Folia Psychiatrica et Neurologica Japonica, Vol. 33, No. 2, 1979
An Autopsy Case of Protracted Necrotic Encephalitis With Marked Atrophy of Unilateral Temporal Lobe Teruo Shirabe, M.D. and Satoru Tawara, M.D.* Division of Neuropathology, Department of Human Pathology, and Division of Neurology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki
INTRODUCTION Acute necrotic encephalitis of the van Bogaert typeio has been recognized as an encephalitis with a fulminant and mostly fatal course. Pathologically confluent necrotic lesions are distributed particularly in unilateral temporal and insular lobes, hippocampus, and cingulate gyrus." It is nowadays considered to be almost identical with herpes simplex encephalitis, along with acute inclusion encephaliti~.~ Recently, however, we experienced an encephalitis with a more insidious onset and unusually protracted course, in which the findings of postmortem examination were compatible with those of acute necrotic encephalitis. We would like to describe the clinical and neuropathological features of this rare condition and discuss the pathophysiology of protraction of acute necrotic encephalitis, comparing the case with other protracted ones with acute necrotic encephalitis or with chronic necrotic encephalitis found in literature.
Received for publication Dec. 18, 1978.
* Present address: Third Department
of Internal Medicine, Miyazaki Medical College, Miyazaki 889-16.
CASE REPORT Clinical History A 44-year-old man was admitted to the Kawasaki Medical School Hospital because of low grade fever, double vision and facial asymmetry on April 2, 1976. Two months prior to admission the patient had been in another hospital for an evaluation of chest pain after being hit, where he had an intermittent low grade fever up to 38OC and occasional headache. He complained of right post-auricular and nuchal pain on March 7. Next day headache, vomiting and double vision developed. On March 9, right facial paresis was noted. His gait became progressively staggering. He easily inclined to the left on walking. A few days later blurred vision was noticed in the right eye. A cerebrospinal fluid examination performed on March 26 demonstrated an initial pressure of 110 mm, 1874/3 cell counts with 95% of lymphocytes, and 243 mg/dl of protein. He was referred to this hospital for further neurological examination. There was a history of a traffic accident with transient unconsciousness and rib fractures one year before. At that time no neurological deficits had remained. Physical examination on admission revealed a poorly nourished and dull-looking
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Admission
Convulsion
&13y27 v4 7 VI4 5VI4 0 )% /7 26 I 111
x
Transfer XI
43 4 9
?;2.1
v
4 7
Rt. abd. palsy Rt. facial palsy Rt. hemiplegia Lt. upper sensory dist Lt. hemiplegia Nuchal rigidity CS F IP
(mrnHzO)
Cell /3 Lymphocyte (%I Protein ( rng/dl) Sugar ( r n d d l )
110 105 150 205 140 125
1874 624 435 523 217 226 95
70 45
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243 240 218 119 160 105 35
26 28 34 39 30
90 75
90
75
85 84 35
36
54 85
5a
63 76 101
94
38
42
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49 33
Fig. 1: The patient’s clinical course with chronological findings of the cerebrospinal fluid.
man with a temperature of 36.4OC. His memory and orientation to time and place were slightly disturbed. Calculation was poor. There were no meningeal irritation signs. Visual acuity was 4/20 on the right and 8/20 on the left. Right facial sensation was slightly impaired. Right abducens and facial nerves were almost completely paralyzed. Hearing was diminished on the right side. Weber test was deviated to the left. Right sided hemiparesis was detected with right grasping power of 17 kg and left of 30 kg. Coordination appeared roughly normal. Deep tendon reflexes were hyperactive in the right extremities. Wartenberg, Hoffmann and Chaddock’s signs were elicited on the right side. There was no sensory impairment in the trunk and extremities. He dragged his left foot on gait. Sphincter disturbance was not seen. Red blood cells were 3.72 millions. White blood cells were 5,000 with a normal differential count. Erythrocytes sedimentation rate was 54mm per hour. A lumbar
puncture yielded clear and colorless cerebrospinal fluid under a pressure of 105 mm; the fluid contained 624/3 cells, with 30% of neutrophils and 70% of lymphocytes; protein was 240 mg/dl and sugar was 26mg/dl; there were no organisms on smear and culture. Brain scintigrams suggested a focal uptake of tracer in the right temporal region. Bilateral carotid and vertebral angiograms were negative. Electroencephalograms demonstrated a background activity of slow alpha waves associated with intermittent theta waves. Virus titers of the serum, including polio, adeno, ECHO, Coxsackie, herpes, mumps, influenza, parainfluenza, rubella and measles, were all within normal limits. An agglutination titer for infectious mononucleosis was 1:448, with negative mono test. The patient’s clinical course and chronological findings of the cerebrospinal fluid are illustrated in Fig. 1. He was treated with various antibiotics as brain abscess or meningoencephalitis of
An Autopsy Case of Protracted Necrotic Encephalitis
167
Fig. 2: The electroencephalogram on September 3, showing periodic lateralized epileptiform discharges (PLEDs) on the leads from the right hemisphere.
Fig. 3 : Schematically illustrated sites of lesions.
unknown cause. Soon after admission sensory impairment of the right half of the body and the left upper extremity became apparent. His temperature rose intermittently up to 38.2OC. In August 1976, corticosteroids were also prescribed because of an appearance of aphthous stomatitis and scrota1 ulcer suggestive of neuro-Behcet’s syndrome. On September 2, the temperature rose to 39OC. Next day tonic-clonic convulsive seizures of the left upper and lower extremities were repeated with subsequent coma and left hemiplegia. The neck became remarkably rigid. Electroencephalograms disclosed periodic lateralized epileptiform discharges (PLEDs) on the leads from the right hemisphere (Fig. 2 ) . In three days his consciousness was almost recovered, but he was found to be more disoriented and mentally deteriorated. He urinated and defecated on the floor of his ward and shouted during the night. He seemed to experience
visual hallucinations. During the next eight months there were no marked changes in his condition. Mild pleocytosis of the cerebrospinal fluid still continued, ranging from 35/3 to 84/3 cell counts. A dilatation of lateral ventricles was found by pneumoencephalograms performed on February 10, 1977. He died of an accompanying aspiration pneumonia on May 1977, after a course of about one year and three months. Neuropathological Findings (A- 178) The sites of lesions of the brain are schematically illustrated in Fig. 3. The brain weighed 1,140 gr. The leptomeninges were slightly turbid and thickened. Gyri of the cerebral hemispheres were atrophic, especially of the right temporal lobe. Arteries of the cerebral base were considerably atherosclerotic. On coronal sections of the brain, the right superior
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An Autopsy Case of Protracted Necrotic Encephalitis temporal gyrus, parahippocampal gyrus and insular lobe were particularly atrophied (Fig. 4). Lateral and third ventricles were moderately enlarged. Histologically the leptomeninges of the brain showed partial infiltrations by small numbers of lymphocytes, monocytes and macrophages. Cerebral cortices of the right temporal lobe, parahippocampal gyrus and insular lobe were most severely atrophied with disarranged cortical architecture (Fig. 5 ) . Nerve cells had almost completely disappeared, accompanied by widespread astrocytic gliosis and capillary proliferations (Fig. 6). Occasionally the cortex showed pseudolaminar necrotic degeneration specifically of the second and third layers. Incidentally slight perivascular infiltrates of lymphocytes were observed. In the white matter beneath these lesions, myelins were relatively well preserved, although reactive astrocytic gliosis was rather prominent. In the gray matter of other lobes of the Legends for Figs. 4-9 Fig. 4: Gross appearance of a coronal section of the cerebral hemispheres through the mammary bodies. Right temporal lobe is particularly atrophic. Lateral and third ventricles are moderately dilated. Fig. 5 : Atrophic right temporal lobe, insular lobe and hippocampus. The cortical ribbons are thinned, while myelins of the white matter are relatively well preserved. Kluver-Barrera, X 1.1. Fig. 6: Right superior temporal lobe. The leptomeninges show mild infiltrations of lymphocytes. Nerve cells of the cortex are almost completely disappeared, accompanied by prominent astrocytic gliosis. The second and third layers show pseudolaminar necrotic lesions. HE, X 126. Fig. 7: Left precentral cortex showing cystic laminar necrosis scattered with lipidladen macrophages, and astrocytic gliosis. HE, X126. Fig. 8: Left thalamus showing mild perivascular infiltrates of lymphocytes. HE, X 252. Fig. 9: Right amygdaloid nucleus showing neutrophilic infiltrates overlapped with remote gliotic lesions. HE, X252.
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cerebral hemispheres, numerous patchy or pseudolaminar necrotic lesions of various sizes were scattered. These lesions were occasionally cystic, disseminated with lipidladen macrophages, and were circumscribed by marginal astrocytic gliosis and capillary proliferations (Fig. 7). Relatively large malacic lesions were found in the left precentral gyrus, left superior temporal gyrus and left medial occipito-temporal gyrus. Pyramidal cells of the Sommer’s sector were seriously lost and granule cells were shrunken. I n the basal ganglia, internal capsules and thalamus, there were scattered minute necrotic lesions of a remote nature. Inflammatory signs in these areas were minimal. Slight perivascular infiltrates of lymphocytes were seen in general (Fig. 8). Only in the right amygdaloid nucleus, however, recent inflammatory lesions with some neutrophilic infiltrates and fibrinous deposits were overlapped with remote gliotic lesions (Fig. 9). Small necrotic lesions were seen also in the chiasm. The cerebellum showed partial loss of Purkinje and granule cells. In the midbrain, pons and medulla oblongata, circumscribed remote necrotic lesions were disseminated. Nuclei of the abducens, facial and acoustic nerves were partially involved. There was a mild gliosis in the inferior olives, Bilateral pyramidal tracts of the medulla oblongata showed considerable pallor with meylin stain. Glial nodules and proliferations of rodshaped microglia were not apparent. Intranuclear inclusion bodies of Cowdry type A were not observed. An electron microscopic examination of the right amygdaloid nucleus failed to find any virions. DISCUSSION
This 44-year-old patient experienced a mental deterioration, right abducens and facial paresis, right and, subsequently, left hemiparesis, and consciousness disturbance
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with an intermittent low grade fever and occasional headache during one year and three months. In the seventh month the illness showed apparent aggravation. Repeated cerebrospinal fluid examinations always revealed chronic inflammatory signs. Electroencephalograms demonstrated periodic lateralized epileptiform discharges during the aggravated period. Virus titers including herpes simplex virus were all within normal limits. Neuropathological examinations revealed marked atrophic changes in the right temporal lobe, insular lobe and hippocampus. Inflammatory signs in these areas were minimal. Slight perivascular infiltrates of lymphocytes were seen on the whole. Only in the amygdaloid nucleus, however, recent inflammatory lesions with some neutrophilic infiltrates and fibrinous deposits were overlapped with remote gliotic lesions. More minute remote malacic lesions were scattered entirely throughout the whole brain, including the left precentral gyrus, right internal capsule, chiasm and pons, and these lesions might satisfactorily explain the neurologic symptoms and signs during his life time. Although pathologically the temporal lobe involvement was specifically dominant, Kluver-Bucy syndrome was not observed clinically, probably because of only unilateral involvement. The lesions in this case were pertinently supposed to be of an infectious origin, especially of viral infection from the chronic and partially recent but not severe inflammatory nature and from the predominantly cortical involvement, together with the clinical picture, although characteristic glial nodules and diffuse proliferations of rod-shaped microglia were not distinct. They were apparently different from those of anoxia, hypoglycemia, pseudoulegyric hepatocerebral disease and other disorders showing cortical involvements. Some vascular factors such as angiospasm or venous stasis may be concerned in a part of their pathogenesis, regarding occasional pseudolaminar
necrotic lesions of the cerebral cortex. Recent inflammatory lesions in the amygdaloid nucleus may suggest that the infectious reaction was still smoldering at the time of death. The distribution of these lesions closely resembles that of acute necrotic encephalitis of the van Bogaert type, which is now recognized as almost identical with herpes simplex encephalitis, along with acute inclusion encephalitis.4 Herpes simplex encephalitis has been generally known as a clinically fulminating and, occasionally, rapidly fatal disease.13 The illness in our case, however, began with a more insidious onset and took a far more protracted course. Periodic lateralized epileptiform discharges (PLEDs) r, have often been recorded on the electroencephalograms of cases with herpes simplex encephalitis.'; Smith et ul.'" have mentioned that periodic lateralized epileptiform discharges would suggest the diagnosis of herpes simplex encephalitis, when associated with an acute encephalitic process, if not pathognomonic. The electroencephalograms in our case also showed periodic lateralized epileptiform discharges at one time. These findings of the electroencephalograms also support the opinion that this case may belong to the category of herpes simplex encephalitis, despite the normal herpes simplex virus titer. Virus titers do not seem to always elevate, conditioned by a period of examination or probably due to problems of subtypes, even in cases proved by autopsy.l3 A few cases of similarly protracted necrotic encephalitis have been recorded in literature. There seem to be two forms of such protracted encephalitis. One is a group of cases with a residual course after an acute and febrile onset described by Booth ct d . , I Radermecker et ul.,It Seitz,12 Totsuka et ul.,Iu Abe et ul.' and Akai et U I . ~ Of these, only the case of Radermecker et ul. had a prodromal period of two weeks during which severe headache continued, before sudden convulsive seizures developed.
An Autopsy Case of Protracted Necrotic Bncephalitis The other is a chronic form with a more insidious onset and chronic progressive course presented by Ishino et ul.' Their case took a slowly progressive course of three years and three months, showing dysarthria, disturbance of memory, euphoria, spastic tetraplegia, emotional incontinence, and, finally, dementia and coma. They designated this type of encephalitis as chronic necrotizing encephalitis. Ours may be regarded as an intermediate form between the two. In all of these protracted cases localized remote necrotic lesions centering around the temporal lobe have been seen. Merely minimal chronic inflammatory signs might be present in some places. Only in our case some recent inflammatory lesions were locally observed. Although the distribution of the lesions is quite similar to that of herpes simplex encephalitis, there is no evidence of herpes virus infection in most cases except that of Booth et d4The case described by Booth et ul. was proved to be an acute inclusion encephalitis of herpes simplex type by brain biopsy in its acute phase. The patient died four years and eight and one-half months after onset of the illness. At autopsy the case also showed only malacic cysts and gliosis, mainly in the temporal and insular lobes, and hippocampus, without any intranuclear inclusion bodies nor glial nodules. In these cases the course may have been protracted probably because the cytotoxicity of the virus was inactivated or the responsibility of the host was impaired or the latent or chronic persistent infection of the virus was sustained. Price et ~ 1 . ' " have indicated a patient of herpes simplex encephalitis developed during the course of Hodgkin's disease, whose illness progressed slowly presumably because of his depressed immune system. Moreover, we have reported in another place a case of herpes simplex encephalitis in which the latent herpes simplex virus was activated probably by preceding purulent lept~meningitis.~~ There are also several cases of recurrent herpes
171
simplex encephalitis in Iiterat~re,~ although the reactivating factors are nuclear. Our case seemed to have aggravated after an administration of corticosteroids. In addition to these, improved treatment of the patients might also have contributed to the protracted course. Nowadays two types of herpes simplex viruses are known.3 Type one is said to produce an acute necrotic encephalitis to an adult. While type two brings about a generalized herpes simplex virus infection to a neonate and serous meningitis to an adult. Thus the disposition of herpes simplex virus infections seems to vary considerably according to its subtypes or its infected hosts. Besides, recently, clinical cases with herpes simplex encephalitis which take a far more benign course without any deficits have become increasingly evident.8 l6 Herpes simplex virus infections may have a far wider spectrum beyond our expectation and bring about protracted or chronic encephalitis at times such as ours, although it is a problem to be solved in the future-to know whether all of these protracted cases are truly variants of herpes simplex encephalitis, and what is the true factor for its protraction. SUMMARY
Clinical and neuropathological findings in a case of an unusually protracted encephalitis have been described. The patient was a 44-year-old man who experienced mental deterioration, right abducens and facial paresis, right and, subsequently, left hemiparesis, and consciousness disturbance with an intermittent low grade fever and occasional headache during one year and three months. Electroenphalograms showed periodic lateralized epileptiform discharges. Virus titers including herpes simplex virus were all normal. Neuropathological examinations revealed marked atrophic changes in the right temporal lobe, insular lobe and hippocampus with minimal inflammatory signs. The distribution of the
T. Shirabe and S. Tawara
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lesions was almost identical with that of acute necrotic encephalitis or herpes simplex encephalitis despite its unusually protracted
course. ACKNOWLEDGMENT
The authors are very grateful to Prof. Shukuro Araki, Chairman of the Third Department of Internal Medicine, Miyazaki Medical College, for his valuable advice and reviewing the manuscript. REFERENCES 1 Abe, M. and Suetsugu, M.: An autopsy
case of necrotizing encephalitis with sequelae of character change and dementia, Adv Neurol Sci (Tokyo), 16: 545, 1972 (in Japanese). 2 Akai, J., Kato, Y. et Takase, M.: Etude clinico-pathologique concernant syndrome de Kluver-Bucy chez l'homme, Discussion dans des cas d'enckphalite nkcrosante, Psychiat Neurol Jap, 70: 67-87, 1977 (in Japanese). 3 Baringer, J. R.: Herpes simplex virus infections of the nervous system, in Textbook of Clinical Neurology, ed. by Vinken, P. J. and Bruyn, G. W., Vol. 34, Infection of the Nervous System, Part 11: 145-159, 1978, North-Holland Pub. Co., Amsterdam. 4 Booth, C. B., Okazaki, H. and Gaulin, J. C.: Acute inclusion encephalitis of herpes simplex type, Neurology, 11: 619-629, 1961. 5 Chatrian, G. E., Shaw, C.-M. and Leffman,
rhinencephalic and insular regions, Folia Psychiat Neurol Jap, 27: 29-42, 1973. 8 Johnson, K. P., Rosenthal, M. S. and Lerner, P. I.: Herpes simplex encephalitis, The course in five virologically proven cases, Arch Neurol, 27: 107-108, 1972. 9 Milstein, J. M. and Biggs, H. E., Jr.: Recurrent encephalitis with elevated titers for herpes simplex, Arch Neurol, 34: 434-436, 1977. 10 Price, R., Chernik, N. L., Horta-Barbosa,
L. and Posner, J. B.: Herpes simplex encephalitis in an anergic patient, Amer J Med, 54: 222-228, 1973. 11 Radermecker, J,, Flament, J., Guazzi, G. C. et Troch, C.: Enckphalite necrosante aigu6 avec survie sans siquelles neuro-psychiatriques graves, Rev Neurol, 106: 368-380, 1962. 12 Seitz, D.: Akute nekrotisierende Encepha-
litis mit protrahiertem Verlauf, Dtsch Z Nervenheilk, 189: 39-52, 1966. 13 Shirabe, T., Nomura, N., Terao, A. and Araki, S. : Herpes simplex encephalitis, A light and electron microscopic study in a fatal case, Folia Psychiat Neurol Jap, 27: 17-27, 1973. 14 Shirabe, T., Okamoto, S. and Yoshimura,
I5 16
17
H.: The significance of periodic lateralized epileptiform discharges in EEG, An electrographic, clinical and pathologic study, Electroencephalogr Clin Neurophysiol, 17: 177193, 1964. 6 Ch'ien, L. T., Boehm, R. M., Robinson, H.,
18
Lui, C. and Frenkel, L. D.: Characteristic early electroencephalographic changes in herpes simplex encephalitis, 34: 361-364, 1977. 7 Ishino, H., Nomura, S. and Sarai. J.:
Chronic necrotizing encephalitis involving mainly the gray matter of the temporo-
19
M.: Coexistent purulent leptomeningitis and herpes simplex encephalitis, Case report with postmortem study, Folia Psychiat Neurol Jap, 28: 379-388, 1974. Shoji, H.: Clinical features of herpes simplex encephalitis, Clin Neurol (Tokyo), 13: 491-498, 1973 (in Japanese). Smith, J. B., Westmoreland, B. F., Reagan, T. J. and Sandok, B. A.: A distinctive clinical EEG profile in herpes simplex encephalitis, Mayo Clin Proc, 50: 469-474, 1975. Tateishi, J., Peters, G. und Minauf, M.: Bericht uber 18 Falle akuter nekrotisierender Encephalitis (van Bogaert) , Adv Neurol Sci (Tokyo), 15: 1032-1040, 1971 (in Japanese). Totsuka, S., Matsumoto, Y., Moro, K., Haneda, T. and Kubota, Y.: A case of acute necrotizing encephalitis with a protracted course, Adv Neurol Sci (Tokyo), 13: 431, 1969 (in Japanese). van Bogaert, L., Radermecker, J. et Devos, J.: Sur une observation mortelle d'enckphalite aigue nkcrosante, Rev Neurol, 92: 329356, 1955.
An Autopsy Case of Protracted Necrotic Encephalitis With Marked Atrophy of Unilateral Temporal Lobe Teruo Shirabe, M.D. and Satoru Tawara, M.D.* Division of Neuropathology, Department of Human Pathology, and Division of Neurology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki
INTRODUCTION Acute necrotic encephalitis of the van Bogaert typeio has been recognized as an encephalitis with a fulminant and mostly fatal course. Pathologically confluent necrotic lesions are distributed particularly in unilateral temporal and insular lobes, hippocampus, and cingulate gyrus." It is nowadays considered to be almost identical with herpes simplex encephalitis, along with acute inclusion encephaliti~.~ Recently, however, we experienced an encephalitis with a more insidious onset and unusually protracted course, in which the findings of postmortem examination were compatible with those of acute necrotic encephalitis. We would like to describe the clinical and neuropathological features of this rare condition and discuss the pathophysiology of protraction of acute necrotic encephalitis, comparing the case with other protracted ones with acute necrotic encephalitis or with chronic necrotic encephalitis found in literature.
Received for publication Dec. 18, 1978.
* Present address: Third Department
of Internal Medicine, Miyazaki Medical College, Miyazaki 889-16.
CASE REPORT Clinical History A 44-year-old man was admitted to the Kawasaki Medical School Hospital because of low grade fever, double vision and facial asymmetry on April 2, 1976. Two months prior to admission the patient had been in another hospital for an evaluation of chest pain after being hit, where he had an intermittent low grade fever up to 38OC and occasional headache. He complained of right post-auricular and nuchal pain on March 7. Next day headache, vomiting and double vision developed. On March 9, right facial paresis was noted. His gait became progressively staggering. He easily inclined to the left on walking. A few days later blurred vision was noticed in the right eye. A cerebrospinal fluid examination performed on March 26 demonstrated an initial pressure of 110 mm, 1874/3 cell counts with 95% of lymphocytes, and 243 mg/dl of protein. He was referred to this hospital for further neurological examination. There was a history of a traffic accident with transient unconsciousness and rib fractures one year before. At that time no neurological deficits had remained. Physical examination on admission revealed a poorly nourished and dull-looking
T. Shirabe and S. Tawara
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Admission
Convulsion
&13y27 v4 7 VI4 5VI4 0 )% /7 26 I 111
x
Transfer XI
43 4 9
?;2.1
v
4 7
Rt. abd. palsy Rt. facial palsy Rt. hemiplegia Lt. upper sensory dist Lt. hemiplegia Nuchal rigidity CS F IP
(mrnHzO)
Cell /3 Lymphocyte (%I Protein ( rng/dl) Sugar ( r n d d l )
110 105 150 205 140 125
1874 624 435 523 217 226 95
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243 240 218 119 160 105 35
26 28 34 39 30
90 75
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85 84 35
36
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Fig. 1: The patient’s clinical course with chronological findings of the cerebrospinal fluid.
man with a temperature of 36.4OC. His memory and orientation to time and place were slightly disturbed. Calculation was poor. There were no meningeal irritation signs. Visual acuity was 4/20 on the right and 8/20 on the left. Right facial sensation was slightly impaired. Right abducens and facial nerves were almost completely paralyzed. Hearing was diminished on the right side. Weber test was deviated to the left. Right sided hemiparesis was detected with right grasping power of 17 kg and left of 30 kg. Coordination appeared roughly normal. Deep tendon reflexes were hyperactive in the right extremities. Wartenberg, Hoffmann and Chaddock’s signs were elicited on the right side. There was no sensory impairment in the trunk and extremities. He dragged his left foot on gait. Sphincter disturbance was not seen. Red blood cells were 3.72 millions. White blood cells were 5,000 with a normal differential count. Erythrocytes sedimentation rate was 54mm per hour. A lumbar
puncture yielded clear and colorless cerebrospinal fluid under a pressure of 105 mm; the fluid contained 624/3 cells, with 30% of neutrophils and 70% of lymphocytes; protein was 240 mg/dl and sugar was 26mg/dl; there were no organisms on smear and culture. Brain scintigrams suggested a focal uptake of tracer in the right temporal region. Bilateral carotid and vertebral angiograms were negative. Electroencephalograms demonstrated a background activity of slow alpha waves associated with intermittent theta waves. Virus titers of the serum, including polio, adeno, ECHO, Coxsackie, herpes, mumps, influenza, parainfluenza, rubella and measles, were all within normal limits. An agglutination titer for infectious mononucleosis was 1:448, with negative mono test. The patient’s clinical course and chronological findings of the cerebrospinal fluid are illustrated in Fig. 1. He was treated with various antibiotics as brain abscess or meningoencephalitis of
An Autopsy Case of Protracted Necrotic Encephalitis
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Fig. 2: The electroencephalogram on September 3, showing periodic lateralized epileptiform discharges (PLEDs) on the leads from the right hemisphere.
Fig. 3 : Schematically illustrated sites of lesions.
unknown cause. Soon after admission sensory impairment of the right half of the body and the left upper extremity became apparent. His temperature rose intermittently up to 38.2OC. In August 1976, corticosteroids were also prescribed because of an appearance of aphthous stomatitis and scrota1 ulcer suggestive of neuro-Behcet’s syndrome. On September 2, the temperature rose to 39OC. Next day tonic-clonic convulsive seizures of the left upper and lower extremities were repeated with subsequent coma and left hemiplegia. The neck became remarkably rigid. Electroencephalograms disclosed periodic lateralized epileptiform discharges (PLEDs) on the leads from the right hemisphere (Fig. 2 ) . In three days his consciousness was almost recovered, but he was found to be more disoriented and mentally deteriorated. He urinated and defecated on the floor of his ward and shouted during the night. He seemed to experience
visual hallucinations. During the next eight months there were no marked changes in his condition. Mild pleocytosis of the cerebrospinal fluid still continued, ranging from 35/3 to 84/3 cell counts. A dilatation of lateral ventricles was found by pneumoencephalograms performed on February 10, 1977. He died of an accompanying aspiration pneumonia on May 1977, after a course of about one year and three months. Neuropathological Findings (A- 178) The sites of lesions of the brain are schematically illustrated in Fig. 3. The brain weighed 1,140 gr. The leptomeninges were slightly turbid and thickened. Gyri of the cerebral hemispheres were atrophic, especially of the right temporal lobe. Arteries of the cerebral base were considerably atherosclerotic. On coronal sections of the brain, the right superior
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T.Shirabe and S. Tawara
An Autopsy Case of Protracted Necrotic Encephalitis temporal gyrus, parahippocampal gyrus and insular lobe were particularly atrophied (Fig. 4). Lateral and third ventricles were moderately enlarged. Histologically the leptomeninges of the brain showed partial infiltrations by small numbers of lymphocytes, monocytes and macrophages. Cerebral cortices of the right temporal lobe, parahippocampal gyrus and insular lobe were most severely atrophied with disarranged cortical architecture (Fig. 5 ) . Nerve cells had almost completely disappeared, accompanied by widespread astrocytic gliosis and capillary proliferations (Fig. 6). Occasionally the cortex showed pseudolaminar necrotic degeneration specifically of the second and third layers. Incidentally slight perivascular infiltrates of lymphocytes were observed. In the white matter beneath these lesions, myelins were relatively well preserved, although reactive astrocytic gliosis was rather prominent. In the gray matter of other lobes of the Legends for Figs. 4-9 Fig. 4: Gross appearance of a coronal section of the cerebral hemispheres through the mammary bodies. Right temporal lobe is particularly atrophic. Lateral and third ventricles are moderately dilated. Fig. 5 : Atrophic right temporal lobe, insular lobe and hippocampus. The cortical ribbons are thinned, while myelins of the white matter are relatively well preserved. Kluver-Barrera, X 1.1. Fig. 6: Right superior temporal lobe. The leptomeninges show mild infiltrations of lymphocytes. Nerve cells of the cortex are almost completely disappeared, accompanied by prominent astrocytic gliosis. The second and third layers show pseudolaminar necrotic lesions. HE, X 126. Fig. 7: Left precentral cortex showing cystic laminar necrosis scattered with lipidladen macrophages, and astrocytic gliosis. HE, X126. Fig. 8: Left thalamus showing mild perivascular infiltrates of lymphocytes. HE, X 252. Fig. 9: Right amygdaloid nucleus showing neutrophilic infiltrates overlapped with remote gliotic lesions. HE, X252.
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cerebral hemispheres, numerous patchy or pseudolaminar necrotic lesions of various sizes were scattered. These lesions were occasionally cystic, disseminated with lipidladen macrophages, and were circumscribed by marginal astrocytic gliosis and capillary proliferations (Fig. 7). Relatively large malacic lesions were found in the left precentral gyrus, left superior temporal gyrus and left medial occipito-temporal gyrus. Pyramidal cells of the Sommer’s sector were seriously lost and granule cells were shrunken. I n the basal ganglia, internal capsules and thalamus, there were scattered minute necrotic lesions of a remote nature. Inflammatory signs in these areas were minimal. Slight perivascular infiltrates of lymphocytes were seen in general (Fig. 8). Only in the right amygdaloid nucleus, however, recent inflammatory lesions with some neutrophilic infiltrates and fibrinous deposits were overlapped with remote gliotic lesions (Fig. 9). Small necrotic lesions were seen also in the chiasm. The cerebellum showed partial loss of Purkinje and granule cells. In the midbrain, pons and medulla oblongata, circumscribed remote necrotic lesions were disseminated. Nuclei of the abducens, facial and acoustic nerves were partially involved. There was a mild gliosis in the inferior olives, Bilateral pyramidal tracts of the medulla oblongata showed considerable pallor with meylin stain. Glial nodules and proliferations of rodshaped microglia were not apparent. Intranuclear inclusion bodies of Cowdry type A were not observed. An electron microscopic examination of the right amygdaloid nucleus failed to find any virions. DISCUSSION
This 44-year-old patient experienced a mental deterioration, right abducens and facial paresis, right and, subsequently, left hemiparesis, and consciousness disturbance
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T. Shirabe and S. Tawatti
with an intermittent low grade fever and occasional headache during one year and three months. In the seventh month the illness showed apparent aggravation. Repeated cerebrospinal fluid examinations always revealed chronic inflammatory signs. Electroencephalograms demonstrated periodic lateralized epileptiform discharges during the aggravated period. Virus titers including herpes simplex virus were all within normal limits. Neuropathological examinations revealed marked atrophic changes in the right temporal lobe, insular lobe and hippocampus. Inflammatory signs in these areas were minimal. Slight perivascular infiltrates of lymphocytes were seen on the whole. Only in the amygdaloid nucleus, however, recent inflammatory lesions with some neutrophilic infiltrates and fibrinous deposits were overlapped with remote gliotic lesions. More minute remote malacic lesions were scattered entirely throughout the whole brain, including the left precentral gyrus, right internal capsule, chiasm and pons, and these lesions might satisfactorily explain the neurologic symptoms and signs during his life time. Although pathologically the temporal lobe involvement was specifically dominant, Kluver-Bucy syndrome was not observed clinically, probably because of only unilateral involvement. The lesions in this case were pertinently supposed to be of an infectious origin, especially of viral infection from the chronic and partially recent but not severe inflammatory nature and from the predominantly cortical involvement, together with the clinical picture, although characteristic glial nodules and diffuse proliferations of rod-shaped microglia were not distinct. They were apparently different from those of anoxia, hypoglycemia, pseudoulegyric hepatocerebral disease and other disorders showing cortical involvements. Some vascular factors such as angiospasm or venous stasis may be concerned in a part of their pathogenesis, regarding occasional pseudolaminar
necrotic lesions of the cerebral cortex. Recent inflammatory lesions in the amygdaloid nucleus may suggest that the infectious reaction was still smoldering at the time of death. The distribution of these lesions closely resembles that of acute necrotic encephalitis of the van Bogaert type, which is now recognized as almost identical with herpes simplex encephalitis, along with acute inclusion encephalitis.4 Herpes simplex encephalitis has been generally known as a clinically fulminating and, occasionally, rapidly fatal disease.13 The illness in our case, however, began with a more insidious onset and took a far more protracted course. Periodic lateralized epileptiform discharges (PLEDs) r, have often been recorded on the electroencephalograms of cases with herpes simplex encephalitis.'; Smith et ul.'" have mentioned that periodic lateralized epileptiform discharges would suggest the diagnosis of herpes simplex encephalitis, when associated with an acute encephalitic process, if not pathognomonic. The electroencephalograms in our case also showed periodic lateralized epileptiform discharges at one time. These findings of the electroencephalograms also support the opinion that this case may belong to the category of herpes simplex encephalitis, despite the normal herpes simplex virus titer. Virus titers do not seem to always elevate, conditioned by a period of examination or probably due to problems of subtypes, even in cases proved by autopsy.l3 A few cases of similarly protracted necrotic encephalitis have been recorded in literature. There seem to be two forms of such protracted encephalitis. One is a group of cases with a residual course after an acute and febrile onset described by Booth ct d . , I Radermecker et ul.,It Seitz,12 Totsuka et ul.,Iu Abe et ul.' and Akai et U I . ~ Of these, only the case of Radermecker et ul. had a prodromal period of two weeks during which severe headache continued, before sudden convulsive seizures developed.
An Autopsy Case of Protracted Necrotic Bncephalitis The other is a chronic form with a more insidious onset and chronic progressive course presented by Ishino et ul.' Their case took a slowly progressive course of three years and three months, showing dysarthria, disturbance of memory, euphoria, spastic tetraplegia, emotional incontinence, and, finally, dementia and coma. They designated this type of encephalitis as chronic necrotizing encephalitis. Ours may be regarded as an intermediate form between the two. In all of these protracted cases localized remote necrotic lesions centering around the temporal lobe have been seen. Merely minimal chronic inflammatory signs might be present in some places. Only in our case some recent inflammatory lesions were locally observed. Although the distribution of the lesions is quite similar to that of herpes simplex encephalitis, there is no evidence of herpes virus infection in most cases except that of Booth et d4The case described by Booth et ul. was proved to be an acute inclusion encephalitis of herpes simplex type by brain biopsy in its acute phase. The patient died four years and eight and one-half months after onset of the illness. At autopsy the case also showed only malacic cysts and gliosis, mainly in the temporal and insular lobes, and hippocampus, without any intranuclear inclusion bodies nor glial nodules. In these cases the course may have been protracted probably because the cytotoxicity of the virus was inactivated or the responsibility of the host was impaired or the latent or chronic persistent infection of the virus was sustained. Price et ~ 1 . ' " have indicated a patient of herpes simplex encephalitis developed during the course of Hodgkin's disease, whose illness progressed slowly presumably because of his depressed immune system. Moreover, we have reported in another place a case of herpes simplex encephalitis in which the latent herpes simplex virus was activated probably by preceding purulent lept~meningitis.~~ There are also several cases of recurrent herpes
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simplex encephalitis in Iiterat~re,~ although the reactivating factors are nuclear. Our case seemed to have aggravated after an administration of corticosteroids. In addition to these, improved treatment of the patients might also have contributed to the protracted course. Nowadays two types of herpes simplex viruses are known.3 Type one is said to produce an acute necrotic encephalitis to an adult. While type two brings about a generalized herpes simplex virus infection to a neonate and serous meningitis to an adult. Thus the disposition of herpes simplex virus infections seems to vary considerably according to its subtypes or its infected hosts. Besides, recently, clinical cases with herpes simplex encephalitis which take a far more benign course without any deficits have become increasingly evident.8 l6 Herpes simplex virus infections may have a far wider spectrum beyond our expectation and bring about protracted or chronic encephalitis at times such as ours, although it is a problem to be solved in the future-to know whether all of these protracted cases are truly variants of herpes simplex encephalitis, and what is the true factor for its protraction. SUMMARY
Clinical and neuropathological findings in a case of an unusually protracted encephalitis have been described. The patient was a 44-year-old man who experienced mental deterioration, right abducens and facial paresis, right and, subsequently, left hemiparesis, and consciousness disturbance with an intermittent low grade fever and occasional headache during one year and three months. Electroenphalograms showed periodic lateralized epileptiform discharges. Virus titers including herpes simplex virus were all normal. Neuropathological examinations revealed marked atrophic changes in the right temporal lobe, insular lobe and hippocampus with minimal inflammatory signs. The distribution of the
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lesions was almost identical with that of acute necrotic encephalitis or herpes simplex encephalitis despite its unusually protracted
course. ACKNOWLEDGMENT
The authors are very grateful to Prof. Shukuro Araki, Chairman of the Third Department of Internal Medicine, Miyazaki Medical College, for his valuable advice and reviewing the manuscript. REFERENCES 1 Abe, M. and Suetsugu, M.: An autopsy
case of necrotizing encephalitis with sequelae of character change and dementia, Adv Neurol Sci (Tokyo), 16: 545, 1972 (in Japanese). 2 Akai, J., Kato, Y. et Takase, M.: Etude clinico-pathologique concernant syndrome de Kluver-Bucy chez l'homme, Discussion dans des cas d'enckphalite nkcrosante, Psychiat Neurol Jap, 70: 67-87, 1977 (in Japanese). 3 Baringer, J. R.: Herpes simplex virus infections of the nervous system, in Textbook of Clinical Neurology, ed. by Vinken, P. J. and Bruyn, G. W., Vol. 34, Infection of the Nervous System, Part 11: 145-159, 1978, North-Holland Pub. Co., Amsterdam. 4 Booth, C. B., Okazaki, H. and Gaulin, J. C.: Acute inclusion encephalitis of herpes simplex type, Neurology, 11: 619-629, 1961. 5 Chatrian, G. E., Shaw, C.-M. and Leffman,
rhinencephalic and insular regions, Folia Psychiat Neurol Jap, 27: 29-42, 1973. 8 Johnson, K. P., Rosenthal, M. S. and Lerner, P. I.: Herpes simplex encephalitis, The course in five virologically proven cases, Arch Neurol, 27: 107-108, 1972. 9 Milstein, J. M. and Biggs, H. E., Jr.: Recurrent encephalitis with elevated titers for herpes simplex, Arch Neurol, 34: 434-436, 1977. 10 Price, R., Chernik, N. L., Horta-Barbosa,
L. and Posner, J. B.: Herpes simplex encephalitis in an anergic patient, Amer J Med, 54: 222-228, 1973. 11 Radermecker, J,, Flament, J., Guazzi, G. C. et Troch, C.: Enckphalite necrosante aigu6 avec survie sans siquelles neuro-psychiatriques graves, Rev Neurol, 106: 368-380, 1962. 12 Seitz, D.: Akute nekrotisierende Encepha-
litis mit protrahiertem Verlauf, Dtsch Z Nervenheilk, 189: 39-52, 1966. 13 Shirabe, T., Nomura, N., Terao, A. and Araki, S. : Herpes simplex encephalitis, A light and electron microscopic study in a fatal case, Folia Psychiat Neurol Jap, 27: 17-27, 1973. 14 Shirabe, T., Okamoto, S. and Yoshimura,
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H.: The significance of periodic lateralized epileptiform discharges in EEG, An electrographic, clinical and pathologic study, Electroencephalogr Clin Neurophysiol, 17: 177193, 1964. 6 Ch'ien, L. T., Boehm, R. M., Robinson, H.,
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Lui, C. and Frenkel, L. D.: Characteristic early electroencephalographic changes in herpes simplex encephalitis, 34: 361-364, 1977. 7 Ishino, H., Nomura, S. and Sarai. J.:
Chronic necrotizing encephalitis involving mainly the gray matter of the temporo-
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M.: Coexistent purulent leptomeningitis and herpes simplex encephalitis, Case report with postmortem study, Folia Psychiat Neurol Jap, 28: 379-388, 1974. Shoji, H.: Clinical features of herpes simplex encephalitis, Clin Neurol (Tokyo), 13: 491-498, 1973 (in Japanese). Smith, J. B., Westmoreland, B. F., Reagan, T. J. and Sandok, B. A.: A distinctive clinical EEG profile in herpes simplex encephalitis, Mayo Clin Proc, 50: 469-474, 1975. Tateishi, J., Peters, G. und Minauf, M.: Bericht uber 18 Falle akuter nekrotisierender Encephalitis (van Bogaert) , Adv Neurol Sci (Tokyo), 15: 1032-1040, 1971 (in Japanese). Totsuka, S., Matsumoto, Y., Moro, K., Haneda, T. and Kubota, Y.: A case of acute necrotizing encephalitis with a protracted course, Adv Neurol Sci (Tokyo), 13: 431, 1969 (in Japanese). van Bogaert, L., Radermecker, J. et Devos, J.: Sur une observation mortelle d'enckphalite aigue nkcrosante, Rev Neurol, 92: 329356, 1955.
