When the drugs don t work- a case of HSV encephalitis. Nicky Price Consultant Virologist Public Health Wales
67 year old Caucasian Female Presenting complaint 2 day history of: Confusion Shivering Headache Myalgia Vomited X1 (no diarrhoea) Bizarre behaviours Poor recall (short and long term) Repetitive questioning No hallucinations, no LOC, no seizures No alcohol or drugs No cough or dysuria No travel history PMH/DH: Nil of relevance
On examination: Expressive dysphasia and memory impairment Disorientated in time (orientated in person/place) Pyrexial (39 C) GCS 14/15 No further abnormality noted CT scan normal LP: 76 RBC DD: Encephalopathic? Cause Rx: IV Aciclovir 10mg/kg q8h, IV Ceftriaxone 2g q12h, IV Amoxicillin 2g q4h. 64 WBC (70% polymorphs/30% lymphocytes) Protein 0.64 (range 0.1-0.4 g/l) CSF glucose 4.5, plasma glucose not available
3 days later Patient felt better However, no change in memory impairment or expressive dysphasia HSV 1 DETECTED by PCR (Stopped antibiotics as cultures negative) HIV test negative (no other immunosuppression)
1 st Dilemma: Should steroids be given? Yes No
1 st Dilemma: Should steroids be given? Corticosteroids have been used, especially if marked cerebral oedema, brain shift or raised intracranial pressure. We Controversial- do not routinely whilst use reduces steroids and swelling, did not also use has them in strong this case. immunomodulatory effect which may help viral replication. The Retrospective Management analysis of Suspected of 45 Viral patients Encephalitis showed that Guideline older age, 2012 lower advises admission to wait for GCS the and RCT lack results of steroids and all independently predicted poorer outcome. Kamei S et al. J not to use routinely. Soloman T et al. Association of British Neurologists and British Infection Neurol Association Neurosurg National Psychiatry Guidelines. 2005, 76:1544-1549. J.Infection 2012 64:347-373 RCT (GACHE trial) currently performed to address this. Martinez-Torres F et al. GACHE Investigators. BMC Neurol 2008;8:40.
1 week into IV aciclovir No real change. Remains pyrexial Still disorientated time Expressive dysphasia Repeat LP: Raised WBC (420) 95% lymphocytes still HSV PCR positive Low density area within left temporal lobe (note previously normal CT scan- can be in 25%) L
R Parasagittal L Parasagittal L Lateral R Lateral R R T T Left Temporal slowing ( a non specific abnormality indicating underlying focal disturbance of cerebral activity)
2 nd Dilemma- Should IV aciclovir dose be increased? Yes No
Should IV aciclovir dose be increased? RCT studies used 10mg/kg q8h IV aciclovir for 10 days versus vidarabine and assessed outcome. This reduced mortality from 50% to 20% (severe morbidity or death from 70% to 30%). Skoldenberg B et al. Lancet 1984;2:707-711. Whitley RJ et al. N Eng J Med 1986;314:144-149. Reports of relapse, so minimum 14 days therapy then utilisednot based on trial data. Soloman T et al. Association of British Neurologists and British Infection Association National Guidelines. J.Infection 2012 64:347-373 Due to continued pyrexia, raised CSF WBC and unchanged clinical picture we increased the dose of IV aciclovir to 15mg/kg tds, (with the caveat to monitor renal function and hydration). (Neonatal HSV is treated at an even higher dose of 20mg/kg q8h for 3 weeks).
3 weeks into IV aciclovir Pyrexia had settled by 2 weeks. Further LP still HSV DETECTED, WBC now 100. Patient feels memory gradually improving. CSF sent for culture and phenotypic resistance. Continue further 2/52 aciclovir and review. 5 weeks into IV aciclovir Further LP still HSV DETECTED, WBC now 56. Previous CSF sent for culture and phenotypic resistance testing- failed to culture. Stable clinical picture, not orientated to time as before
3 rd Dilemma- Should we continue present regimen? Currently Day 35 of IV aciclovir Should we: A) Continue B) Consider aciclovir resistance and switch to foscarnet? C) Add in foscarnet to the aciclovir? D) Switch to oral valaciclovir?
Resistance to aciclovir? dntp (A,C,G,T) P P P + P P Inhibit the growing dntp chain and viral replication P DNA POL Viral replication Foscarnet aciclovir P P P P Thymidine kinase Cellular kinases Can t culture this CSF. Only 1 case in HSE literature of virologically confirmed aciclovir resistance in immunocompetents. Kakiuchi S et al. J Clin Micro 2013; 51 :356-359 Prevalence of aciclovir resistance is 0.1%-0.7% in immunocompetent patients and 3.5%-10% in those with immunosuppression in general clinical isolates. Collins P and M.N. Ellis. J Med Virol 1993 Suppl 1 58-66. Stranska R et al. J Clin Virol 2005. 32:7-18
Foscarnet-switch or add? RISK BENEFIT Toxicity- marked reduction in renal function Reduction in VL Good CSF penetration Unlikely resistance in this case
Oral valaciclovir Adult patients received between 10mg/kg q8h to 20mg/kg q8h for 14-21 days, then randomised to placebo or valaciclovir 2g q8h for 90 days. The results are on the trial website. There was no statistical analysis provided. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. http://clinicaltrials.gov/ct2/show/nct00031486, [accessed 20.10.13]. Oral valaciclovir 1g q8h given for 21 days in confirmed HSE in Vietnam. 4 patients were studied and the [aciclovir] CSF was above the IC 50 required to inhibit HSV1 or HSV2. However, there is no full outcome data in this study. Pouplin T et al. 2011. AAC; 55: 3624-3626. Insufficient outcome data on oral valaciclovir for HSE use.
Management of Encephalitis Guidelines 2012 HSV/VZV Encephalitis confirmed NO Immunosuppressed? Or age 3 months-12 years? YES 14 days IV aciclovir 21 days IV aciclovir Repeat LP PCR Positive? NO YES Stop aciclovir 7 days IV aciclovir Soloman T et al. Association of British Neurologists and British Infection Association National Guidelines. J.Infection 2012 64:347-373
CSF Indices Post aciclovir Wk 0 Wk 1 Wk 3 Wk 5 CT Value 29 29 37 36 WBC 64 420 100 56 Improving CSF Indices Stable clinical picture
3 rd Dilemma- Should we continue present regimen? Currently Day 35 of IV aciclovir Should we: A) Continue in view of improving CSF and stable clinical picture (F/U imaging not available) B) Consider aciclovir resistance and switch to foscarnet? C) Add in foscarnet to the aciclovir? D) Switch to oral valaciclovir?
Follow on 2 weeks later the LP showed only 14 WBC and was HSV PCR negative. 47 days of IV aciclovir. Patient was transferred to a neurological rehabilitation unit for 2 months Neurocognitive assessments: (Addenbrookes Cognitive Evaluation-Revised) At 5 weeks into IV aciclovir 62/100 At end of aciclovir treatment 70/100
Summary Poor prognosis even with antivirals 58% moderately or severely disabled or death Death in up to 15% 42% favourable outcome (mild or no disability) 14% full recovery Mailles et al. 2012. Long term outcome of patients presenting with acute infectious encephalitis of various causes in France. CID 54: 1455-1464 Individual cases often thought provoking, especially when aciclovir use is 47 days! Await RCT GACHE results