Aust. N.Z. J. Med. (1977), 7, pp. 408413 CASE REPORT
Herpes Simplex Encephalitis R. S. Boyle” and P. J. Landyt From the Princess Alexandra Hospital, Brisbane
Summary: Herpes simplex encephalitis. R. S. Boyle and P. J. Landy, Aust. N.Z. 2. Med., 1977, 7, pp. 4 0 8 4 1 3.
In this paper seven cases of severe viral encephalitis seen over a four year period at the Princess Alexandra Hospital, Brisbane, are presented. Four of these cases were proven cases of Herpes simplex encephalitis on the basis of viral culture, and three were probable cases of Herpes simplex encephalitis on the basis of rising serum antibody titres. A summary of the clinical aspects and laboratory investigations of the cases is followed by a brief discussion of the diagnostic and therapeutic problems of this condition.
Herpes Simplex virus is probably the commonest cause of sppradic, necrotising encephalitis occurring in temperate climates.’ Since the advent in 1969 of “specific” anti-viral therapy, early diagnosis of Herpes Simplex encephalitis (HSE) and evaluation of the efficacy of its treatment have become more important. While increasing numbers of cases are being reported in the literature, and the clinical entity is becoming more clearly defined, there is still uncertainty as to the best way to manage this condition. During the four years, 1972 to 1975, seven cases of severe encephalitis which were subsequently shown to be either proven or probable cases of HSE have been seen by one of us (P.J.L.).Four are proven cases (Cases 1, 4,5, 6) on the basis of virus isolation from brain biopsy during life or from post-mortem speciNeurology Registrar. tSenior Neurologist. Correspondence: Dr. R. S. Boyle, Neurology Registrar, Princess Alexandra Hospital, lpswich Road, Woolloongabba, Brisbane, Queensland 41 02 Accepted for publication: 21 March, 1977
mens. Three of the patients (Cases 2, 3, 7) had a four-fold or greater rise in antibody titre and, one of these (Case 7) had positive immunofluorescence on brain biopsy. Thus these three are probable cases of HSE. Case Reports Case 1
This 53-year-old woman presented with a 24 hour history of fever, headache and confusion. On examination she was found to have marked nuchal rigidity and to be febrile. Her conscious level rapidly deteriorated, and she died four days after admission, on the evening that idoxuridine was obtained for her treatment. She was treated with dexamethasone in high dosage (40 mg/day) from the time of admission. Case 2 This 16-year-old male was admitted three days after the onset of severe frontal headache. This headache was followed within 24 hours by fever and deterioration in his conscious state. At the time of admission he was found to be confused and febrile with nuchal rigidity. The only focal neurological sign was a nominal dysphasia, which became apparent as his conscious state improved. He was treated with a two-week course of tetracosactrin (1 mg daily), and during this time his level of consciousness steadily improved. He was reviewed approximately four months after the onset of the illness, and at that stage he exhibited quite marked nominal dysphasia, with poor short term memory and poor concentration. He had also developed seizures which proved difficult to control. He was not able to work in the open community. Case 3
This woman, aged 52 years, was admitted to Princess Alexandra Hospital (PAH) approximately one month after discharge from another hospital, where she had been given a course of cytosine arabinoside for presumed HSE (the records of this admission are not available to us). At the time of her admission to PAH, she was confused and very drowsy, with no localising CNS signs. Her relatives stated that her level of consciousness had deteriorated over the preceding two weeks. She was treated with a further three courses of cytosine arabinoside, the total dose being 6 g, together with dexamethasone in high dosage. Her mental state did not improve, and she was transferred to a Mental Hospital. Despite the large amount of cytosine arabinoside used, there was no marrow depression detected by examination of the peripheral blood. Case 4 This 54-year-old male was admitted with a three day history of fever, headache, confusion and increasing drowsiness.
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HERPES SIMPLEX ENCEPHALITIS
Eighteen hours prior to admission he suffered a grand ma1 convulsion, which commenced with left sided facial twitching. Over the next 24 hours his condition rapidly deteriorated, initially with the development of a left homonymous hemianopia and left hemiparesis ; subsequently he lapsed into coma, with marked extensor spasms. Brain biopsy was performed and treatment with dexamethasone and cytosine arabinoside commenced. However, his condition did not improve, and by the tenth day after admission it was evident that he had developed disseminated intravascular coagulopathy, with a generalised bleeding tendency. He died 14 days after admission, and post-mortem revealed extensive recent haemorrhages in most organs examined. The use of cytosine arabinoside in this case was complicated by the development of marked thrombocytopenia, with the lowest platelet level recorded being 30,000/mm3. The haematologist felt that his state of disseminated intravascular coagulopathy (the result of extensive brain necrosis initially), played a major role in the development of thrombocytopenia.
Case 5 A 14-year-old girl was admitted with a one month history of increasing headache, and a four day history of an influenzal-type illness with fever and myalgia. She had become irritable and confused 24 hours prior to admission, and was noted by her parents to have a right hemiparesis on the morning of her admission. On examination she was very drowsy and irritable, with nuchal rigidity, fever and a right hemiplegia, right hemianaesthesia and hemianopia. Treatment with cytosine arabinoside and dexamethasone was commenced 24 hours after admission, following a brain biopsy. Over the subsequent two weeks, she made a dramatic recovery and at the time of her discharge, three weeks after the onset of the illness, there was no noticeable neurological deficit. Psychometric testing, performed three months after discharge revealed no abnormality. Cytosine arabinoside therapy in this case was complicated by neutropenia, the lowest white cell count recorded being 1900/mm3 with 16’; neutrophils. This was 18 days after cytosine arabinoside was ceased, and was not associated with any infection.
Case 6 This 14-year-old girl was admitted with a five day history of headache and fever. She had become confused and drowsy over the two days prior to admission. She was found on examination to be febrile, drowsy and confused and had marked nuchal rigidity. This girl fared very badly in comparison with the previous case. Her level of consciousness continued to deteriorate over the first two weeks in hospital. She became deeply comatose, with extensor plantar responses, and manifested the ocular sign of “bobbing”, indicating pontine involvement. This “bobbing” persisted from the third to the eighth week. Despite two courses of cytosine arabinoside and continuous dexamethasone treatment, she improved very little. At the time of review, six months after the onset of her illness, she was found to be mute, incontinent and unable to co-operate in any way with the nursing staff. Cytosine therapy in her case resulted in considerable marrow depression, the lowest white cell count recorded being 21W/mm3, with 30% neutrophils ; this occurred seven days after the cessation of cytosine arabinoside.
Case I This 66-year-old male presented with a four day history of headache, fever and fluctuating confusion. One day prior to admission he developed a total expressive aphasia. On admission he was found to be febrile, with an expressive aphasia and a partial receptive dysphasia. Six hours after admission he developed epilepsia partialis continua, affecting the right arm. This was controlled with intravenous diazepam; it then became evident that he had a right monoplegia affecting the arm, which progressed to a right hemiplegia over the next 24 hours. He was submitted to a temporal lobe brain biopsy, and was commenced on cytosine arabinoside four days after admission. His consciousness improved initially, but four days after commencement of cytosine arabinoside he became comatose, with a left third nerve palsy. Repeat carotid angiography at this stage revealed marked swelling of the left temporal lobe. It was felt that this was probably due to an inflammatory response to the encephalitic process, rather than the result of the brain biopsy (in view of the virtually atraumatic nature of the biopsy). He was treated with mannitol, dexamethasone was continued, and his consciousness gradually improved. The right hemiplegia also gradually resolved. He was eventually discharged to the care of his wife. At the time of review, six months after the onset of the illness, he was found to be coping with a protected domestic life. There were minimal residual signs of a right hemiparesis, but there was still marked expressive dysphasia and obvious intellectual impairment. In this case cytosine arabinoside therapy did not produce marrow depression as detected by examination of the peripheral blood. These clinical aspects are summarised in Tables 1 and 2. Methods and Results Cerebro-spinul Fluid Findings
Lumbar puncture was carried out in all cases and the results are shown in Table 3 with the time interval from onset of mental symptoms, i.e. confusion and/or deterioration in consciousness, shown in days. It can be seen that, as has been reported p r ev i o ~ sl y ~ - ~ the , typical findings were those of a lymphocytic pleocytosis together with elevated protein levels. Frankly haemorrhagic CSF was not a feature in any of our cases. The CSF sugar levels were universally normal. Serological Studies
Blood was submitted for complement fixation tests for herpes simplex antibodies in five of the seven cases. Four-fold TABLE 1 ‘ Cases and outcome Case
Age
Sex
Outcome
1 2
53 16
F M
3 4 5 6 I
52 54 14 14 66
F M F F M
Death Epilepsy. Moderate intellectual impairment Gross intellectual impairment Death Full recovery Gross intellectual impairment R. hemiparesis, dysphasia, moderate intellectual impairment
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BOYLE AND LANDY TABLE 2
TABLE 4
Drugs used in therapy
Results of serum complement fixation titres for viral antibodies
Idoxuridine
Cytosine arabinoside
Case
Time base (days)
First specimen
Lag* (days)
Second specimen
ACTH
Dexamethasone
+
1 7
+
3
-
Dose
Days
Dose (g)
Days'
7
1/16
33
]/I28
28
L/256
3540 None submitted 3 7 9
1/32
30
11128
12
1/128
24 14
1/32 1/16
16
1/16
None submitted
Died the evening idoxuridine obtained
-
-
+
Lag Third (days) specimen
-
~
Case
7, NO. 4
-
2.0 1 .o 3.0 2.0 1.6 1.6 1.6 2.0
10-14 46-49 54-59 5-8 2-6 8-12 3&34 8-12
'Time basis is taken from onset of encephalitic stage
or greater rises in titres over a two week or longer period were found in Cases 2 , 3 , 6 and 7. These were taken to indicate herpes simplex as a probable aetiological factor, although the possibility of the rise in titres being due to incidental herpes infection must be considered6 No blood was submitted for serology in Cases 1 or 4, but the positive diagnosis of HSE was established by other means. Only one specimen was submitted in Case 5, but the diagnosis again was established by other means. The high titre in the one specimen submitted in Case 5, however, was highly suggestive of a recent herpes simplex infection. Because of the time lag involved, this is an unsuitable means of establishing the diagnosis, if early therapy is to be undertaken. In three cases, including one proven case of HSE, viral culture was attempted from the CSF but did not yield any viral growth. Table 4 shows the titres recorded. Electroencephalographic Results Electroencephalograms were performed in all cases. Upton and Gumpert7 described four sequential abnormalities of the EEG which because of their time relation they felt were typical of HSE. We were not able to demonstrate any such typical pattern, although all EEGs were markedly abnormal and showed
~
-
~
'Time between taking of sequential specimens, and initial time base as in Table 2
features which have been mentioned in past reports7,*; notably diffuse slowing of background activity, focal temporal lobe disturbances and the appearance of periodic complexes. In our limited experience there were no features on the EEG which could allow us to indicate the prognosis. Elian' felt that the presence of periodic complexes was a poor prognostic feature, although not specific for HSE. We found that the presence of periodic complexes did not correlate with the prognosis. Radio-isotope Brain Scan
Technetium brain scanning was performed in all except Case 3. In Table 5, it can be seen that, in general, EEG and brain scan findings correlated well, with respect to lateralisation of the process. Three of our four definite cases of HSE (4,5 and 6) had marked scan changes, as did two of the three probable cases (2 and 7). A brain scan performed on Case 1, our other definite case, showed no abnormality at five days after the onset of encephalitis symptoms. Radcliffeg has pointed out that isotope scanning may be negative early in the clinical course of this disease, and this may be the explanation of a negative scan in Case 1.
TABLE 5 Technetium brain scan and EEG results
Case
TABLE 3
11128 -
Time ofscan' (days)
Technetium scan
EEG localisation
Periodic complexes
CSF results (time base same as for Table 2)
Case 1
Time (days)
Protein Sugar WCC RBC (mg/IOOml) (mg/100ml) (per mm') monos (per mm') (NR 2 W O ) (NR 4&80)
1
5 2 3
4 5 6 7
2 16 7 41 58 4 3 3 9
50 76 200 183 160 18
40 62 168 639 126
50 LOO 98 100
100 100 100 100
70 99 100
183 20 90 228 ? 1
150 92 43 37 0
44 152 84 144 83 91 71 64 167 126 66
53 57 60 43 60 65' 59' 72 62 64 64
Normal
Generalised slow wave activity
-
11
Increased uptake L hemisphere
L hemisphere slow wave focus
-
3
-
Not done
Generalised slow wave activity
-
4
8
Increased uptake R temporal region
R hemisphere slow wave focus
5
1
Increased uptake R hemisphere
R hemisphere slow wave focus
6
8
Increased uptake both temporal regions
Generalised slow wave activity
1
8
Increased uptake L temporal region
L temporal slow wave focus
1
5
2
'After cytosine therapy.
'Time basis as in Table 2.
+ -
+ +
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1977
Time' (days)
41 1
HERPES SIMPLEX ENCEPHALITIS TABLE 6
TABLE 7
Results of angiography
Results of temporal lobe biopsy
Investigalion
Findings Case
Time* (days]
Inclusion bodies
virus isolation
lmmunotiuorescence
.-
3
?7
RCA
N A D (performed at another hospital)
4
8
RCA
Temporal SOL with capillary blush Midline shifted to left Early venous drainage in area of Sylvian fissure
5
I
RCA
Temporal SOL with capillary blush
6
40
LCA
NAD
8
BCA
I?
LCA
NAD Temporal SOL with capillary blush Midline shift to right
7
*Same time basis as in Table 2
Neuro-radiological Studies (see Table 6 ) Carotid angiography was performed at this hospital in Cases 4, 5, 6 and 7. In Cases 4, 5 and 7 features suggestive of HSE were found, i.e. (1) Capillary phase abnormalities with prominent vascular blush; (2) Early venous drainage; (3) Shift of midline structures; (4) Evidence of a temporal lobe space occupying lesion. In the recent series of Pexman'O, all of his cases showed marked abnormalities. Two of our cases (4 and 7) showed evidence of midline shift, while in Cases 4, 5 and 7, capillary phase abnormalities were found. Unlike Pexman's series, none of our cases showed multiple site involvement. From our limited experience it seems that isotope scanning is a more sensitive diagnostic test in the early stages of the disease than carotid angiography. In Case 3, an air encephalogram was performed which was normal and we would agree with Amin", that there is no need to proceed to this investigation. In this case the right carotid angiogram had previously been performed at another hospital, approximately one week after the onset of a confusional state, and was reported as normal. Brain Biopsy (see Table 7) The predilection for the virus to attack the temporal lobes and limbic areas has been demonstrated in the past'*, and temporal lobe biopsy can be expected to yield positive results in a large percentage of cases. In our series, temporal lobe biopsy was performed during life in Cases 4, 5 , 6 and 7 and in all these cases necrotising encephalitis with marked round cell infiltration, cerebral oedema and neuronolysis were demonstrated. Eosinophilic intranuclear inclusion bogies were found in Cases 4, 5 and 7. While these are typical of HSE they are not diagnostic of the disease, nor does their absence exclude the diagnosis. At the present time in our city, the only definitive means of diagnosing HSE appears to be isolation of the virus from brain biopsy specimens. The virus was isolated in Cases 4, 5 and 6, but not in Case 7. In Case 6 the virus was isolated in the absence of inclusion bodies in the brain biopsy specimen, while in Case 7, the virus was not isolated despite the presence of these inclusion bodies. Cases 1 and 4 were submitted to post mortem examination which revealed, in Case 4,a large area of haemorrhagic necrosis replacing the right temporal lobe with widely scattered smaller areas of haemorrhagic necrosis throughout the cerebral tissue. In Case 1, both temporal lobes were replaced by haemorrhagic necrotic tissue, the left being involved to a greater extent than the right. It is interesting to note that, in this
4
Postmortem N o biopsy No biopsy 8
5 6 7
8 8
I
2 3
-
+
Not done
+ +
+
Not done
+
-
+ +
-
+ +
+
'Time base same as for Table 2.
case, although multiple post mortem biopsy specimens were sent for viral culture from both temporal lobes and other areas microscopically normal, only one specimen (from the left temporal lobe) grew herpes virus. Each specimen was inoculated into a separate tube. The virus was isolated from post-mortem specimens in Case 4, as well as from a brain biopsy performed during life. The biopsy specimens in Cases 5, 6 and 7 were submitted to immunofluorescence studies and in all three the result was strongly positive for herpes simplex. This is despite the fact that in Case 7 the virus was not isolated in culture from the biopsy specimen. The method used was an indirect immunofluorescence technique, using conjugated anti-IgM. Immunofluorescence techniques should give positive results for herpes simplex virus in four to six hours after the specimen is received, but they have not replaced viral cultures as the definitive means of diagnosis in our laboratories at present. L ~ n g s o n 'recently ~ provided an excellent review of the techniques which may be employed. Facilities for electron microscopic examinations of biopsy specimens were not available, but the use of this technique to demonstrate intranuclear viral particles is thought by many workers to be a definitive means of making the diagnosis of herpes simplex infe~ti0n.I~ Discussion
Seven cases of severe encephalitis have been described, four of which (1,4, 5 and 6) have been proven by viral culture to be due to herpes simplex. The remaining three (2, 3 and 7) have been classified as probable cases of herpes simplex encephalitis on the basis of a four-fold or greater rise in antibody titre. Of the seven cases described, two cases (1 and 4) died. Of the remaining five cases, only one, Case 5, made a complete recovery, the other four patients being intellectually handicapped to a significant extent. These results seem to be in accord with previously published reports, and indicate the devastating permanent effect that the herpes simplex virus frequently has on the human nervous system. The clinical pattern of the illness has been better defined over recent years, and probably for this reason the diagnosis
412
BOYLE A N D LANDY
in our hospital is being considered more frequently than in the past. We found that the diagnosis had to be considered in a patient who presented with a rapid deterioration in level of consciousness, following a non-specific prodromal illness of short duration, in which fever, headache and nuchal rigidity were frequent features. CSF findings of an elevated protein and monocytic pleocytosis supported the diagnosis of HSE. Neuroradiological and isotope scanning evidence of a temporal lobe vascular mass lesion were further supporting features of HSE. The EEG was also useful in supporting the diagnosis, with slow activity, sometimes lateralised to one hemisphere, and the appearance of periodic complexes being prominent features. In our hospital, definitive diagnosis still rests on viral culture. Other workers, who have had more experience in the techniques, feel that immunofluorescence studies and electron microscopic observation on affected brain tissue are definitive means of establishing the diagnosis. In either case it is clear that the final diagnosis still rests on a brain biopsy specimen. While this is an invasive technique, we feel that, if controlled studies are to be made on the efficacy of treatment of the disease, then the diagnosis must be unequivocally made. The drugs which are currently used in the treatment of this disease are, in themselves, potentially lethal, due mainly to their marrow depressant effect. Thus, a decision as to whether or not they are effective in arresting the disease process is vitally important. In addition to the cases described above, there have been only two cases biopsied in the four year period in whom the clinical diagnosis of HSE was not supported by viral culture or rising antibody titres. Both these cases showed histological features consistent with a severe viral encephalitis. In none of the cases biopsied did we feel that the procedure had any significant complication. Hence we believe that it is a necessary step to obtain a biopsy specimen, and one in which the risk involved is not great. Moreover, the needling of an affected temporal lobe will distinguish a viral encephalitis from a bacterial brain abscess, a condition which can mimic HSE, and which is potentially curable. As indicated above, there is. still no certainty
VOL.
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as to whether the use of either cytotoxic or corticosteroid drugs is effective in this disease. All of our cases were treated with steroids, and five (Cases 3, 4, 5, 6 and 7) with cytosine arabinoside. Idoxuridine was obtained with a view to using it in Case 1. The report of the Boston Inter-Hospital Study Group suggests that there is no real place for the use of idoxuridine therapy for HSE. The nature of idoxuridine toxicity (with respect to marrow depres~ion)’~-’~ has long been recognised. The report of the Boston InterHospital Study Groupi5 highlighted what is probably even a more disturbing feature, i.e. the lack of efficacy of this treatment in the control of spread of the virus. Cytosine arabinoside, a pyrimidine antagonist, has been used for some years in the treatment of HSE without any definite decision being ‘made as to its safety or efficacy. Five of our seven patients (see Table 2) received at least one course of this drug in doses ranging from 4 to 8 mgJkgJday over a five day course, in IV bolus injections given over a five minute period. Results similar to those reported by Gilbert et al.” were found; an early response, thought possibly related to therapy, occurred in Case 5. Rapid response to cytosine arabinoside therapy has been reported in a number of other papers4, , but to our knowledge no controlled trial has yet been carried out. While cytosine arabinoside therapy may have contributed to the death of Case 4, we feel that disseminated intravascular coagulopathy was probably a more significant factor. Neutropenia developed in most of the other cases and in two of them appeared seven and 18 days respectively after therapy with cytosine arabinoside was ceased; it then resolved spontaneously. Steroids were used at some stage in all cases, tetracosactrin being the sole therapeutic agent used in Case 2, while dexamethasone was used in the six other cases. The use of steroids in HSE is controversial. There have been objections to the use of steroids, on the theoretical grounds that steroids interfere with both interferon and antibody production.” However others have reported encouraging results with the use of de~amethasone.’~Johnson et aL2 reported dramatic improvement in two of their cases
’’,’’
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HERPES SIMPLEX ENCEPHALITIS
after steroid therapy alone. The debate continues on the use of steroids: the rationale for their use in our cases was reduction in cerebral oedema at a time when blood and CSF interferon should both have reached significant levels. Steroid therapy may also be useful in damping down the severe immunological response which probably occurs in the area of necrotising encephalitis. Despite the better delineation of the disease which has become apparent over recent years, the question as to efficacy of treatment remains as great a problem as ever. Obviously, we cannot draw any conclusions from these small numbers, but would emphasise the importance of the outcome of any controlled therapeutic trial. References 1. Leading article (1972): Herpes encephalitis, Brir. med. J . 1, 581. 2. JOHNSON, K. P.. ROSENTHAL, M. S . and LERNER, P I (1972): Herpes simplex encephalitis-The course in five virologically proven cases, Arch. Neurol. 17, 103 3. OLSEN, c. L.. BUESCHER, E. L., ARTENSTEIN, M. S. and PARKMAN, P. D. (1967): Herpesvirus infections of the human central nervous system, New Engl. J. Med. 177, 1271. 4. MCAULEY, D. L. and GLASGOW, G. L.11974): Herpes simplex encephalitis treatment with cytosine arabinoside, Ausr. N . Z . J . M r d . 4, 274.
413
5 . Leading article (1973): Herpes Simplex encephalitis, Lancet 2, 1426. 6. JOHNSON, R. T.. OLSEN,L. C. and B U ~ S C H EE.RL. , (1968): Herpes simplex virus infection of the nervous system-problems in laboratory diagnosis, Arch. Neurol. 18, 260. 7. UPTON.A. and GUMPERT, J . (1970): Electroencephalography in diagnosis of herpes simplex encephalitis, Luncet 1, 650. 8. ELIAN,M. E. (1975): Herpes simplex encephalitis-prognosis and long term follow-up, Arch. Neurol. 32, 39. 9. RADcLirFa. W. B., GUNTO,F. C , ADWCK. D F. and KRIGMAN, M. R (1972): Early localisation of herpes simplex encephalitis by radionuclide imaging and caroiid angiography. Radiology 105, 603. 10. PEXMAN, J H. W (1974): The angiographic and brain scan features of acute herpes simplex encephalitis, Brir J . Radiol. 47, 179. 1 1 . AMIN,P. H. (1972)- Radiological findings in herpes simplex encephalitis, Brit. J . Radiol. 45, 652. 12. HUGHES,L (19691: In: Virus diseases and the nervous system. Blackwell Scientific Publications 13. LONCSON,M. (1973): lmmunofluorescence in the diagnosis of herpes encephalitis, Postgrad. med. J . 49, 403. 14. HARLAND, W. A,, ADAMS, J. H. and MCSEVENEY, D. (1967):Herpes simplex particles in acute necrotising encephdlltk, Lancer 2, 581. 15. Boston Interhospital Study Group (1975): Failure of high dose 5-lodo Z'deoxyuridine in the therapy of herpes simplex virus encephalitis. NPU. Engl J . Med. 192, 599 16. NOLAN,D. C., CARRUTHERS, M. M. and LEUNER, A M (1970): Herpes virus homonis encephalitis in Michigan-report of 13 cases, including SIX treated with Idoxuridine. NPW Engl. 1. M r d 282, 10. 17. BREEDON, C . 1.. HALL,T. C. and TYLER,H. R (1966): Herpes simplex encephalitis treated with systemic 5-lodo Z'deoxyuridine, Ann. intern. Med. 65, 1050. 18 NOLAN,D. C., LAUTER,C. B. and LERNEn, A. M. (1973): Idoxuridine In herpes simplex (Type-I) encephalitis, Ann. intern. Med. 7 8 , 243. 19. GILBERT, D. N.. JOHNSON. M.T., LUBY, I . P. and SANFORD, 1. P. (1913): Herpesvirus homiuis Type-I encephalitis treated with cytarabine: an unresolved problem, Medicine 52, 331 20. FAURIS,W. A and BLOW,M. E (1972). Cytarabine treatment of herpes simplex encephalitis, Arch. Neurol 21, 99. 21. HRYNUIK, W., FOERSTER, J . , SHOJANIA. M. and CHOW,A. (1972):Cytarahme for herpes virus infections, J . Arnrr. med. ASS. 219, 715. 22 LONGSON,M. and BESWICK. T. S. L. (1971): Dexamethasone treatment in herpes simplex encephalitis, Loncrt 1 , 749. 23. UPTON,A. R. M., BARWICK, D. D. and FOSTER, J . B. (1971):Dexamethasone treatment in herpes simplex encephalitis. Lancet 1,290.
Herpes Simplex Encephalitis R. S. Boyle” and P. J. Landyt From the Princess Alexandra Hospital, Brisbane
Summary: Herpes simplex encephalitis. R. S. Boyle and P. J. Landy, Aust. N.Z. 2. Med., 1977, 7, pp. 4 0 8 4 1 3.
In this paper seven cases of severe viral encephalitis seen over a four year period at the Princess Alexandra Hospital, Brisbane, are presented. Four of these cases were proven cases of Herpes simplex encephalitis on the basis of viral culture, and three were probable cases of Herpes simplex encephalitis on the basis of rising serum antibody titres. A summary of the clinical aspects and laboratory investigations of the cases is followed by a brief discussion of the diagnostic and therapeutic problems of this condition.
Herpes Simplex virus is probably the commonest cause of sppradic, necrotising encephalitis occurring in temperate climates.’ Since the advent in 1969 of “specific” anti-viral therapy, early diagnosis of Herpes Simplex encephalitis (HSE) and evaluation of the efficacy of its treatment have become more important. While increasing numbers of cases are being reported in the literature, and the clinical entity is becoming more clearly defined, there is still uncertainty as to the best way to manage this condition. During the four years, 1972 to 1975, seven cases of severe encephalitis which were subsequently shown to be either proven or probable cases of HSE have been seen by one of us (P.J.L.).Four are proven cases (Cases 1, 4,5, 6) on the basis of virus isolation from brain biopsy during life or from post-mortem speciNeurology Registrar. tSenior Neurologist. Correspondence: Dr. R. S. Boyle, Neurology Registrar, Princess Alexandra Hospital, lpswich Road, Woolloongabba, Brisbane, Queensland 41 02 Accepted for publication: 21 March, 1977
mens. Three of the patients (Cases 2, 3, 7) had a four-fold or greater rise in antibody titre and, one of these (Case 7) had positive immunofluorescence on brain biopsy. Thus these three are probable cases of HSE. Case Reports Case 1
This 53-year-old woman presented with a 24 hour history of fever, headache and confusion. On examination she was found to have marked nuchal rigidity and to be febrile. Her conscious level rapidly deteriorated, and she died four days after admission, on the evening that idoxuridine was obtained for her treatment. She was treated with dexamethasone in high dosage (40 mg/day) from the time of admission. Case 2 This 16-year-old male was admitted three days after the onset of severe frontal headache. This headache was followed within 24 hours by fever and deterioration in his conscious state. At the time of admission he was found to be confused and febrile with nuchal rigidity. The only focal neurological sign was a nominal dysphasia, which became apparent as his conscious state improved. He was treated with a two-week course of tetracosactrin (1 mg daily), and during this time his level of consciousness steadily improved. He was reviewed approximately four months after the onset of the illness, and at that stage he exhibited quite marked nominal dysphasia, with poor short term memory and poor concentration. He had also developed seizures which proved difficult to control. He was not able to work in the open community. Case 3
This woman, aged 52 years, was admitted to Princess Alexandra Hospital (PAH) approximately one month after discharge from another hospital, where she had been given a course of cytosine arabinoside for presumed HSE (the records of this admission are not available to us). At the time of her admission to PAH, she was confused and very drowsy, with no localising CNS signs. Her relatives stated that her level of consciousness had deteriorated over the preceding two weeks. She was treated with a further three courses of cytosine arabinoside, the total dose being 6 g, together with dexamethasone in high dosage. Her mental state did not improve, and she was transferred to a Mental Hospital. Despite the large amount of cytosine arabinoside used, there was no marrow depression detected by examination of the peripheral blood. Case 4 This 54-year-old male was admitted with a three day history of fever, headache, confusion and increasing drowsiness.
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409
HERPES SIMPLEX ENCEPHALITIS
Eighteen hours prior to admission he suffered a grand ma1 convulsion, which commenced with left sided facial twitching. Over the next 24 hours his condition rapidly deteriorated, initially with the development of a left homonymous hemianopia and left hemiparesis ; subsequently he lapsed into coma, with marked extensor spasms. Brain biopsy was performed and treatment with dexamethasone and cytosine arabinoside commenced. However, his condition did not improve, and by the tenth day after admission it was evident that he had developed disseminated intravascular coagulopathy, with a generalised bleeding tendency. He died 14 days after admission, and post-mortem revealed extensive recent haemorrhages in most organs examined. The use of cytosine arabinoside in this case was complicated by the development of marked thrombocytopenia, with the lowest platelet level recorded being 30,000/mm3. The haematologist felt that his state of disseminated intravascular coagulopathy (the result of extensive brain necrosis initially), played a major role in the development of thrombocytopenia.
Case 5 A 14-year-old girl was admitted with a one month history of increasing headache, and a four day history of an influenzal-type illness with fever and myalgia. She had become irritable and confused 24 hours prior to admission, and was noted by her parents to have a right hemiparesis on the morning of her admission. On examination she was very drowsy and irritable, with nuchal rigidity, fever and a right hemiplegia, right hemianaesthesia and hemianopia. Treatment with cytosine arabinoside and dexamethasone was commenced 24 hours after admission, following a brain biopsy. Over the subsequent two weeks, she made a dramatic recovery and at the time of her discharge, three weeks after the onset of the illness, there was no noticeable neurological deficit. Psychometric testing, performed three months after discharge revealed no abnormality. Cytosine arabinoside therapy in this case was complicated by neutropenia, the lowest white cell count recorded being 1900/mm3 with 16’; neutrophils. This was 18 days after cytosine arabinoside was ceased, and was not associated with any infection.
Case 6 This 14-year-old girl was admitted with a five day history of headache and fever. She had become confused and drowsy over the two days prior to admission. She was found on examination to be febrile, drowsy and confused and had marked nuchal rigidity. This girl fared very badly in comparison with the previous case. Her level of consciousness continued to deteriorate over the first two weeks in hospital. She became deeply comatose, with extensor plantar responses, and manifested the ocular sign of “bobbing”, indicating pontine involvement. This “bobbing” persisted from the third to the eighth week. Despite two courses of cytosine arabinoside and continuous dexamethasone treatment, she improved very little. At the time of review, six months after the onset of her illness, she was found to be mute, incontinent and unable to co-operate in any way with the nursing staff. Cytosine therapy in her case resulted in considerable marrow depression, the lowest white cell count recorded being 21W/mm3, with 30% neutrophils ; this occurred seven days after the cessation of cytosine arabinoside.
Case I This 66-year-old male presented with a four day history of headache, fever and fluctuating confusion. One day prior to admission he developed a total expressive aphasia. On admission he was found to be febrile, with an expressive aphasia and a partial receptive dysphasia. Six hours after admission he developed epilepsia partialis continua, affecting the right arm. This was controlled with intravenous diazepam; it then became evident that he had a right monoplegia affecting the arm, which progressed to a right hemiplegia over the next 24 hours. He was submitted to a temporal lobe brain biopsy, and was commenced on cytosine arabinoside four days after admission. His consciousness improved initially, but four days after commencement of cytosine arabinoside he became comatose, with a left third nerve palsy. Repeat carotid angiography at this stage revealed marked swelling of the left temporal lobe. It was felt that this was probably due to an inflammatory response to the encephalitic process, rather than the result of the brain biopsy (in view of the virtually atraumatic nature of the biopsy). He was treated with mannitol, dexamethasone was continued, and his consciousness gradually improved. The right hemiplegia also gradually resolved. He was eventually discharged to the care of his wife. At the time of review, six months after the onset of the illness, he was found to be coping with a protected domestic life. There were minimal residual signs of a right hemiparesis, but there was still marked expressive dysphasia and obvious intellectual impairment. In this case cytosine arabinoside therapy did not produce marrow depression as detected by examination of the peripheral blood. These clinical aspects are summarised in Tables 1 and 2. Methods and Results Cerebro-spinul Fluid Findings
Lumbar puncture was carried out in all cases and the results are shown in Table 3 with the time interval from onset of mental symptoms, i.e. confusion and/or deterioration in consciousness, shown in days. It can be seen that, as has been reported p r ev i o ~ sl y ~ - ~ the , typical findings were those of a lymphocytic pleocytosis together with elevated protein levels. Frankly haemorrhagic CSF was not a feature in any of our cases. The CSF sugar levels were universally normal. Serological Studies
Blood was submitted for complement fixation tests for herpes simplex antibodies in five of the seven cases. Four-fold TABLE 1 ‘ Cases and outcome Case
Age
Sex
Outcome
1 2
53 16
F M
3 4 5 6 I
52 54 14 14 66
F M F F M
Death Epilepsy. Moderate intellectual impairment Gross intellectual impairment Death Full recovery Gross intellectual impairment R. hemiparesis, dysphasia, moderate intellectual impairment
410
VOL.
BOYLE AND LANDY TABLE 2
TABLE 4
Drugs used in therapy
Results of serum complement fixation titres for viral antibodies
Idoxuridine
Cytosine arabinoside
Case
Time base (days)
First specimen
Lag* (days)
Second specimen
ACTH
Dexamethasone
+
1 7
+
3
-
Dose
Days
Dose (g)
Days'
7
1/16
33
]/I28
28
L/256
3540 None submitted 3 7 9
1/32
30
11128
12
1/128
24 14
1/32 1/16
16
1/16
None submitted
Died the evening idoxuridine obtained
-
-
+
Lag Third (days) specimen
-
~
Case
7, NO. 4
-
2.0 1 .o 3.0 2.0 1.6 1.6 1.6 2.0
10-14 46-49 54-59 5-8 2-6 8-12 3&34 8-12
'Time basis is taken from onset of encephalitic stage
or greater rises in titres over a two week or longer period were found in Cases 2 , 3 , 6 and 7. These were taken to indicate herpes simplex as a probable aetiological factor, although the possibility of the rise in titres being due to incidental herpes infection must be considered6 No blood was submitted for serology in Cases 1 or 4, but the positive diagnosis of HSE was established by other means. Only one specimen was submitted in Case 5, but the diagnosis again was established by other means. The high titre in the one specimen submitted in Case 5, however, was highly suggestive of a recent herpes simplex infection. Because of the time lag involved, this is an unsuitable means of establishing the diagnosis, if early therapy is to be undertaken. In three cases, including one proven case of HSE, viral culture was attempted from the CSF but did not yield any viral growth. Table 4 shows the titres recorded. Electroencephalographic Results Electroencephalograms were performed in all cases. Upton and Gumpert7 described four sequential abnormalities of the EEG which because of their time relation they felt were typical of HSE. We were not able to demonstrate any such typical pattern, although all EEGs were markedly abnormal and showed
~
-
~
'Time between taking of sequential specimens, and initial time base as in Table 2
features which have been mentioned in past reports7,*; notably diffuse slowing of background activity, focal temporal lobe disturbances and the appearance of periodic complexes. In our limited experience there were no features on the EEG which could allow us to indicate the prognosis. Elian' felt that the presence of periodic complexes was a poor prognostic feature, although not specific for HSE. We found that the presence of periodic complexes did not correlate with the prognosis. Radio-isotope Brain Scan
Technetium brain scanning was performed in all except Case 3. In Table 5, it can be seen that, in general, EEG and brain scan findings correlated well, with respect to lateralisation of the process. Three of our four definite cases of HSE (4,5 and 6) had marked scan changes, as did two of the three probable cases (2 and 7). A brain scan performed on Case 1, our other definite case, showed no abnormality at five days after the onset of encephalitis symptoms. Radcliffeg has pointed out that isotope scanning may be negative early in the clinical course of this disease, and this may be the explanation of a negative scan in Case 1.
TABLE 5 Technetium brain scan and EEG results
Case
TABLE 3
11128 -
Time ofscan' (days)
Technetium scan
EEG localisation
Periodic complexes
CSF results (time base same as for Table 2)
Case 1
Time (days)
Protein Sugar WCC RBC (mg/IOOml) (mg/100ml) (per mm') monos (per mm') (NR 2 W O ) (NR 4&80)
1
5 2 3
4 5 6 7
2 16 7 41 58 4 3 3 9
50 76 200 183 160 18
40 62 168 639 126
50 LOO 98 100
100 100 100 100
70 99 100
183 20 90 228 ? 1
150 92 43 37 0
44 152 84 144 83 91 71 64 167 126 66
53 57 60 43 60 65' 59' 72 62 64 64
Normal
Generalised slow wave activity
-
11
Increased uptake L hemisphere
L hemisphere slow wave focus
-
3
-
Not done
Generalised slow wave activity
-
4
8
Increased uptake R temporal region
R hemisphere slow wave focus
5
1
Increased uptake R hemisphere
R hemisphere slow wave focus
6
8
Increased uptake both temporal regions
Generalised slow wave activity
1
8
Increased uptake L temporal region
L temporal slow wave focus
1
5
2
'After cytosine therapy.
'Time basis as in Table 2.
+ -
+ +
AUGUST
Case
1977
Time' (days)
41 1
HERPES SIMPLEX ENCEPHALITIS TABLE 6
TABLE 7
Results of angiography
Results of temporal lobe biopsy
Investigalion
Findings Case
Time* (days]
Inclusion bodies
virus isolation
lmmunotiuorescence
.-
3
?7
RCA
N A D (performed at another hospital)
4
8
RCA
Temporal SOL with capillary blush Midline shifted to left Early venous drainage in area of Sylvian fissure
5
I
RCA
Temporal SOL with capillary blush
6
40
LCA
NAD
8
BCA
I?
LCA
NAD Temporal SOL with capillary blush Midline shift to right
7
*Same time basis as in Table 2
Neuro-radiological Studies (see Table 6 ) Carotid angiography was performed at this hospital in Cases 4, 5, 6 and 7. In Cases 4, 5 and 7 features suggestive of HSE were found, i.e. (1) Capillary phase abnormalities with prominent vascular blush; (2) Early venous drainage; (3) Shift of midline structures; (4) Evidence of a temporal lobe space occupying lesion. In the recent series of Pexman'O, all of his cases showed marked abnormalities. Two of our cases (4 and 7) showed evidence of midline shift, while in Cases 4, 5 and 7, capillary phase abnormalities were found. Unlike Pexman's series, none of our cases showed multiple site involvement. From our limited experience it seems that isotope scanning is a more sensitive diagnostic test in the early stages of the disease than carotid angiography. In Case 3, an air encephalogram was performed which was normal and we would agree with Amin", that there is no need to proceed to this investigation. In this case the right carotid angiogram had previously been performed at another hospital, approximately one week after the onset of a confusional state, and was reported as normal. Brain Biopsy (see Table 7) The predilection for the virus to attack the temporal lobes and limbic areas has been demonstrated in the past'*, and temporal lobe biopsy can be expected to yield positive results in a large percentage of cases. In our series, temporal lobe biopsy was performed during life in Cases 4, 5 , 6 and 7 and in all these cases necrotising encephalitis with marked round cell infiltration, cerebral oedema and neuronolysis were demonstrated. Eosinophilic intranuclear inclusion bogies were found in Cases 4, 5 and 7. While these are typical of HSE they are not diagnostic of the disease, nor does their absence exclude the diagnosis. At the present time in our city, the only definitive means of diagnosing HSE appears to be isolation of the virus from brain biopsy specimens. The virus was isolated in Cases 4, 5 and 6, but not in Case 7. In Case 6 the virus was isolated in the absence of inclusion bodies in the brain biopsy specimen, while in Case 7, the virus was not isolated despite the presence of these inclusion bodies. Cases 1 and 4 were submitted to post mortem examination which revealed, in Case 4,a large area of haemorrhagic necrosis replacing the right temporal lobe with widely scattered smaller areas of haemorrhagic necrosis throughout the cerebral tissue. In Case 1, both temporal lobes were replaced by haemorrhagic necrotic tissue, the left being involved to a greater extent than the right. It is interesting to note that, in this
4
Postmortem N o biopsy No biopsy 8
5 6 7
8 8
I
2 3
-
+
Not done
+ +
+
Not done
+
-
+ +
-
+ +
+
'Time base same as for Table 2.
case, although multiple post mortem biopsy specimens were sent for viral culture from both temporal lobes and other areas microscopically normal, only one specimen (from the left temporal lobe) grew herpes virus. Each specimen was inoculated into a separate tube. The virus was isolated from post-mortem specimens in Case 4, as well as from a brain biopsy performed during life. The biopsy specimens in Cases 5, 6 and 7 were submitted to immunofluorescence studies and in all three the result was strongly positive for herpes simplex. This is despite the fact that in Case 7 the virus was not isolated in culture from the biopsy specimen. The method used was an indirect immunofluorescence technique, using conjugated anti-IgM. Immunofluorescence techniques should give positive results for herpes simplex virus in four to six hours after the specimen is received, but they have not replaced viral cultures as the definitive means of diagnosis in our laboratories at present. L ~ n g s o n 'recently ~ provided an excellent review of the techniques which may be employed. Facilities for electron microscopic examinations of biopsy specimens were not available, but the use of this technique to demonstrate intranuclear viral particles is thought by many workers to be a definitive means of making the diagnosis of herpes simplex infe~ti0n.I~ Discussion
Seven cases of severe encephalitis have been described, four of which (1,4, 5 and 6) have been proven by viral culture to be due to herpes simplex. The remaining three (2, 3 and 7) have been classified as probable cases of herpes simplex encephalitis on the basis of a four-fold or greater rise in antibody titre. Of the seven cases described, two cases (1 and 4) died. Of the remaining five cases, only one, Case 5, made a complete recovery, the other four patients being intellectually handicapped to a significant extent. These results seem to be in accord with previously published reports, and indicate the devastating permanent effect that the herpes simplex virus frequently has on the human nervous system. The clinical pattern of the illness has been better defined over recent years, and probably for this reason the diagnosis
412
BOYLE A N D LANDY
in our hospital is being considered more frequently than in the past. We found that the diagnosis had to be considered in a patient who presented with a rapid deterioration in level of consciousness, following a non-specific prodromal illness of short duration, in which fever, headache and nuchal rigidity were frequent features. CSF findings of an elevated protein and monocytic pleocytosis supported the diagnosis of HSE. Neuroradiological and isotope scanning evidence of a temporal lobe vascular mass lesion were further supporting features of HSE. The EEG was also useful in supporting the diagnosis, with slow activity, sometimes lateralised to one hemisphere, and the appearance of periodic complexes being prominent features. In our hospital, definitive diagnosis still rests on viral culture. Other workers, who have had more experience in the techniques, feel that immunofluorescence studies and electron microscopic observation on affected brain tissue are definitive means of establishing the diagnosis. In either case it is clear that the final diagnosis still rests on a brain biopsy specimen. While this is an invasive technique, we feel that, if controlled studies are to be made on the efficacy of treatment of the disease, then the diagnosis must be unequivocally made. The drugs which are currently used in the treatment of this disease are, in themselves, potentially lethal, due mainly to their marrow depressant effect. Thus, a decision as to whether or not they are effective in arresting the disease process is vitally important. In addition to the cases described above, there have been only two cases biopsied in the four year period in whom the clinical diagnosis of HSE was not supported by viral culture or rising antibody titres. Both these cases showed histological features consistent with a severe viral encephalitis. In none of the cases biopsied did we feel that the procedure had any significant complication. Hence we believe that it is a necessary step to obtain a biopsy specimen, and one in which the risk involved is not great. Moreover, the needling of an affected temporal lobe will distinguish a viral encephalitis from a bacterial brain abscess, a condition which can mimic HSE, and which is potentially curable. As indicated above, there is. still no certainty
VOL.
7,
NO.
4
as to whether the use of either cytotoxic or corticosteroid drugs is effective in this disease. All of our cases were treated with steroids, and five (Cases 3, 4, 5, 6 and 7) with cytosine arabinoside. Idoxuridine was obtained with a view to using it in Case 1. The report of the Boston Inter-Hospital Study Group suggests that there is no real place for the use of idoxuridine therapy for HSE. The nature of idoxuridine toxicity (with respect to marrow depres~ion)’~-’~ has long been recognised. The report of the Boston InterHospital Study Groupi5 highlighted what is probably even a more disturbing feature, i.e. the lack of efficacy of this treatment in the control of spread of the virus. Cytosine arabinoside, a pyrimidine antagonist, has been used for some years in the treatment of HSE without any definite decision being ‘made as to its safety or efficacy. Five of our seven patients (see Table 2) received at least one course of this drug in doses ranging from 4 to 8 mgJkgJday over a five day course, in IV bolus injections given over a five minute period. Results similar to those reported by Gilbert et al.” were found; an early response, thought possibly related to therapy, occurred in Case 5. Rapid response to cytosine arabinoside therapy has been reported in a number of other papers4, , but to our knowledge no controlled trial has yet been carried out. While cytosine arabinoside therapy may have contributed to the death of Case 4, we feel that disseminated intravascular coagulopathy was probably a more significant factor. Neutropenia developed in most of the other cases and in two of them appeared seven and 18 days respectively after therapy with cytosine arabinoside was ceased; it then resolved spontaneously. Steroids were used at some stage in all cases, tetracosactrin being the sole therapeutic agent used in Case 2, while dexamethasone was used in the six other cases. The use of steroids in HSE is controversial. There have been objections to the use of steroids, on the theoretical grounds that steroids interfere with both interferon and antibody production.” However others have reported encouraging results with the use of de~amethasone.’~Johnson et aL2 reported dramatic improvement in two of their cases
’’,’’
AUGUST
1977
HERPES SIMPLEX ENCEPHALITIS
after steroid therapy alone. The debate continues on the use of steroids: the rationale for their use in our cases was reduction in cerebral oedema at a time when blood and CSF interferon should both have reached significant levels. Steroid therapy may also be useful in damping down the severe immunological response which probably occurs in the area of necrotising encephalitis. Despite the better delineation of the disease which has become apparent over recent years, the question as to efficacy of treatment remains as great a problem as ever. Obviously, we cannot draw any conclusions from these small numbers, but would emphasise the importance of the outcome of any controlled therapeutic trial. References 1. Leading article (1972): Herpes encephalitis, Brir. med. J . 1, 581. 2. JOHNSON, K. P.. ROSENTHAL, M. S . and LERNER, P I (1972): Herpes simplex encephalitis-The course in five virologically proven cases, Arch. Neurol. 17, 103 3. OLSEN, c. L.. BUESCHER, E. L., ARTENSTEIN, M. S. and PARKMAN, P. D. (1967): Herpesvirus infections of the human central nervous system, New Engl. J. Med. 177, 1271. 4. MCAULEY, D. L. and GLASGOW, G. L.11974): Herpes simplex encephalitis treatment with cytosine arabinoside, Ausr. N . Z . J . M r d . 4, 274.
413
5 . Leading article (1973): Herpes Simplex encephalitis, Lancet 2, 1426. 6. JOHNSON, R. T.. OLSEN,L. C. and B U ~ S C H EE.RL. , (1968): Herpes simplex virus infection of the nervous system-problems in laboratory diagnosis, Arch. Neurol. 18, 260. 7. UPTON.A. and GUMPERT, J . (1970): Electroencephalography in diagnosis of herpes simplex encephalitis, Luncet 1, 650. 8. ELIAN,M. E. (1975): Herpes simplex encephalitis-prognosis and long term follow-up, Arch. Neurol. 32, 39. 9. RADcLirFa. W. B., GUNTO,F. C , ADWCK. D F. and KRIGMAN, M. R (1972): Early localisation of herpes simplex encephalitis by radionuclide imaging and caroiid angiography. Radiology 105, 603. 10. PEXMAN, J H. W (1974): The angiographic and brain scan features of acute herpes simplex encephalitis, Brir J . Radiol. 47, 179. 1 1 . AMIN,P. H. (1972)- Radiological findings in herpes simplex encephalitis, Brit. J . Radiol. 45, 652. 12. HUGHES,L (19691: In: Virus diseases and the nervous system. Blackwell Scientific Publications 13. LONCSON,M. (1973): lmmunofluorescence in the diagnosis of herpes encephalitis, Postgrad. med. J . 49, 403. 14. HARLAND, W. A,, ADAMS, J. H. and MCSEVENEY, D. (1967):Herpes simplex particles in acute necrotising encephdlltk, Lancer 2, 581. 15. Boston Interhospital Study Group (1975): Failure of high dose 5-lodo Z'deoxyuridine in the therapy of herpes simplex virus encephalitis. NPU. Engl J . Med. 192, 599 16. NOLAN,D. C., CARRUTHERS, M. M. and LEUNER, A M (1970): Herpes virus homonis encephalitis in Michigan-report of 13 cases, including SIX treated with Idoxuridine. NPW Engl. 1. M r d 282, 10. 17. BREEDON, C . 1.. HALL,T. C. and TYLER,H. R (1966): Herpes simplex encephalitis treated with systemic 5-lodo Z'deoxyuridine, Ann. intern. Med. 65, 1050. 18 NOLAN,D. C., LAUTER,C. B. and LERNEn, A. M. (1973): Idoxuridine In herpes simplex (Type-I) encephalitis, Ann. intern. Med. 7 8 , 243. 19. GILBERT, D. N.. JOHNSON. M.T., LUBY, I . P. and SANFORD, 1. P. (1913): Herpesvirus homiuis Type-I encephalitis treated with cytarabine: an unresolved problem, Medicine 52, 331 20. FAURIS,W. A and BLOW,M. E (1972). Cytarabine treatment of herpes simplex encephalitis, Arch. Neurol 21, 99. 21. HRYNUIK, W., FOERSTER, J . , SHOJANIA. M. and CHOW,A. (1972):Cytarahme for herpes virus infections, J . Arnrr. med. ASS. 219, 715. 22 LONGSON,M. and BESWICK. T. S. L. (1971): Dexamethasone treatment in herpes simplex encephalitis, Loncrt 1 , 749. 23. UPTON,A. R. M., BARWICK, D. D. and FOSTER, J . B. (1971):Dexamethasone treatment in herpes simplex encephalitis. Lancet 1,290.
