Herpes Simplex Virus Encephalitis Benedict Daniel Michael

1. Herpes Simplex Virus Encephalitis Benedict Daniel Michael Benedict Michael (NIHR Doctoral Research Registrar in Neurology ) works at the Institute of Infection and Global Health, University of Liverpool and the Walton Centre Neurology NHS Foundation Trust, Liverpool. He has a particular interest in both clinical practice and research into neurological infectious disease and the para-infectious neuroimmunologicalresponse. This session provides an overview of issues relating to the clinical features, acute investigation, diagnosis and management of herpes simplex virus encephalitis • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment

2. Learning Objectives • By the end of this session you will be able to: • Illustrate the pathogenesis of herpes simplex virus encephalitis • Describe the clinical features which should raise suspicion of herpes simplex virus encephalitis • Define the appropriate acute investigations which should be performed for patients with suspected herpes simplex virus encephalitis • Discuss the appropriate treatment for herpes simplex virus encephalitis • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment

3. Overview This session explores the aetiology, clinical features, acute investigations and treatment of patients with herpes simplex virus (HSV) encephalitis. First it describes the pathophysiology of HSV encephalitis. Then it examines why cases of encephalitis are missed or diagnosed and treated late. This is important as mortality rates are 70% in untreated cases and can be as low as 10-20% if patients are treated early. Finally, it provides a clear, structured approach to investigation, diagnosis and treatment of HSV encephalitis. • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment

4. Pathogenesis I Herpes simplex virus 1 is a relatively large double-stranded ubiquitous DNA virus. The vast majority of people are infected before adulthood. The virus traverses mucous membranes and then travels, by retrograde axonal transport, to the trigeminal ganglion where it establishes latency through complex mechanisms to avoid the host immune system. There is periodic reactivation and antegrade axonal transport to allow for viral shedding and infection of new hosts. The pathophysiologic processes controlling reactivation are not fully understood, but are likely to involve Toll-like receptors and interferons. • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment

5. Pathogenesis II In the majority of people, reactivation of HSV1 will only result in asymptomatic viral shedding or the common cold sore. However, in a proportion of people, HSV1 reactivation will result in brain infection and inflammation. Unlike many other causes of viral encephalitis, HSV1 does not appear to enter the brain through a viraemic illness and permeability of the blood brain barrier. Rather there is either further retrograde axonal transport of HSV1 into the central nervous system (CNS) or there is reactivation of latent virus already present in the CNS. Indeed, in post-mortem studies of patients with no history of neurological illness or disability, HSV1 DNA is identified in the brains of a proportion. Therefore the presence or absence of a cold sore does not inform the clinician that the HSV1 is the cause of encephalitis • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment

6. Pathogenesis III Generally patients with immunocompromise are at increased risk of brain infection. However, HSV1 is no more common in those with immunocompromise. There is a bimodal distribution of incidence with peaks seen in young and older adults. • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment The histopathological features show apoptosis, haemorrhage and necrosis (arrow A), perivascular cuffing (arrow B) and infiltration of leukocytes. This occurs predominantly in the medial temporal and inferior frontal lobes. It remains unclear to what extent the neuronal injury and death is due to direct viral cytopathy, apoptosis, hypoxia, excitotoxic injury or other, possibly cytokine-mediated, mechanisms.

7. The Clinical Features Which Should Raise Suspicion of HSV Encephalitis I The classical clinical features are headache or altered or reduced consciousness or personality or behaviour change in a patient with a fever or history of a febrile illness. However, as demonstrated in the table, 28% of patients with encephalitis do not have a fever on admission. Importantly 11% of patients with proven HSV1 encephalitis were  not febrile on admission.  Specific features reported in HSV1 encephalitis include those involving the temporal and frontal lobes, such as olfactory hallucinations, simple and complex partial seizures, bizarre behaviour and neuropsychiatric features. However, these are not sufficiently sensitive or specific to establish or refute the diagnosis. Therefore cerebrospinal fluid (CSF) analysis and, to a lesser extent, neuro-imaging are vital to diagnosis. Altered consciousness, personality or behaviour should not be attributed to an infection outside of the central nervous system, such as a urinary tract infection, in an otherwise healthy patient unless there is strong evidence for this. Indeed, many patients with proven encephalitis will have gastrointestinal, respiratory or urinary symptoms. • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment

8. The Clinical Features Which Should Raise Suspicion of HSV Encephalitis II • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment

9. The Clinical Features Which Should Raise Suspicion of HSV Encephalitis III • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment Do not rely on a low Glasgow coma score as this is a very crude proxy of cerebral dysfunction. Indeed in the two recent studies described only 5 of 13 (38%) had a GCS<15 and 37 of 203 (18%) had a GCS <8. Instead get a collateral history and assess this and the patient carefully for evidence of altered personality, behaviour and cognition, including neuro-psychiatric features. Never dismiss the statement of a friend or relative that a patient is 'not quite themselves'. Perform a full neurological examination, including mental state assessment and fundoscopy.

10. Clinical Features Supporting the Diagnosis of a CNS Infection I The wide range of clinical features require that many patients are investigated. In a recent study, of 217 patients with suspected CNS infections at 10 hospitals, 44 had the diagnosis confirmed. Clinical features supporting the diagnosis of a CNS infection are outlined in the table below. • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment

11. Clinical Features Supporting the Diagnosis of a CNS Infection II • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment • Often there is both clinical and histopathological overlap between encephalitis and meningitis and the term 'meningoencephalitis' is often used. • Nevertheless, clinical features reflecting involvement of the brain parenchyma may point towards a diagnosis of encephalitis: • Seizures • Focal neurological signs (including movement disorders) • Neuropsychiatric features

12. Acute Investigations I CSF examination from a lumbar puncture (LP) is the most important investigation as this can confirm or refute the diagnosis and direct treatment towards a viral, bacterial or mycobacterial pathogen. Lumbar Puncture A lumbar puncture should be performed urgently for all patients in whom encephalitis is suspected unless there are clinical contraindications, as outlined in the table on the next slide. These clinical features have been found to be reliable and sensitive at identifying which patients are likely to have brain shift precluding an LP. CT If the contraindications are present a computed tomography (CT) scan of the brain should be arranged urgently and if this does not show the outlined features, an urgent LP performed. Coagulation abnormalities Patients with coagulation abnormalities should have these corrected before performing a LP and platelet count should be >100x109/l • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment

13. Acute Investigations II • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment

14. Investigations I Often clinicians inappropriately request a CT to 'rule out raised intracranial pressure before a LP'. However, a CT scan cannot do this and indeed a LP may be safe in patients with raised intracranial pressure. The CT should only be performed before a LP to identify if significant brain shift is present, thereby precluding a LP, in those patients in whom it is likely, as determined by the clinical features outlined. Delays in performing the LP have been demonstrated to delay the diagnosis and treatment in acute CNS infections and this results in increased morbidity and mortality. The routine CSF parameters and interpretation are shown in the next slide. • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment

15. Investigations II • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment The first CSF white cell count may be normal in approximately 10% of cases. If the clinical suspicion remains, the LP should be repeated 24-48 hours later.

16. Pathogen Identification Although a wide range of pathogens can cause encephalitis a staged approach to pathogen identification, as outlined in the table provides a pragmatic way to proceed. • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment

17. Symptoms and Investigations I • All patients with encephalitis should be considered for HIV testing for the following reasons: • Patients with immune compromise can develop encephalitis due to a wide range of pathogens and if HIV infection is identified the extent of investigation will need to be expanded • HIV seroconversion illness can present as a meningoencephalitis • HIV testing is particularly important as many of the conditions presenting as meningoencephalitis are treatable. • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment Learning Point: HIV antibody testing may be negative early during infection. Therefore, if clinical suspicion remains, the patient should be tested for the HIV P24 antigen and/or have HIV antibody testing repeated at a latter date

18. Symptoms and Investigations II Brain biopsy Brain biopsy should be considered when the investigatons have been negative and the patient continues to deteriorate, despite empirical treatment. All patients All patients should have microscopy and immunohistory, bacterial culture, extended fungal and mycobacterial culture, viral PCR (as for CSF). Immune suppressed patients For immune suppressed patients, carry out India ink stain for Cryptococcus, Ziehl-Neelsen stain for TB. • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment

19. MRI and EEG • Euro-imaging, preferably magnetic resonance imaging (MRI), can identify evidence of brain parenchymal inflammation. This may also point towards the aetiology, for example: • Fronto-temporal changes may be seen in HSV encephalitis • Hippocampal changes in limbic encephalitis, such as that due to VGKC antibodies • Basal ganglia changes in some arboviralencephalitides • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment • Brain stem changes are seen in rhombencephalitis, such as that due to Listeria monocytogenes • Electroencephalography (EEG) should be requested when subtle-motor or non-convulsive status epilepticus is suspected, for example a patient with fluctuating levels of consciousness, or if subtle motor features, such as eye lid movement, are present. • Periodic Lateralising Epileptiform Discharges (PLEDs) were once thought to be pathognomic for HSV1 encephalitis, but are now recognised to be present in a wide spectrum of conditions.

20. Management I • Attention should be given to: • Oxygenation • Fluid and hydration • Nasogastric and parenteral feeding • Patients with a reduced coma score or impaired gag reflex, should be assessed by an intensive care team. • In most immunocompetent patients acyclovir (10mg/kg three times/day) should be given intravenously as soon as there is a strong suspicion of viral encephalitis, based on the clinical presentation and initial CSF and/or imaging findings. If performing these investigations is likely to lead to long delays and the clinical suspicion is strong, then treatment should be started at once. • Acyclovir is a nucleoside analogue that reduces mortality from >70% to 10-20% when encephalitis is due to HSV1. However, approximately 60% of survivors have significant neurological and neuro-psychiatric morbidity despite this. • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment

21. Management II Delays from admission to treatment of >24 hours are associated with a worse outcome. If patients are <30 years old and have aciclovir started before a significant decline in neurological function survival can be as high as 100% with 60% not having any significant sequelae. Unfortunately, urgent investigation and treatment does not appear to be the norm in practice (see Bell et al. Clinical Medicine 2009, Michael et al. QJM 2010). • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment

22. Complications I Renal function should be monitored closely and adequate hydration maintained, because of the rare risk of renal failure. Other rare adverse effects include local inflammation at the site of the intravenous cannula, hepatitis, and bone marrow failure. As it is often not possible to determine whether the infection is due to a virus or bacteria in the acute phase, it is reasonable to commence both acyclovir and a 3rd generation cephalosporin. Nevertheless, due to the risks of opportunistic infection, antibiotic resistance and nephrotoxicity, the prescription of antimicrobials should be regularly reviewed in the light of test results • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment

23. Complications II If the patient deteriorates despite treatment, look for complications of encephalitis: Venous sinus thrombosis Venous system by CT or MRI. The image on the right is a magnetic resonance venogram demonstrating occlusino of the left transverse and siqmoid sinuses. Syndrome of Inappropriate Antiduiretic Hormone Secretion-check blood and urine sodium • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment Cerebral infarction Perform a CT or MRI Aspiration pneumonia Perform a chest radiograph Subtle motor or non-convulsive status epilepticus Perform an EEG

24. Complications III • Common neurological sequelae of HSV encephalitis include: • Epilepsy • Anosmia • Focal neurological weakness • Aphasia • A severe amnesic state • Rarely an acute oro-exploratory phenomenon may be seen • Often patients report that headaches, fatigue and cognitive cause significant disability and handicap. • Patients and their family should be put in contact with patient-orientated support services, such as the Encephalitis Society, so that they have improved access to information, neuropsychological and social support. • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment

25. Key Points • HSV is the most common cause of encephalitis. This is a neurological emergency as early diagnosis and acyclovir decreases the risk of mortality and morbidity significantly • There are a wide range of clinical features that can be seen, but the presence of alterations in behaviour, consciousness or cognition should raise suspicion. Some features reflecting fronto-temporal dysfunction may be suggestive of HSV encephalitis. However, the diagnosis can only be made by PCR of the CSF. • Even in HSV encephalitis the first LP may be normal. Therefore, a second LP should be performed 24-48 hours later • The lumbar puncture does not have to be delayed for neuro-imaging unless specific clinical contraindications are present. • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment

26. Summary • Having completed this session you will now be able to: • Illustrate the pathogenesis of herpes simplex virus encephalitis. • Describe the clinical features which should raise suspicion of herpes simplex virus encephalitis • Define the appropriate acute investigations which should be performed for patients with suspected herpes simplex virus encephalitis • Discuss the appropriate treatment for herpes simplex virus encephalitis • References and Further Reading • Solomon T, Hart I, Beeching NJ. Viral Encephalitis: A clinician's guide. Practical Neurology 2007; 7:288-305. • Granerod J, Ambrose HE, Davies NWS, Clewley JP et al. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infectious Diseases 2010; 10: 835–44. • Michael BD, Sidhu M, Stoeter D, Roberts M, et al. The Epidemiology and Management of Adult Suspected Central Nervous System Infections - a retrospective cohort study in the NHS Northwest Region. Quarterly Journal of Medicine 2010; doi:10.1093/qjmed/hcq121. • Granerod J, Tam CC, Crowcroft NS, et al. Challenge of the unknown : A systematic review of acute encephalitis in non-outbreak situations. Neurology 2010;75;924 • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment

27. Question 1 • herpes simplex virus encephalitis • Learning Objectives • Overview • Pathogenesis • Suspicious Clinical Features • Diagnostic Clinical features • Acute Investigations • Investigations • Pathogen identification • Symptom investigations • Neuro-Imaging • Management • Complications • Key points • Summary • Self Assessment Select the single best answer from the options given. Click on the answer to see if it is correct and read an explanation. Which one of the following statements is correct? Not all patients with HSV encephalitis have a fever on admission or a history of fever Feature such reflecting frontal or temporal lobe dysfunction, such as olfactory aura, can make the diagnosis of HSV encephalitis HSV is a rare infection typically found in the immunocompromised Patients with HSV encephalitis will typically have cold sores