Q J Med 2004; 97: 325-330
QJM vol. 97 no. 6 © Association of Physicians 2004; all rights reserved.
Herpes simplex encephalitis: an audit of the use of laboratory diagnostic tests
From the Departments of 1Neurology, 2Neurological Intensive Care and 3Neuroimmunology, The National Hospital for Neurology and Neurosurgery, London, 4Department of Clinical Neurosciences, Guy's, King's and St Thomas’ School of Medicine, London, and 5Department of Clinical Virology, Royal Free and University College Medical School, London, UK
Received 17 November 2003 and in revised form 5 March 2004
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Background: The combination of both PCR and intrathecal antibody studies is recommended to confirm or refute the diagnosis of herpes simplex encephalitis (HSE).
Aim: To investigate the pattern of use of laboratory tests in the diagnosis of suspected cases of HSE, and to determine the final diagnosis in cases proven not to be HSE.
Design: Structured audit.
Methods: We reviewed the case-notes of all patients who, over a five-year time period, presented with suspected encephalitis; and/or were prescribed aciclovir. Clinical and laboratory criteria were used to categorize the likelihood of HSE.
Results: We identified 222 patients: 10 (5%) had definite HSE, 24 (10%) possible HSE, and 144 (65%) a definite alternative diagnosis. In 44 (20%), no final diagnosis was made, but the diagnosis of HSE was excluded. PCR was performed in 68 (31%), intrathecal antibody studies in 24 (11%), and brain biopsy in 17 (8%). A wide range of diseases mimicked HSE, but most common were inflammatory diseases and other infections of the central nervous system.
Discussion: Laboratory tests, particularly intrathecal antibody assays, are under-used in the diagnosis of HSE. Although early empirical treatment of suspected HSE is essential, confirmation or exclusion of the diagnosis is equally important to avoid overlooking alternative diagnoses. Identification of the aetiology of encephalitis is of particular importance, given the current concerns of emerging infections and bioterrorism.
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Introduction |
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Herpes simplex virus encephalitis (HSE) is a rare but feared complication of a ubiquitous human viral infection. Clinically, it is notoriously difficult to diagnose, even in the later stages of the established disease. There is a wide spectrum of presentation, varying from focal to generalized cerebral dysfunction, with consequences ranging from death or severe disability to full recovery.1,2 Herpes simplex virus (HSV)-2 accounts for about 80% of cases in the newborn, but after the neonatal period, HSV-1 is the predominant cause of HSE, being responsible for more than 90% of cases.3,4 Routine cerebral imaging studies within the first 2–4 days after onset of neurological symptoms may be unremarkable.5,6 Consequently, laboratory diagnostic tests are paramount in confirming or refuting the clinical diagnosis of HSE. Diagnosis is based upon either the direct identification of HSV in the brain or cerebrospinal fluid (CSF), or the detection of an intrathecal HSV-specific antibody response. This ‘two-pronged’ approach to the laboratory diagnosis of HSE has been codified in a consensus report from the European Concerted Action on Virus Meningitis and Encephalitis.7
From the early 1990s, the use of brain biopsy as the ‘gold standard’ diagnostic test for direct detection of the virus has largely superseded by the use of the polymerase chain reaction (PCR) to detect HSV DNA in the CSF.8 When HSV PCR was compared to brain biopsy, the sensitivity was 98%, specificity 94%, positive predictive value 95% and negative predictive value 98%.9 False negative results may occur occasionally in bloody specimens through inhibition of PCR.8 Negative results may also be found when the CSF has been obtained 5–10 days after starting aciclovir therapy,8,10,11 and (rarely) in the absence of treatment, when lumbar puncture has been performed very early after the onset of symptoms (1–4 days), or delayed approximately 10 days or more into the disease process.9,11
Since a negative HSV PCR result does not completely exclude the possibility of HSE, an intrathecal antibody response specific to HSV should also be sought. Two suitable methods have been validated: either calculation of an HSV-specific antibody index; or HSV-specific immunoblotting of oligoclonal IgG.12 Both require comparison of HSV-specific antibody reactivity in CSF and serum samples taken on the same day. Unfortunately, tests for intrathecal antibody synthesis are underused. In part, this is because a week or more has to elapse after the onset of neurological symptoms before the virus-specific humoral response is measurable.7 In addition, non-specific results may arise through cross-reaction with varicella zoster antibodies.7 Hence the sensitivity and specificity values of the assay are only about 80%.13
However, the availability of accurate laboratory diagnosis is not sufficient to reduce mortality from HSE. The single most important factor is the early initiation of high-dose intravenous aciclovir, which has reduced mortality rates from 70% to between 6 and 19%.14–16 Indeed, it is imperative to start aciclovir at the earliest opportunity without waiting for laboratory confirmation to ensure the best outcome for HSE.16 A consequence of this policy is that many encephalitides are likely to be treated with aciclovir without initial or final proof of the aetiological agent being HSV. While this seems pragmatic, the danger is that with the comfort of ‘encephalitis patients’ being treated blindly with aciclovir, alternative diagnoses, which may require very different treatments, are not being actively considered in parallel. For example in Finland, HSE only accounts for about a tenth of CNS infections with a known viral aetiology.17 Indeed, if no laboratory tests are performed to exclude HSE, then the ‘red flag’ of negative results does not occur and the clinician is not forced to think about other causes.
We therefore carried out an audit of all patients with suspected encephalitis so as to ascertain how often laboratory diagnosis of HSE was undertaken, and if HSE was not confirmed what the final diagnoses were.
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Methods |
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The setting for this retrospective audit was a regional neurosciences centre, serving the surrounding district general hospitals. Since HSV PCR was available as a diagnostic service from 1993 onwards, a five year period from 1.1.94 to 31.12.98 was chosen. Hospital records were searched electronically for patients with a discharge diagnosis suggestive of encephalitis using the ICD 9 and 10 classification systems (i.e. ICD9 323.4, 323.8; ICD10 G04.0, 4.1, 4.2, 4.8, 4.9 & G05.0, 5.2, 5.8); the categories chosen were broad so as to include all possible cases. The electronic and paper databases of the neuromedical intensive care unit were hand-searched for patients with encephalopathies of possible infectious aetiology. The neuroimmunology departmental database of CSF analyses was searched for patients with positive HSV-specific immunoblotting of oligoclonal IgG. The names of all patients who had been prescribed aciclovir, for whatever reason, were obtained from pharmacy records. In addition, informal inquiries were made to microbiology and neurology staff about the names of those with suspected HSE over the period. Once the cohort had been identified, the notes were obtained and hand searched by a consultant neurologist (JC). Only encephalopathic adults aged over 18 years were considered.
Encephalopathy was defined as a depressed or altered level of consciousness persisting at least 24 h (including lethargy, extreme irritability or a significant change in personality or behaviour). Encephalitis was defined as encephalopathy plus two or more of the following: pyrexia >37.5°C, seizure(s), focal neurological findings, CSF pleocytosis (>5 wbc/µl), or characteristic abnormal results of neuroimaging (CT or MRI).
The cohort was split into four groups.
Definite HSE
A clinical picture of encephalitis as defined above, with HSE diagnosed by laboratory tests. This required one of the following: HSV detected in CSF or brain biopsy and/or an HSV-specific intrathecal antibody response.
Possible HSE
A clinical picture suggestive of encephalitis as defined above, but HSE not fully excluded by the use of both PCR and intrathecal antibody tests.
Non-HSE
Where a clear and unambiguous alternative diagnosis was identified.
Unknown
Either the clinical picture did not fit the case definition of encephalitis and/or HSE was excluded by the use of both PCR and intrathecal antibody tests. In addition, no clear and unambiguous alternative diagnosis had been reached.
Laboratory investigations for HSE were done at the time of admission, and not retrospectively. HSV DNA was detected using a nested PCR which distinguished types 1 and 2.8 The test for intrathecal HSV-specific antibody involved isoelectric focusing of serum and CSF IgG. HSV-specific oligoclonal bands were detected by immunoblotting against pooled HSV-1 and –2 antigens.12 The presence of HSV-specific bands in CSF, but not serum, indicated local synthesis.
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A total of 335 patients were identified between 1 January 1994 and 31 December 1998: 161 from the ICD 9 and 10 categorization, 40 from the records of the neuromedical intensive care unit, and 154 from those prescribed aciclovir. These various methods of ascertainment resulted in some duplication, and the net final number of patients was 222. Case notes were obtained and reviewed for all of the patients. Some 80% of this cohort was from the surrounding district general hospitals, the remainder being from other neuroscience centres. There was no significant change in the frequency of HSV PCR use over the study period.
The results are outlined in Table 1. Of the 222 patients, 68 (31%) had HSV-PCR carried out on CSF; the remaining 154 (69%) did not. In 24/222 patients (11%) an HSV-specific intrathecal antibody response was searched for. Only in 9/222 (4%) were both HSV PCR and intrathecal antibody tests done. The final number of definite cases of HSE was 10/222 (5%), with 5/10 being diagnosed on the basis of the HSV-PCR result. Of the remaining five, three were diagnosed histologically on brain biopsy, and two on the basis of an HSV-specific intrathecal antibody response. One of the PCR positive cases was due to HSV-2, occurring in a patient with co-existent chronic lymphocytic leukaemia;18 the remainder were all due to HSV-1. Considering the possible cases of HSE, only 15 patients’ CSF samples were tested for HSV DNA by PCR (7 within 10 days of symptom onset) and remarkably, none of the 24 CSF samples were tested for intrathecal antibody synthesis. However, in six encephalitis cases classified as unknown, HSE could be excluded, as both HSV PCR and HSV-specific intrathecal antibody studies were negative. In these cases, the intrathecal antibody studies were performed on CSF sampled 7 days or more into the illness.
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Table 2 shows the range of alternative diagnoses reached in the non-HSE group of patients. The inflammatory category was the largest group, including a majority of acute disseminated encephalomyelitis (ADEM) but also Behçet's disease and malignant presentations of multiple sclerosis. The second largest group comprised a variety of CNS infections. Tumours masquerading as suspected HSE were relatively common, and the early use of steroids before definite diagnosis on one occasion led to temporary masking of what ultimately proved to be an intracerebral lymphoma. Fourteen brain biopsies were performed that showed no evidence of HSE. Seven of these showed astrocytoma, one lymphoma, two Behçet's disease and four were non-diagnostic.
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Turning to the question of empirical treatment of HSE, aciclovir was given to all the definite cases but one. In this case the presentation was of an acute encephalitis but HSE was not diagnosed and aciclovir was not given. Several months later, the patient was transferred to the UK and admitted to hospital for investigation and management. At this time, lumbar puncture was performed and diagnosis of the acute illness was made by detection of intrathecal production of anti-HSV antibodies. In the possible group 22/24 (92%) of patients received aciclovir whereas 23/44 (52%) in the unknown group and 92/144 (64%) of the non-HSE group were treated.
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Discussion |
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This study systematically analyses the use of laboratory diagnostic tests for HSE over 5 years at a central London neuroscience centre. Despite a possible specialist referral bias, the data are robust because 80% of referrals were from district general hospitals and the case-note ascertainment was 100%.
Could cases of HSE have been missed during this 5 years? Probably ‘yes’, since the 24 possible cases had the characteristic clinical features of HSE. Indeed HSE was considered a real possibility since 92% received aciclovir, but unfortunately HSE was not fully excluded by laboratory tests.
As regards the laboratory diagnosis of HSE, it is unusual in medicine to have a diagnostic test with the positive predictive value of PCR, and yet as our data show, it was carried out in only 31% of patients, whereas 65% were treated with intravenous aciclovir for HSE. Secondly, the methods to detect an intrathecal HSV-specific antibody response were strikingly underused, being applied in only 11% of cases.
The importance of making a definite positive or negative HSE diagnosis would seem self-evident: accurate treatment and prognosis, avoidance of further unnecessary tests and unnecessary therapeutic measures. Yet it is clear that the diagnostic process is often incomplete, certainly not matching the consensus statement developed in 1996 for laboratory diagnosis of HSE.7 Why then are the laboratory tests for HSE not being used more often? Lumbar puncture is contra-indicated in a minority of patients because of the possibility of brainstem herniation, but otherwise surely CSF examination is mandatory in cases of unexplained encephalitis or encephalopathy? In fact our data indicate that <5% of the cohort had cerebral imaging indicative of raised intracranial pressure (data not shown). We believe that, in part, the lack of use of the appropriate diagnostic tests was driven by the delay in CSF sampling and receipt of the test result. Thus clinicians felt that the PCR result would not arrive back in time to influence the management of their patient, particularly perhaps, as 65% of the total cohort received empirical aciclovir. Yet, as shown in Table 2, the spectrum of conditions which mimicked HSE was wide, many of which required completely different treatment strategies, involving antibiotics, anti-coagulation, steroids, tumour debulking, etc. A rapid negative PCR result, complemented by a negative intrathecal HSV-specific antibody study, would surely re-focus the initial diagnostic process and increase the chance of a correct therapeutic intervention.
This audit demonstrates that PCR is underused. In addition, only 2/10 definite HSE cases were diagnosed through the detection of intrathecal HSV-specific antibody production. This reinforces the use of intrathecal antibody tests to complement PCR, and awareness of the utility of these assays should be raised. There is a definite need for a 24 h turnaround PCR service for HSV (and other viruses), as well as access to CSF antibody assays at all hospitals admitting encephalitic or encephalopathic patients. Furthermore, the importance of confirming the cause of suspected viral encephalitis is even greater, given the recent epidemiological and public health concerns both of bioterrorism and emerging infections.19,20 Rapid and definite exclusion of HSV as the aetiology of encephalitis is a vital step to stimulate the search for alternative infectious aetiologies such as the West Nile virus.
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Acknowledgments |
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NWSD was funded through a personal training award from the Charitable Foundation of Guy's and St Thomas’ Hospitals.
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Footnotes |
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Address correspondence to: Dr J. Chataway, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG. e-mail: jeremy.chataway{at}st-marys.nhs.uk
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