205
be diagnosed retrospectively by identification of a specific intrathecal immune response to the virus.9 However, in the early stages of infection (within 10 days of neurological diagnosis) even highly sensitive
can
EDITORIALS
immunoassay techniques may yield false-negative results. Detection of viral antigen in CSFI° may lead to a diagnosis during this antibody-negative "window" period, but routine procedures of adequate sensitivity and/or specificity are as yet not available. Little viral antigen appears in CSF," and existing immunoassays, at the limits of their sensitivity, are poorly reproducible and unreliable. Scintigraphic imaging of the accumulation of a virus-specific drug targeted to
Acute diagnosis of herpes simplex
encephalitis Without specific antiviral
therapy the mortality of herpes simplex encephalitis (HSE) can be as high as 70%.1 Controlled studies have shown that prompt
diagnosis followed by acyclovir treatment leads to an impressive reduction in mortality and morbidity.2,3 Earlier antiviral agents used in HSE had many side-effects and specific diagnosis was therefore thought to be essential before initiation of therapy.4 Results of the acyclovir trials2,3soon led to the recommendation that specific diagnosis before
longer required.’ Nevertheless, HSE is difficult to diagnose clinically, and electroencephalographic recordings5 and computed tomographic scans6 may be normal in the early stages of the disease. Moreover, abnormalities observed with these techniques are not specific for HSE. Whitley et al,in a study of 432 patients who underwent brain biopsy for specific treatment was
no
diagnosis, showed that 55% of those with presumptive HSE were incorrectly diagnosed, while 16% of these patients had other, treatable, conditions.
Consequently,
if
empirical acyclovir therapy is initiated it is important to continue the search for a specific diagnosis lest other, possibly treatable, disorders be overlooked. Virologists have long sought to develop reliable, non-invasive methods for early diagnosis of HSE. After quantification of serum and cerebrospinal fluid (CSF) antibody to herpes simplex virus (HSV), HSE
infected tissue within the central nervous system looks promising,l2 and procedures and tracer compounds have been developed,13,14 but this approach has not been fully evaluated in man. The results of Aurelius and colleagues in this issue (p 189) suggest that the virologists’ search may be over. In a retrospective study of 43 patients with virologically confirmed HSE, polymerase chain reaction (PCR) amplification of DNA extracted from CSF allowed the detection of the viral genome (a fragment of the HSV glycoprotein D gene) in 41 samples taken from patients at the time of hospital admission. 1 other sample became positive when a greater volume of CSF was used for extraction of target DNA. There was only 1 false-negative result (from a child with biopsy-proven HSE who had been treated promptly with acyclovir). The specificity of the technique is shown by the fact that there were no false-positive results in 87 CSF samples taken from patients with non-HSE focal encephalitis. These results accord with those of other workers,t5-17 and provide clear evidence that viral DNA is present in lumbar CSF during the acute stages of infection. Contamination of samples via introduction of extraneous DNA to the specimen or the reaction cocktail has been the main drawback of the PCR technique. Although CSF seems to be the ideal starting sample for PCR amplification, since this fluid is normally free of HSV DNA and is anatomically protected from external contamination, prevention of extracorporeal contamination with HSV or its genome is especially difficult. HSV is ubiquitous and most adults will harbour and periodically excrete the virus throughout life. Thus attending physicians, nurses, and laboratory staff are all potential sources of contamination. Aurelius et al, through rigorous attention to detail, careful design, and control of laboratory procedures diminished this risk within their laboratory. Prospective studies of their approach are now indicated to determine whether it is practicable for clinical staff routinely to collect adequately "clean" samples for PCR investigation. If this technique proves reliable for acute diagnosis of the disease in hospital practice it may be possible to identify a wider spectrum of clinical manifestations of HSV infection of the central nervous system. Because
206
no
technique has been available for reliable diagnosis
of the disease in the acute stages, there have been few case-reports of "mild" forms ofHSE18 and most cases will go unrecognised. An association between subclinical (possibly recurrent) HSE and subsequent psychiatric or psychotic illness has long been suggested ;19 perhaps prospective longitudinal studies will now settle this issue. Another area in which PCR may prove valuable is in investigation of treatment "failures". A complete course of treatment with either vidarabine2° or acyclovir21 has occasionally been followed by readmission with encephalitis. The differential diagnosis includes incomplete treatment of the initial encephalitic episode (necessitating further acyclovir therapy), drug resistant HSE (necessitating an alternative
herpes simplex encephalitis after conventional acyclovir therapy. JAMA 1988; 259: 1051-53. 22. Rotbart HA. Enzymatic RNA amplification of enteroviruses. J Clin Microbiol 1990; 28: 438-42. 23. Shankar P, Manjunath N. Mohan KK, et al. Rapid diagnosis of tuberculous meningitis by polymerase chain reaction. Lancet 1991; 337: 5-7.
antiviral
agent), or a perivenous leucoencephalopathy (not requiring antiviral therapy but perhaps improved by anti-inflammatory corticosteroids). PCR techniques for the identification of enterovirus infection of the central nervous system22 and Mycobacterium tuberculosisZ3 have also been developed. The application of these and other virusspecific PCR methods should lead to accurate diagnosis of the 60-70% of cases of acute encephalitis of presumed viral origin.
1.
16. Puchhammer-Stockl E, Popow-Kraupp T, Heinz FX, Mandl CW, Kunz C. Establishment of PCR for the early diagnosis of herpes simplex encephalitis. J Med Virol 1990; 32: 77-82. 17. Klapper PE, Cleator GM, Dennett C, Lewis AG. Diagnosis of herpes encephalitis via Southern blotting of CSF DNA amplified by polymerase chain reaction. J Med Virol 1990; 32: 261-64. 18. Klapper PE, Cleator GM, Longson M. Mild forms of herpes encephalitis. J Neurol Neurosurg Psychiatry 1984; 47: 1247-50. 19. Cleobury JF, Skinner GRB, Thonless ME, Wildy MP. Association between psychopathic disorders and serum antibody to herpes simplex (type 1). Br Med J 1971; i: 438-41. 20. Dix RD, Baringer JR, Panitch HS, et al. Recurrent herpes simplex encephalitis: recovery of virus after Ara-A treatment. Ann Neurol 1983; 13: 196-200. 21. Van Landingham KE, Marsteller HB, Ross GW, Hayden FG. Relapse of
Whitley RJ, Soong SJ, Dolin R, et al. Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis. N Engl J Med 1977; 297: 289-94.
Sköldenberg B, Forsgren M, Alestig K, et al. Acyclovir versus vidarabine in herpes simplex encephalitits. Lancet 1984; ii: 707-11. 3. Whitley RJ, Alford CA, Hirsch MS, et al. Vidarabine versus acyclovir therapy in herpes simplex encephalitits. N Engl J Med 1986: 314: 2.
144-49. 4. Editorial. Herpes simplex encephalitis. Lancet 1986; i: 535-36. 5. Brick JF, Brick JE, Morgan JJ, Gutierrez AR. EEG and pathologic findings in patients undergoing brain biopsy for suspected encephalitis. Electroencephalographr Clin Neurophysiol 1990; 76: 86-89. 6. Greenberg SB, Taber L, Septimus E, et al. Computerized tomography in brain biopsy proven herpes simplex encephalitits. Arch Neurol 1981; 38: 58-59. 7. Whitley RJ, Cobbs CG, Alford CA, et al. Diseases that mimic herpes simplex encephalitits. JAMA 1989; 262: 234-39. 8. Kahlon J, Chatterjee S, Lakeman FD, Lee F, Nahmias AJ, Whitley RJ. Detection of antibodies to herpes simplex virus in the cerebrospinal fluid of patients with herpes simplex encephalitis. J Infect Dis 1987; 155: 38-44. 9. Lakeman FD, Koga J, Whitley RJ. Detection of antigen to herpes simplex virus in cerebrospinal fluid from patients with herpes simplex encephalitis. J Infect Dis 1987; 155: 1172-78. 10. Klapper PE, Cleator GM, Lewis AG. Obstacle to early diagnosis of herpex simples encephalitis via CSF. Lancet 1990; 336: 385-86. 11. Price RW, Saito Y, Fox JJ. Prospects for the use of radiolabelled antiviral drugs in the diagnosis of herpes simplex encephalitis. Biochem Pharmacol 1983; 32: 2455-61. 12. Cleator GM, Klapper PE, Lewis AG, Sharma HL, Longson M. Specific neuro-radiological diagnosis of herpes encephalitis in an animal model. Arch Virol 1988; 101: 1-12. 13. Tovell DR, Samuel J, Mercer JR, et al. The in vitro evaluation of nucleoside analogues as probes for use in the non-invasive diagnosis of herpes simplex encephalitis. Drug Des Deliv 1988; 3: 213-21. 14. Powell KF, Anderson NE, Fnth RW, Croxson MC. Non-invasive diagnosis of herpes simplex encephalitis. Lancet 1990; 335: 357-58. 15. Rowley AH, Whitley RJ, Lakeman FD, Wolinsky SM. Rapid detection of herpes-simplex-virus DNA in cerebrospinal fluid of patients with herpes simplex encephalitis. Lancet 1990; 335: 440-41.
The
rising
cost
of independence
One morning last November a group of British doctors enjoyed a rare and possibly unique experience. Unrestrained by budgetary restriction, overdrained resources, or government "cuts" they were able to estimate the needs of their institution then vote themselves the funds required. Members of the General Medical Council (GMC) could do this because their activities are funded entirely by an annual fee levied on doctors, because the Council itself determines the size of the fee, and because all doctors have to pay it if they wish to work in the National Health Service or indeed in most private hospitals. In the November debate, the GMC justified the near trebling of the fee (from 30 to 80) by saying that it needed the money to meet its statutory obligation to maintain professional standards-though one member did ask acerbicly what standard of performance should be demanded, say, of psychiatrists by a society that chooses to treat the mentally ill by sending them to prison or accommodating them in cardboard boxes. There is no doubt that without this year’s increase the GMC would be headed for the rocks. Its existing deficit is about 1million and, as became clear in November, the Council’s financial management has been far too amateurish for an organisation with an estimated expenditure this year of 8-5 million. About 30% of that sum will be spent on running the Council’s disciplinary procedures and this percentage is likely to increase. Despite the fact that the Professional Conduct Committee now sits for a record number of days each year, the Council is accumulating an undesirable "waiting list" and most cases now last longer and cost more (in one case recently, nearly 1 million). Over the next few years those costs are likely to accelerate way beyond the rate of inflation. And that is before the GMC launches its new, and probably expensive, scheme to monitor professional
performance.
be diagnosed retrospectively by identification of a specific intrathecal immune response to the virus.9 However, in the early stages of infection (within 10 days of neurological diagnosis) even highly sensitive
can
EDITORIALS
immunoassay techniques may yield false-negative results. Detection of viral antigen in CSFI° may lead to a diagnosis during this antibody-negative "window" period, but routine procedures of adequate sensitivity and/or specificity are as yet not available. Little viral antigen appears in CSF," and existing immunoassays, at the limits of their sensitivity, are poorly reproducible and unreliable. Scintigraphic imaging of the accumulation of a virus-specific drug targeted to
Acute diagnosis of herpes simplex
encephalitis Without specific antiviral
therapy the mortality of herpes simplex encephalitis (HSE) can be as high as 70%.1 Controlled studies have shown that prompt
diagnosis followed by acyclovir treatment leads to an impressive reduction in mortality and morbidity.2,3 Earlier antiviral agents used in HSE had many side-effects and specific diagnosis was therefore thought to be essential before initiation of therapy.4 Results of the acyclovir trials2,3soon led to the recommendation that specific diagnosis before
longer required.’ Nevertheless, HSE is difficult to diagnose clinically, and electroencephalographic recordings5 and computed tomographic scans6 may be normal in the early stages of the disease. Moreover, abnormalities observed with these techniques are not specific for HSE. Whitley et al,in a study of 432 patients who underwent brain biopsy for specific treatment was
no
diagnosis, showed that 55% of those with presumptive HSE were incorrectly diagnosed, while 16% of these patients had other, treatable, conditions.
Consequently,
if
empirical acyclovir therapy is initiated it is important to continue the search for a specific diagnosis lest other, possibly treatable, disorders be overlooked. Virologists have long sought to develop reliable, non-invasive methods for early diagnosis of HSE. After quantification of serum and cerebrospinal fluid (CSF) antibody to herpes simplex virus (HSV), HSE
infected tissue within the central nervous system looks promising,l2 and procedures and tracer compounds have been developed,13,14 but this approach has not been fully evaluated in man. The results of Aurelius and colleagues in this issue (p 189) suggest that the virologists’ search may be over. In a retrospective study of 43 patients with virologically confirmed HSE, polymerase chain reaction (PCR) amplification of DNA extracted from CSF allowed the detection of the viral genome (a fragment of the HSV glycoprotein D gene) in 41 samples taken from patients at the time of hospital admission. 1 other sample became positive when a greater volume of CSF was used for extraction of target DNA. There was only 1 false-negative result (from a child with biopsy-proven HSE who had been treated promptly with acyclovir). The specificity of the technique is shown by the fact that there were no false-positive results in 87 CSF samples taken from patients with non-HSE focal encephalitis. These results accord with those of other workers,t5-17 and provide clear evidence that viral DNA is present in lumbar CSF during the acute stages of infection. Contamination of samples via introduction of extraneous DNA to the specimen or the reaction cocktail has been the main drawback of the PCR technique. Although CSF seems to be the ideal starting sample for PCR amplification, since this fluid is normally free of HSV DNA and is anatomically protected from external contamination, prevention of extracorporeal contamination with HSV or its genome is especially difficult. HSV is ubiquitous and most adults will harbour and periodically excrete the virus throughout life. Thus attending physicians, nurses, and laboratory staff are all potential sources of contamination. Aurelius et al, through rigorous attention to detail, careful design, and control of laboratory procedures diminished this risk within their laboratory. Prospective studies of their approach are now indicated to determine whether it is practicable for clinical staff routinely to collect adequately "clean" samples for PCR investigation. If this technique proves reliable for acute diagnosis of the disease in hospital practice it may be possible to identify a wider spectrum of clinical manifestations of HSV infection of the central nervous system. Because
206
no
technique has been available for reliable diagnosis
of the disease in the acute stages, there have been few case-reports of "mild" forms ofHSE18 and most cases will go unrecognised. An association between subclinical (possibly recurrent) HSE and subsequent psychiatric or psychotic illness has long been suggested ;19 perhaps prospective longitudinal studies will now settle this issue. Another area in which PCR may prove valuable is in investigation of treatment "failures". A complete course of treatment with either vidarabine2° or acyclovir21 has occasionally been followed by readmission with encephalitis. The differential diagnosis includes incomplete treatment of the initial encephalitic episode (necessitating further acyclovir therapy), drug resistant HSE (necessitating an alternative
herpes simplex encephalitis after conventional acyclovir therapy. JAMA 1988; 259: 1051-53. 22. Rotbart HA. Enzymatic RNA amplification of enteroviruses. J Clin Microbiol 1990; 28: 438-42. 23. Shankar P, Manjunath N. Mohan KK, et al. Rapid diagnosis of tuberculous meningitis by polymerase chain reaction. Lancet 1991; 337: 5-7.
antiviral
agent), or a perivenous leucoencephalopathy (not requiring antiviral therapy but perhaps improved by anti-inflammatory corticosteroids). PCR techniques for the identification of enterovirus infection of the central nervous system22 and Mycobacterium tuberculosisZ3 have also been developed. The application of these and other virusspecific PCR methods should lead to accurate diagnosis of the 60-70% of cases of acute encephalitis of presumed viral origin.
1.
16. Puchhammer-Stockl E, Popow-Kraupp T, Heinz FX, Mandl CW, Kunz C. Establishment of PCR for the early diagnosis of herpes simplex encephalitis. J Med Virol 1990; 32: 77-82. 17. Klapper PE, Cleator GM, Dennett C, Lewis AG. Diagnosis of herpes encephalitis via Southern blotting of CSF DNA amplified by polymerase chain reaction. J Med Virol 1990; 32: 261-64. 18. Klapper PE, Cleator GM, Longson M. Mild forms of herpes encephalitis. J Neurol Neurosurg Psychiatry 1984; 47: 1247-50. 19. Cleobury JF, Skinner GRB, Thonless ME, Wildy MP. Association between psychopathic disorders and serum antibody to herpes simplex (type 1). Br Med J 1971; i: 438-41. 20. Dix RD, Baringer JR, Panitch HS, et al. Recurrent herpes simplex encephalitis: recovery of virus after Ara-A treatment. Ann Neurol 1983; 13: 196-200. 21. Van Landingham KE, Marsteller HB, Ross GW, Hayden FG. Relapse of
Whitley RJ, Soong SJ, Dolin R, et al. Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis. N Engl J Med 1977; 297: 289-94.
Sköldenberg B, Forsgren M, Alestig K, et al. Acyclovir versus vidarabine in herpes simplex encephalitits. Lancet 1984; ii: 707-11. 3. Whitley RJ, Alford CA, Hirsch MS, et al. Vidarabine versus acyclovir therapy in herpes simplex encephalitits. N Engl J Med 1986: 314: 2.
144-49. 4. Editorial. Herpes simplex encephalitis. Lancet 1986; i: 535-36. 5. Brick JF, Brick JE, Morgan JJ, Gutierrez AR. EEG and pathologic findings in patients undergoing brain biopsy for suspected encephalitis. Electroencephalographr Clin Neurophysiol 1990; 76: 86-89. 6. Greenberg SB, Taber L, Septimus E, et al. Computerized tomography in brain biopsy proven herpes simplex encephalitits. Arch Neurol 1981; 38: 58-59. 7. Whitley RJ, Cobbs CG, Alford CA, et al. Diseases that mimic herpes simplex encephalitits. JAMA 1989; 262: 234-39. 8. Kahlon J, Chatterjee S, Lakeman FD, Lee F, Nahmias AJ, Whitley RJ. Detection of antibodies to herpes simplex virus in the cerebrospinal fluid of patients with herpes simplex encephalitis. J Infect Dis 1987; 155: 38-44. 9. Lakeman FD, Koga J, Whitley RJ. Detection of antigen to herpes simplex virus in cerebrospinal fluid from patients with herpes simplex encephalitis. J Infect Dis 1987; 155: 1172-78. 10. Klapper PE, Cleator GM, Lewis AG. Obstacle to early diagnosis of herpex simples encephalitis via CSF. Lancet 1990; 336: 385-86. 11. Price RW, Saito Y, Fox JJ. Prospects for the use of radiolabelled antiviral drugs in the diagnosis of herpes simplex encephalitis. Biochem Pharmacol 1983; 32: 2455-61. 12. Cleator GM, Klapper PE, Lewis AG, Sharma HL, Longson M. Specific neuro-radiological diagnosis of herpes encephalitis in an animal model. Arch Virol 1988; 101: 1-12. 13. Tovell DR, Samuel J, Mercer JR, et al. The in vitro evaluation of nucleoside analogues as probes for use in the non-invasive diagnosis of herpes simplex encephalitis. Drug Des Deliv 1988; 3: 213-21. 14. Powell KF, Anderson NE, Fnth RW, Croxson MC. Non-invasive diagnosis of herpes simplex encephalitis. Lancet 1990; 335: 357-58. 15. Rowley AH, Whitley RJ, Lakeman FD, Wolinsky SM. Rapid detection of herpes-simplex-virus DNA in cerebrospinal fluid of patients with herpes simplex encephalitis. Lancet 1990; 335: 440-41.
The
rising
cost
of independence
One morning last November a group of British doctors enjoyed a rare and possibly unique experience. Unrestrained by budgetary restriction, overdrained resources, or government "cuts" they were able to estimate the needs of their institution then vote themselves the funds required. Members of the General Medical Council (GMC) could do this because their activities are funded entirely by an annual fee levied on doctors, because the Council itself determines the size of the fee, and because all doctors have to pay it if they wish to work in the National Health Service or indeed in most private hospitals. In the November debate, the GMC justified the near trebling of the fee (from 30 to 80) by saying that it needed the money to meet its statutory obligation to maintain professional standards-though one member did ask acerbicly what standard of performance should be demanded, say, of psychiatrists by a society that chooses to treat the mentally ill by sending them to prison or accommodating them in cardboard boxes. There is no doubt that without this year’s increase the GMC would be headed for the rocks. Its existing deficit is about 1million and, as became clear in November, the Council’s financial management has been far too amateurish for an organisation with an estimated expenditure this year of 8-5 million. About 30% of that sum will be spent on running the Council’s disciplinary procedures and this percentage is likely to increase. Despite the fact that the Professional Conduct Committee now sits for a record number of days each year, the Council is accumulating an undesirable "waiting list" and most cases now last longer and cost more (in one case recently, nearly 1 million). Over the next few years those costs are likely to accelerate way beyond the rate of inflation. And that is before the GMC launches its new, and probably expensive, scheme to monitor professional
performance.
