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

• 64 WBC (70% polymorphs/30% lymphocytes)

• Protein 0.64 (range 0.1-0.4 g/L)

• CSF glucose 4.5, plasma glucose not available

DD: Encephalopathic ? Cause Rx: IV Aciclovir 10mg/kg q8h, IV Ceftriaxone 2g q12h , IV Amoxicillin 2g q4h.

• 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)

• Yes

• No

1st Dilemma: Should steroids be given?

1st Dilemma: Should steroids be given? • Corticosteroids have been used, especially if marked

cerebral oedema, brain shift or raised intracranial pressure.

• Controversial- whilst reduces swelling, also has strong immunomodulatory effect which may help viral replication.

• Retrospective analysis of 45 patients showed that older age, lower admission GCS and lack of steroids all independently predicted poorer outcome. Kamei S et al. J Neurol Neurosurg Psychiatry 2005, 76:1544-1549.

• RCT (GACHE trial) currently performed to address this. Martinez-Torres F et al. GACHE Investigators. BMC Neurol 2008;8:40.

We do not routinely use steroids and did not use them in this case. The Management of Suspected Viral Encephalitis Guideline 2012 advises to wait for the RCT results and not to use routinely. Soloman T et al. Association of British Neurologists and British Infection Association National Guidelines. J.Infection 2012 64:347-373

• 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

L

Low density area within left temporal lobe (note previously normal CT scan- can be in 25%)

RRTT

Left Temporal slowing ( a non specific abnormality indicating underlying focal disturbance of cerebral activity)

R P

aras

agit

tal

L Pa

rasa

gitt

al

L La

tera

l R

Lat

eral

• Yes

• No

2nd Dilemma- Should IV aciclovir dose be increased?

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 utilised- not 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

3rd 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?

• 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

P +PP

Viral replication

P

DNA POL

P P

P

dNTP (A,C,G,T)

Thymidine kinase

Cellular kinases

P P

P

aciclovir

Inhibit the growing dNTP chain and viral replication

Foscarnet-switch or add?

• Reduction in VL

• Good CSF penetration

RISK BENEFIT

• Toxicity- marked

reduction in renal function

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 IC50 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

Soloman T et al. Association of British Neurologists and British Infection Association National Guidelines. J.Infection 2012 64:347-373

HSV/VZV Encephalitis confirmed

Immunosuppressed? Or age 3 months-12 years?

14 days IV aciclovir 21 days IV aciclovir

Repeat LP

PCR Positive?

Stop aciclovir 7 days IV aciclovir

NO YES

NO YES

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

3rd 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