medical Research Service of the Department of Veterans M a i m and Research Grant 1929-A-1from the National Multiple Sclerosis Society. W.G.S. i s supported i n p a r t by a J u l e s a n d Doris S t e i n Professorship awarded by Research to Prevent Blindness, Inc. Received November 6 , 1991. Accepted for publication i n final form February 11,1992. Address correspondence and reprint requests to Dr. John W. Rose, Neurovirology Research Laboratory (15 lB), VA Medical Center, 500 Foothill Drive, Salt Lake City, UT 84148.
1812 NEUROLOGY 42 September 1992
References 1. Whitley RJ, Soong S-J, Dolin R, Galasso GJ, Ch'ien LT, Alford CA, The Collaborative Study Group. Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis. N Engl J Med 1977;297:289-294. 2. Baringer JR, Stroop WG. Problems and promise in management of Herpes virus infections of t h e nervous system. Antiviral chemotherapy: new directions for clinical application and research. Amsterdam: Elsevier Science Publishing Co., Inc., 1986:270-273. 3. Schroth G, Gawehn J , Thron A, Vallbracht A, Voigt K. Early diagnosis of herpes simplex encephalitis by MRI. Neurology 1987;37:179-183. 4. Puchhammer-Stock1 E, Popow-Kraupp T, Heinz F, Mandl C, Kunz C. Establishment of PCR for the early diagnosis of herpes simplex encephalitis. J Med Virol 1990;32:7782. 5 . K a u f m a n DM, Zimmerman RD, Leeds NE. Computed tomography i n herpes simplex encephalitis. Neurology 1979;29:1392-1396. 6. Roizman B. The structure and isomerization of herpes simplex virus genomes. Cell 1979;16:481-494. 7. Stroop W, Rock D, Fraser N. Localization of herpes simplex i n the trigeminal and olfactory systems of the mouse central nervous system during acute and latent infections by in situ hybridization. Lab Invest 1984;51:27-38. 8. Lach B, Atack E . Disseminated hemorrhagic leukoencephalomyelitis with localized herpes simplex brainstem infection. Acta NeuroDathol (Berl) 1988:75:354-361. 9. Esiri MM. Herpes simplex encephalitis: a n immunohistological study of t h e distribution of viral antigen within the brain. J Neurol Sci 1982;54:209-226. 10. Hayward GS, Frenkel N, Roizman B. Anatomy of herpes simplex virus DNA: strain differences and heterogeneity in the locations of restriction endonuclease cleavage sites. Proc Natl Acad Sci USA 1975;72:1768-1772.
Atypical herpes simplex encephalitis: Clinical, virologic, and neuropathologic evaluation John W. Rose, William G. Stroop, Fumisuke Matsuo, et al. Neurology 1992;42;1809 DOI 10.1212/WNL.42.9.1809 This information is current as of September 1, 1992 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/42/9/1809.full.html
Citations
This article has been cited by 3 HighWire-hosted articles: http://www.neurology.org/content/42/9/1809.full.html##otherarticl es
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1992 by AAN Enterprises, Inc.. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
