- Email: [email protected]
Subacute inclusion body encephalitis
COMMENTS CURRENT
ON LITERATURE
Subacute inclusion body encephalitis
S i N C E D a w s o n ' s 1 original reports i n 1933 and 1934 of an unusual subacute progressive encephalitis, there has been increasing recognition of such a disorder affecting children and young people in which many cortical neurons and glial cells show type A intranuclear inclusion bodies. In 1945 van Bogaert ~ recorded the findings in 3 similar patients and described the condition as a subacute sclerosing leukoencephalitis. In retrospect these cases were thought to represent essentially the same disorder. Patients with subacute inclusion body encephalitis are usually under the age of 20 years. The course of the illness, which has a gradual onset, is either acute or subacute, progressing as a rule to a fatal outcome. Low-grade, fluctuating fever is considered characteristic. Evidence of meningeal irritation is minimal. Spinal fluid findings are within normal limits, with the exception of increased pressure and a slight pleocytosis early in the course of the disease. The eerebrospinal fluid has been shown to reduce colloidal gold solutions regularly in lower dilutions, producing a first zone "paretic" curve. Mental deterioration is a prominent feature, accompanied in the child and the adolescent by night terrors or hallucinations and followed by a stage in which periodic involuntary movements occur at regular intervals of from 5 to 10 seconds. In this stage the electroencephalographie tracing is considered characteristic and, by
some, pathognomonic with periodic highvoltage complexes of a stereotyped pattern. A terminal phase marked by optic atrophy and akinetic mutism with signs suggestive of decortication leads to death. The total duration of the disease is extremely variable, from 6 weeks to 2 years or progressing more slowly, as long as 8 years. Autopsy studies have shown widespread involvement of both gray and white matter with eosinophilie intranuclear inclusion bodies in neurons and neuroglia. Associated with the presence of the inclusion bodies is an infiltration of lymphocytes and plasma cells. In some instances neuronal intracytoplasmic inclusion bodies which are smaller have been seen in addition to the larger intranuclear inclusion bodies. This is particularly true in the more slowly progressing subacute form of the disease. Both types of inclusion bodies are variable in size and form. The effect of the destructive agent is marked in the nuclei of both the astroeyte and the oligodendrite with prominent changes being noted in the nuclei of these cells. Remissions appear to be possible in the early stages of the disease. Kurtzke 3 in 1956 described a nonfatal case with the unusual features of acute onset, diagnosis during life, and clinical improvement beginning 5 months after the onset of the disease. Craniotomy which had been performed for sus465
466
Comments on current literature
pected brain tumor revealed only cerebral edema. On the microscopic examination of biopsy tissue from the brain, inclusion bodies characteristic of inclusion encephalitis were observed in neurons and glial cells. The subsequent course of this patient indicated serious residual damage although considerable mental function was regained. Attempts to isolate and identify a viral agent have not given consistent, reproducible results. In a few instances serologic studies were suggestive, but not conclusive, of recent herpetic infection. In certain cases a viral agent thought to be similar to herpes simplex has been recovered; difficulty was encountered, however, in establishing the agent in experimental animals ordinarily susceptible to strains of herpes virus. * The inclusion bodies seen in necropsy material from patients with inclusion encephalitis are variable in form and size, in comparison with those seen in herpes simplex meningoencephalitis which are considered more constant in form and size. In proved cases of herpes simplex meningoencephalitis, the gross pathology of the brain at necropsy has been consistently characteristic, a constant feature in all cases being necrosis of the temporal cortex accompanied by hemorrhage and tissue breakdown. The problem of etiology in inclusion body encephalitis is discussed in a recent publication by Simpson ~ of the University of Edinburgh, Scotland. Over a period of several years, Simpson encountered a number of patients with this condition who had evidence of previous liver disease or definite history of clinical hepatitis. Ten cases of subacute encephalitis of the Dawson-van Bogaert type are reported. Five patients showed evidence of previous liver disease and 3 had a definite history of clinical hepatitis. One patient had no history of jaundice, but the plasma thymol turbidity test was 8 units, and in this patient a 4-plus colloidal gold reaction was obtained. All 10 were censidered to be typical cases of inclusion body encephalitis in every respect, except that 1 of the patients was still living after 8 years, and the spinal fluid in this
March 1962
case had never shown the paretic type of Lange curve. Attempts to recover a viral agent from blood, spinal fluid, and brain tissue taken at necropsy were without success. An eleventh case, considered atypical, was of particular interest in that eventual recovery was virtually complete. This case was that of an l 1-year-old girl who had had jaundice with extreme lassitude and fatigue 16 months before the onset of a subacute encephalitis with focal seizures and signs suggesting mental deterioration. On admission to the neurological service she showed extreme fear and was very restless with questionable spasticity on the right side. An electroencephalogram at this time showed widespread delta activity with greater amplitude in the right central region. The cerebrospinal fluid contained 22 lymphocytes per cubic millimeter, 50 rag. per cent of protein, and showed a Lange curve of 1113330000. Within the next few days the spinal fluid cell count increased to 32 lymphocytes with a Lange curve of 4555532100. The Wassermann reaction was consistently negative. This child improved slowly over a period of 4 months with recovery virtually complete in 7 months after the onset of an encephalitis similar in many respects to the Dawson type. In connection with the report of these cases, Simpson raises the question whether subacute inclusion body might represent a rare manifestation of infection with a strain of virus which usually causes hepatitis. He reviews the recorded cases of the Dawson-van Bogaert type of encephalopathy in which jaundice was known to have antedated the onset of central nervous system manifestations. Thiry 6 in 1956 and Brucher and DecheU in 1957 considered that the preceding jaundice which occurred in their patients represented a hepatic stage in the invasion of the body by a possible viral agent responsible for the subacute encephalitis. Simpson points out, however, that if "the association of jaundice with encephalitis after a long latent period . . . is confirmed, then the interpretation is rather different.
Volume 60 Number 3
T h e virus of infective hepatitis . . . with its known predilection for childhood subicteric infection and its frequent tendency to remain in the body as a potential pathogen would be a suitable candidate for the causative agent of subacute inclusion-body encephalitis. ''~ Techniques are now available which permit the isolation and propagation in tissue culture of viruses capable of causing hepatitis in the h u m a n subject. By this means virus isolates f r o m the blood of h e p a t i t i s patients have been shown t o produce the disease in h u m a n volunteers. 8 Utilization of such techniques in a study of patients with encephalitis in asociation with hepatitis or liver disease should prove of m a j o r interest. RUSSELL J. BLATTNER~ M.D,
REFERENCES
1. Dawson, J. R., Jr.: Cellular Inclusions in Cerebral Lesions of Lethargic Encephalitis, Am. J. Path. 9: 7, 1933.
C o m m e n t s on current literature
2. 3. 4.
5. 6. 7.
8.
467
Cellular Inclusions in Cerebral Lesions of Epidemic Encephalitis, Arch. Neurol. & Psychiat. 31: 685, 1934. van Bogaert, L.: Une leuco-enc~phalite scl6rosante subaiqu~, J. Neurol., Neurosurg. & Psychiat. 8: 101, 1945. Kurtzke, J. F.: Inclusion Body Encephalitis: A Nonfatal Case, Neurology 6: 371, 1956. Foley, John, and Williams, Dennis: Inclusion Encephalitis and Its Relation to Subacute Sclerosing Leucoencephalitis, Quart J. Med. 22: 157, 1953. Simpson, John A.: Subacute Inclusion-Body Encephalitis: A Possible Association With Infective Hepatitis, Lancet 2: 685, 1961. Thiry, S.: Leucoenc~phalite scl~rosante subaiqu~, Rev. m~d. Liege 11: 225, 1956. Brucher, J. M., and Dechef, G.: Etude anatomo-clinique d'un cas de leucoenc~phalite scl~rosante subaiqu~, Acta neurol, et psychiat. belg. 57: 775, 1957. Rightsel, W. A., Keltsch, R. A., Taylor, A. R., Boggs, J. D., and McLean, I. W., Jr.: Status Report on Tissue-Culture Cultivated Hepatitis Virus: I. Virology Laboratory Studies, J, A. M. A. 177: 671, 1961. Boggs, J. D., Capps, R. B., Weiss, C. F., and McLean, I. W., Jr.: Status Report on TissueCulture Cultivated Hepatitis Virus: II. Clinical Trials, J. A. M. A. 177: 678, 1961.
ON LITERATURE
Subacute inclusion body encephalitis
S i N C E D a w s o n ' s 1 original reports i n 1933 and 1934 of an unusual subacute progressive encephalitis, there has been increasing recognition of such a disorder affecting children and young people in which many cortical neurons and glial cells show type A intranuclear inclusion bodies. In 1945 van Bogaert ~ recorded the findings in 3 similar patients and described the condition as a subacute sclerosing leukoencephalitis. In retrospect these cases were thought to represent essentially the same disorder. Patients with subacute inclusion body encephalitis are usually under the age of 20 years. The course of the illness, which has a gradual onset, is either acute or subacute, progressing as a rule to a fatal outcome. Low-grade, fluctuating fever is considered characteristic. Evidence of meningeal irritation is minimal. Spinal fluid findings are within normal limits, with the exception of increased pressure and a slight pleocytosis early in the course of the disease. The eerebrospinal fluid has been shown to reduce colloidal gold solutions regularly in lower dilutions, producing a first zone "paretic" curve. Mental deterioration is a prominent feature, accompanied in the child and the adolescent by night terrors or hallucinations and followed by a stage in which periodic involuntary movements occur at regular intervals of from 5 to 10 seconds. In this stage the electroencephalographie tracing is considered characteristic and, by
some, pathognomonic with periodic highvoltage complexes of a stereotyped pattern. A terminal phase marked by optic atrophy and akinetic mutism with signs suggestive of decortication leads to death. The total duration of the disease is extremely variable, from 6 weeks to 2 years or progressing more slowly, as long as 8 years. Autopsy studies have shown widespread involvement of both gray and white matter with eosinophilie intranuclear inclusion bodies in neurons and neuroglia. Associated with the presence of the inclusion bodies is an infiltration of lymphocytes and plasma cells. In some instances neuronal intracytoplasmic inclusion bodies which are smaller have been seen in addition to the larger intranuclear inclusion bodies. This is particularly true in the more slowly progressing subacute form of the disease. Both types of inclusion bodies are variable in size and form. The effect of the destructive agent is marked in the nuclei of both the astroeyte and the oligodendrite with prominent changes being noted in the nuclei of these cells. Remissions appear to be possible in the early stages of the disease. Kurtzke 3 in 1956 described a nonfatal case with the unusual features of acute onset, diagnosis during life, and clinical improvement beginning 5 months after the onset of the disease. Craniotomy which had been performed for sus465
466
Comments on current literature
pected brain tumor revealed only cerebral edema. On the microscopic examination of biopsy tissue from the brain, inclusion bodies characteristic of inclusion encephalitis were observed in neurons and glial cells. The subsequent course of this patient indicated serious residual damage although considerable mental function was regained. Attempts to isolate and identify a viral agent have not given consistent, reproducible results. In a few instances serologic studies were suggestive, but not conclusive, of recent herpetic infection. In certain cases a viral agent thought to be similar to herpes simplex has been recovered; difficulty was encountered, however, in establishing the agent in experimental animals ordinarily susceptible to strains of herpes virus. * The inclusion bodies seen in necropsy material from patients with inclusion encephalitis are variable in form and size, in comparison with those seen in herpes simplex meningoencephalitis which are considered more constant in form and size. In proved cases of herpes simplex meningoencephalitis, the gross pathology of the brain at necropsy has been consistently characteristic, a constant feature in all cases being necrosis of the temporal cortex accompanied by hemorrhage and tissue breakdown. The problem of etiology in inclusion body encephalitis is discussed in a recent publication by Simpson ~ of the University of Edinburgh, Scotland. Over a period of several years, Simpson encountered a number of patients with this condition who had evidence of previous liver disease or definite history of clinical hepatitis. Ten cases of subacute encephalitis of the Dawson-van Bogaert type are reported. Five patients showed evidence of previous liver disease and 3 had a definite history of clinical hepatitis. One patient had no history of jaundice, but the plasma thymol turbidity test was 8 units, and in this patient a 4-plus colloidal gold reaction was obtained. All 10 were censidered to be typical cases of inclusion body encephalitis in every respect, except that 1 of the patients was still living after 8 years, and the spinal fluid in this
March 1962
case had never shown the paretic type of Lange curve. Attempts to recover a viral agent from blood, spinal fluid, and brain tissue taken at necropsy were without success. An eleventh case, considered atypical, was of particular interest in that eventual recovery was virtually complete. This case was that of an l 1-year-old girl who had had jaundice with extreme lassitude and fatigue 16 months before the onset of a subacute encephalitis with focal seizures and signs suggesting mental deterioration. On admission to the neurological service she showed extreme fear and was very restless with questionable spasticity on the right side. An electroencephalogram at this time showed widespread delta activity with greater amplitude in the right central region. The cerebrospinal fluid contained 22 lymphocytes per cubic millimeter, 50 rag. per cent of protein, and showed a Lange curve of 1113330000. Within the next few days the spinal fluid cell count increased to 32 lymphocytes with a Lange curve of 4555532100. The Wassermann reaction was consistently negative. This child improved slowly over a period of 4 months with recovery virtually complete in 7 months after the onset of an encephalitis similar in many respects to the Dawson type. In connection with the report of these cases, Simpson raises the question whether subacute inclusion body might represent a rare manifestation of infection with a strain of virus which usually causes hepatitis. He reviews the recorded cases of the Dawson-van Bogaert type of encephalopathy in which jaundice was known to have antedated the onset of central nervous system manifestations. Thiry 6 in 1956 and Brucher and DecheU in 1957 considered that the preceding jaundice which occurred in their patients represented a hepatic stage in the invasion of the body by a possible viral agent responsible for the subacute encephalitis. Simpson points out, however, that if "the association of jaundice with encephalitis after a long latent period . . . is confirmed, then the interpretation is rather different.
Volume 60 Number 3
T h e virus of infective hepatitis . . . with its known predilection for childhood subicteric infection and its frequent tendency to remain in the body as a potential pathogen would be a suitable candidate for the causative agent of subacute inclusion-body encephalitis. ''~ Techniques are now available which permit the isolation and propagation in tissue culture of viruses capable of causing hepatitis in the h u m a n subject. By this means virus isolates f r o m the blood of h e p a t i t i s patients have been shown t o produce the disease in h u m a n volunteers. 8 Utilization of such techniques in a study of patients with encephalitis in asociation with hepatitis or liver disease should prove of m a j o r interest. RUSSELL J. BLATTNER~ M.D,
REFERENCES
1. Dawson, J. R., Jr.: Cellular Inclusions in Cerebral Lesions of Lethargic Encephalitis, Am. J. Path. 9: 7, 1933.
C o m m e n t s on current literature
2. 3. 4.
5. 6. 7.
8.
467
Cellular Inclusions in Cerebral Lesions of Epidemic Encephalitis, Arch. Neurol. & Psychiat. 31: 685, 1934. van Bogaert, L.: Une leuco-enc~phalite scl6rosante subaiqu~, J. Neurol., Neurosurg. & Psychiat. 8: 101, 1945. Kurtzke, J. F.: Inclusion Body Encephalitis: A Nonfatal Case, Neurology 6: 371, 1956. Foley, John, and Williams, Dennis: Inclusion Encephalitis and Its Relation to Subacute Sclerosing Leucoencephalitis, Quart J. Med. 22: 157, 1953. Simpson, John A.: Subacute Inclusion-Body Encephalitis: A Possible Association With Infective Hepatitis, Lancet 2: 685, 1961. Thiry, S.: Leucoenc~phalite scl~rosante subaiqu~, Rev. m~d. Liege 11: 225, 1956. Brucher, J. M., and Dechef, G.: Etude anatomo-clinique d'un cas de leucoenc~phalite scl~rosante subaiqu~, Acta neurol, et psychiat. belg. 57: 775, 1957. Rightsel, W. A., Keltsch, R. A., Taylor, A. R., Boggs, J. D., and McLean, I. W., Jr.: Status Report on Tissue-Culture Cultivated Hepatitis Virus: I. Virology Laboratory Studies, J, A. M. A. 177: 671, 1961. Boggs, J. D., Capps, R. B., Weiss, C. F., and McLean, I. W., Jr.: Status Report on TissueCulture Cultivated Hepatitis Virus: II. Clinical Trials, J. A. M. A. 177: 678, 1961.