Medical Hypotheses Melficrrl ffyporbeses (1990) 33, 177 - 179 ‘6 Lon@nan Group UK Ltd 1990
Nonfulminant Herpes Simplex Encephalitis Cause for Mesial Temporal Sclerosis M. SCHLITT,
A.P. BUCHER, E.A. QUINDLEN,
R. JENNINGS
Departments of Neurosurgery and Pathology, Room 714 Mastin Medical Center, 245 1 Fillingim Street, Mobile, AL 366 17, USA
as a
and F.O. BASTIAN
Building,
University
of South
Alabama
Abstract - Although mesial temporal sclerosis has been recognized for more than 100 years, its etiology remains unknown. It is proposed that a common infectious agent, herpes simplex virus type-l, may cause this disorder by means of a nonfulminant infection of mesial temporal lobe structures, which is resolved by the immune system and becomes gliotic in the course of healing by the central nervous system. Brain sections from a long-term experiment in a model of herpes simplex encephalitis reveal such a scar, which shows a high concentration of glial fibrillary acidic protein, without any evidence of residual herpes antigen, by immunocytochemistry.
Introduction
Complex partial seizures are commonly encountered in clinical practice and make up approximately 25% or more of seizure disorders in adults (1). Mesial temporal sclerosis (MTS) is present in as many as 65% of individuals with complex partial seizures (2). The pathologic definition of MTS is controversial (3, 4), but is dependent on finding, at least, an increase in glial cells in the cortex overlying the hippocampal structures. Neuronal loss with gliosis in areas CAl, CA4 and the dentate gyrus of the hippocampus is pathognomonic and frequently, more widespread damage can be found in nearby cortex. Theories regarding the etiology of this disorder include hypoxia due to recurrent seizures (5), birth trauma (4,6), vascular spasm (7), brain edema (8), infection (4, 9, lo), and poorly understood genetic disease (11). Recent experimental models have de-
fined groups of cells which die after prolonged stimulation of the perforant pathway and whose death lead to experimental temporal lobe epilepsy (11). The localization of MTS, however, parallels the early stages of herpes simplex encephalitis (HSE); in the normal adult host, the viral brain infection is thought to begin in the medial aspects of the temporal lobe (12). Because of the high frequency of antibody against type-l herpes simplex virus (HSV-1) (13) and the relative infrequency of HSE, the possibility of nonfulminant infection of the brain with HSV-1 must be considered. It is therefore hypothesized that some patients with partial seizures originating from a temporal focus have suffered subclinical infections of mesial temporal regions with HSV- 1. The mesia1 temporal sclerosis resulting from the healing of the viral infection would be the pathologic marker of ancient infection as well as the seizure focus. This hypothesis was tested recently when one of a
177
178
Fig. 1 Gross brain from long term survivor showing gliosis of the most medial aspect of the left pyriform cortex.
group of long-term survivors of an experimental model of HSE was sacrificed, eleven months after inoculation with HSV- 1. Methods Five adult rabbits were inoculated in the left ofactory bulb in March 1986 with a relatively avirulent HSV-1 designated ‘35’ at this institution (from the laboratory of Drs. John Oakes and Robert Lausch). Two of these animals succumbed due to the infection; two members of the group were serially euthanized after two weeks and the brains studied microscopically for evidence of infection as a part of a previous study of experimental HSE (unpublished observations). As other members of the group showed evidence only for mild infection, it was decided to allow the last member of the group a prolonged post-operative survival. The rabbit was euthanized in February 1987, after institution of deep anesthesia. The brain was perfused with ten percent formalin and removed. After further formalin fixation for three days the region containing the pyriform cortices was cut, imbedded in paraffin, and sectioned serially. Brain sections were stained with hematoxylin and eosin, and with a peroxidase-antiperoxidase method for HSV-1 (14). Adjacent serial sections were immunostained for glial fibrillary acidic protein (GFAP), also using a peroxidaseantiperoxidase technnique. Comparable sections from a sham-infected rabbit were stained with hematoxylin and eosin.
MEDICAL
HYPOTHESES
Fig. 2 Section of pyriform cortex showing gliosis.
Results On gross examination, the most medial aspect of the left pyriform cortex showed a gliotic area (Fig. 1). Microscopic examination of the brain sections showed hypercellularity in and around the scar and, to a lesser degree, in the contralateral mesial pyriform cortex. Immunostaining of sections for herpes simplex virus showed no residual antigen. Staining for GFAP was positive in the areas of hypercellularity, bilaterally, in the. pyriform cortices (Fig. 2). The remainder of the brain was uninvolved by the gliotic process. Comparisons with similar sections from a sham infected rabbit showed no obvious changes in the dentate fasola or hippocampal areas CA1 - 4. Discussion Seizure disorders are among man’s oldest afflictions, yet only over the last one hundred years has medical or surgical treatment been possible. Diagnosis improved with the advent of electroencephalography and, more recently, video monitoring. However, the pathogenesis of most seizure disorders remains poorly understood. Despite micromonitoring techniques and histochemical methods for specific cells and their projections (11, 15), and although interesting seizure disorders can be created by electrical and chemical stimulation (16, 17), the relationship of human epilepsy to these studies is unclear because pathologic find-
NONFULMINANT
HERPES
SIMPLEX
179
ENCEPHALITIS
ings analogous to those seen in human seizure disorders are often lacking. In contrast, implication of a common infectious agent as a possible etiology is attractive if it can be shown that the agent is capable of causing a limited infection, does not persist in easily proved condition, results in a glial scar and is compatible with survival. As demonstrated in this report, HSV-1 can fulfill these criteria in an experimental model. Adherence to the second criterion above-disappearance of the responsible biologic agent-hampers the search for intact HSV1 in cortical resections. However, techniques for proving the presence of the HSV-1 genome have already been attempted on a few specimens of mesial temporal sclerosis, with encouraging results (18).
3.
4.
5.
6.
7. 8. 9.
Conclusions
Experimental work here presented demonstrates that HSV-1 can cause a range of pathologic lesions ranging from mild gliosis to tissue destruction, confined to mesial temporal structures. Furthermore, such lesions are not incompatible with life in this experimental model system. Such evidence lends credence to the hypothesis that HSV-I might be responsible for some cases of mesial temporal sclerosis-and to the notion that a nonfulminant brain infection with this virus can occur.
10. 11.
12.
13. 14.
Acknowledgement 15. This research was supported in part number 3 -63113, from the College of South Alabama.
by an intramural grant, of Medicine, University
References 1. Penry JK. Perspectives in complex partial seizures. p. 1 - 14 in Advances in Neurology. (JK Penry, DD Daly, eds) Raven Press, New York, 1975. 2. Babb TL, Brown WJ. Pathological findings in epilepsy.
16.
17.
18.
p.511 - 539 in Surgical Treatment of the Epilepsies. (J Engel Jr, ed) Raven Press, New York, 1987. Armstrong DD, Bruton CJ. Postscript: What terminology is appropriate for tissue pathology? How does it predict outcome? p.541- 552 in Surgical Treatment of the Epilepsies. (J Engel Jr, ed) Raven Press, New York, 1987. Hamada H, Kobayashi E, Mihara T, Asakura T, Kitamura K. A morphological study on vascular changes in the surgically resected tissues of temporal lobe epilepsywith a special reference to the etiology. Folia Psychiat et Neurol 30(3): 435 - 53, 1976. Falconer MA, Serafetinides EA, Corsellis JAN. Etiology and pathogenesis of temporal lobe epilepsy. Arch Neurol 10: 233 -48, 1974. Earle KM, Baldwin M, Penfield W. Incisural sclerosis and temporal lobe seizures produced by hippocampal herniation at birth. Arch Neurol and Psychiat 69: 27 -42, 1953. Spielmeyer W. Die pathogenaese des epileptischen krampfes. Z Ges Neurol Psychiatr 109: 501 - 20, 1927. Scholz W. Uber die entstehung des hirn-befundes bel der epilepsie. Z Ges Neurol Psychiatr 145: 471, 1933. Cavanaugh JB, Meyer A. Aetological aspects of Ammon’s horn sclerosis associated with temporal lobe epilepsy. Brit Med J 2: 1403-07, 1956. Rasmussan T, Olezewski J, Lloyd-Smith D. Focal seizures due to chronic encephalitis. Neurology 8: 435.-45, 1958. Sloviter RS. Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science 235: 73 - 76, 1987. Haymaker W, Smith MG, van Bogaert L, de Chenar C. Pathology of viral disease in man characterized by nuclear inclusions. With emphasis on herpes simplex and subacute inclusion encephalitis. p. 118 - 162 in Viral encephalitis. (WS Fields, RJ Blattner eds) Charles C. Thomas, Springfield, Ill, 1958. Johnson RT. The contribution of virologic research to clinical neurology. N Engl J Med 307: 660 - 62, 1982. Sternberger LA ed. Immunocytochemistry. 2nd edition John Wiley & Sons, New York, 1979. Scheibel ME, Crandall PH, Scheibel AB. The Hippocampal-dentate complex in temporal lobe epilepsy. Epilepsia 15: 55-80, 1974. Goddard GV, McIntyre DC, Leech CK. A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol 25: 295 - 330, 1969. Kopeloff LM, Barrera SE, Kopeloff N. Recurrent convulsive seizures in animals produced by immunologic and chemical means. Am J Psychiat 98: 881-902, 1942. Gannicliffe A, Saldanha JA, Itzhaki RF, Sutton RNP. Herpes simplex viral DNA in temporal lobe epilepsy. Lancet 1 (8422): 214- 15. 1985.
Nonfulminant Herpes Simplex Encephalitis Cause for Mesial Temporal Sclerosis M. SCHLITT,
A.P. BUCHER, E.A. QUINDLEN,
R. JENNINGS
Departments of Neurosurgery and Pathology, Room 714 Mastin Medical Center, 245 1 Fillingim Street, Mobile, AL 366 17, USA
as a
and F.O. BASTIAN
Building,
University
of South
Alabama
Abstract - Although mesial temporal sclerosis has been recognized for more than 100 years, its etiology remains unknown. It is proposed that a common infectious agent, herpes simplex virus type-l, may cause this disorder by means of a nonfulminant infection of mesial temporal lobe structures, which is resolved by the immune system and becomes gliotic in the course of healing by the central nervous system. Brain sections from a long-term experiment in a model of herpes simplex encephalitis reveal such a scar, which shows a high concentration of glial fibrillary acidic protein, without any evidence of residual herpes antigen, by immunocytochemistry.
Introduction
Complex partial seizures are commonly encountered in clinical practice and make up approximately 25% or more of seizure disorders in adults (1). Mesial temporal sclerosis (MTS) is present in as many as 65% of individuals with complex partial seizures (2). The pathologic definition of MTS is controversial (3, 4), but is dependent on finding, at least, an increase in glial cells in the cortex overlying the hippocampal structures. Neuronal loss with gliosis in areas CAl, CA4 and the dentate gyrus of the hippocampus is pathognomonic and frequently, more widespread damage can be found in nearby cortex. Theories regarding the etiology of this disorder include hypoxia due to recurrent seizures (5), birth trauma (4,6), vascular spasm (7), brain edema (8), infection (4, 9, lo), and poorly understood genetic disease (11). Recent experimental models have de-
fined groups of cells which die after prolonged stimulation of the perforant pathway and whose death lead to experimental temporal lobe epilepsy (11). The localization of MTS, however, parallels the early stages of herpes simplex encephalitis (HSE); in the normal adult host, the viral brain infection is thought to begin in the medial aspects of the temporal lobe (12). Because of the high frequency of antibody against type-l herpes simplex virus (HSV-1) (13) and the relative infrequency of HSE, the possibility of nonfulminant infection of the brain with HSV-1 must be considered. It is therefore hypothesized that some patients with partial seizures originating from a temporal focus have suffered subclinical infections of mesial temporal regions with HSV- 1. The mesia1 temporal sclerosis resulting from the healing of the viral infection would be the pathologic marker of ancient infection as well as the seizure focus. This hypothesis was tested recently when one of a
177
178
Fig. 1 Gross brain from long term survivor showing gliosis of the most medial aspect of the left pyriform cortex.
group of long-term survivors of an experimental model of HSE was sacrificed, eleven months after inoculation with HSV- 1. Methods Five adult rabbits were inoculated in the left ofactory bulb in March 1986 with a relatively avirulent HSV-1 designated ‘35’ at this institution (from the laboratory of Drs. John Oakes and Robert Lausch). Two of these animals succumbed due to the infection; two members of the group were serially euthanized after two weeks and the brains studied microscopically for evidence of infection as a part of a previous study of experimental HSE (unpublished observations). As other members of the group showed evidence only for mild infection, it was decided to allow the last member of the group a prolonged post-operative survival. The rabbit was euthanized in February 1987, after institution of deep anesthesia. The brain was perfused with ten percent formalin and removed. After further formalin fixation for three days the region containing the pyriform cortices was cut, imbedded in paraffin, and sectioned serially. Brain sections were stained with hematoxylin and eosin, and with a peroxidase-antiperoxidase method for HSV-1 (14). Adjacent serial sections were immunostained for glial fibrillary acidic protein (GFAP), also using a peroxidaseantiperoxidase technnique. Comparable sections from a sham-infected rabbit were stained with hematoxylin and eosin.
MEDICAL
HYPOTHESES
Fig. 2 Section of pyriform cortex showing gliosis.
Results On gross examination, the most medial aspect of the left pyriform cortex showed a gliotic area (Fig. 1). Microscopic examination of the brain sections showed hypercellularity in and around the scar and, to a lesser degree, in the contralateral mesial pyriform cortex. Immunostaining of sections for herpes simplex virus showed no residual antigen. Staining for GFAP was positive in the areas of hypercellularity, bilaterally, in the. pyriform cortices (Fig. 2). The remainder of the brain was uninvolved by the gliotic process. Comparisons with similar sections from a sham infected rabbit showed no obvious changes in the dentate fasola or hippocampal areas CA1 - 4. Discussion Seizure disorders are among man’s oldest afflictions, yet only over the last one hundred years has medical or surgical treatment been possible. Diagnosis improved with the advent of electroencephalography and, more recently, video monitoring. However, the pathogenesis of most seizure disorders remains poorly understood. Despite micromonitoring techniques and histochemical methods for specific cells and their projections (11, 15), and although interesting seizure disorders can be created by electrical and chemical stimulation (16, 17), the relationship of human epilepsy to these studies is unclear because pathologic find-
NONFULMINANT
HERPES
SIMPLEX
179
ENCEPHALITIS
ings analogous to those seen in human seizure disorders are often lacking. In contrast, implication of a common infectious agent as a possible etiology is attractive if it can be shown that the agent is capable of causing a limited infection, does not persist in easily proved condition, results in a glial scar and is compatible with survival. As demonstrated in this report, HSV-1 can fulfill these criteria in an experimental model. Adherence to the second criterion above-disappearance of the responsible biologic agent-hampers the search for intact HSV1 in cortical resections. However, techniques for proving the presence of the HSV-1 genome have already been attempted on a few specimens of mesial temporal sclerosis, with encouraging results (18).
3.
4.
5.
6.
7. 8. 9.
Conclusions
Experimental work here presented demonstrates that HSV-1 can cause a range of pathologic lesions ranging from mild gliosis to tissue destruction, confined to mesial temporal structures. Furthermore, such lesions are not incompatible with life in this experimental model system. Such evidence lends credence to the hypothesis that HSV-I might be responsible for some cases of mesial temporal sclerosis-and to the notion that a nonfulminant brain infection with this virus can occur.
10. 11.
12.
13. 14.
Acknowledgement 15. This research was supported in part number 3 -63113, from the College of South Alabama.
by an intramural grant, of Medicine, University
References 1. Penry JK. Perspectives in complex partial seizures. p. 1 - 14 in Advances in Neurology. (JK Penry, DD Daly, eds) Raven Press, New York, 1975. 2. Babb TL, Brown WJ. Pathological findings in epilepsy.
16.
17.
18.
p.511 - 539 in Surgical Treatment of the Epilepsies. (J Engel Jr, ed) Raven Press, New York, 1987. Armstrong DD, Bruton CJ. Postscript: What terminology is appropriate for tissue pathology? How does it predict outcome? p.541- 552 in Surgical Treatment of the Epilepsies. (J Engel Jr, ed) Raven Press, New York, 1987. Hamada H, Kobayashi E, Mihara T, Asakura T, Kitamura K. A morphological study on vascular changes in the surgically resected tissues of temporal lobe epilepsywith a special reference to the etiology. Folia Psychiat et Neurol 30(3): 435 - 53, 1976. Falconer MA, Serafetinides EA, Corsellis JAN. Etiology and pathogenesis of temporal lobe epilepsy. Arch Neurol 10: 233 -48, 1974. Earle KM, Baldwin M, Penfield W. Incisural sclerosis and temporal lobe seizures produced by hippocampal herniation at birth. Arch Neurol and Psychiat 69: 27 -42, 1953. Spielmeyer W. Die pathogenaese des epileptischen krampfes. Z Ges Neurol Psychiatr 109: 501 - 20, 1927. Scholz W. Uber die entstehung des hirn-befundes bel der epilepsie. Z Ges Neurol Psychiatr 145: 471, 1933. Cavanaugh JB, Meyer A. Aetological aspects of Ammon’s horn sclerosis associated with temporal lobe epilepsy. Brit Med J 2: 1403-07, 1956. Rasmussan T, Olezewski J, Lloyd-Smith D. Focal seizures due to chronic encephalitis. Neurology 8: 435.-45, 1958. Sloviter RS. Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science 235: 73 - 76, 1987. Haymaker W, Smith MG, van Bogaert L, de Chenar C. Pathology of viral disease in man characterized by nuclear inclusions. With emphasis on herpes simplex and subacute inclusion encephalitis. p. 118 - 162 in Viral encephalitis. (WS Fields, RJ Blattner eds) Charles C. Thomas, Springfield, Ill, 1958. Johnson RT. The contribution of virologic research to clinical neurology. N Engl J Med 307: 660 - 62, 1982. Sternberger LA ed. Immunocytochemistry. 2nd edition John Wiley & Sons, New York, 1979. Scheibel ME, Crandall PH, Scheibel AB. The Hippocampal-dentate complex in temporal lobe epilepsy. Epilepsia 15: 55-80, 1974. Goddard GV, McIntyre DC, Leech CK. A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol 25: 295 - 330, 1969. Kopeloff LM, Barrera SE, Kopeloff N. Recurrent convulsive seizures in animals produced by immunologic and chemical means. Am J Psychiat 98: 881-902, 1942. Gannicliffe A, Saldanha JA, Itzhaki RF, Sutton RNP. Herpes simplex viral DNA in temporal lobe epilepsy. Lancet 1 (8422): 214- 15. 1985.
