Viral Meningitis: a real pain in the neck!

A current review of viral meningitis.

Dr Fiona McGillClinical Research Fellow, Liverpool Brain Infections Group

Specialist Registrar in Infectious Diseases and Medical Microbiology

Outline

• Background• How big is the problem.• What causes viral meningitis.• What happens to people who have viral

meningitis– In the short term - symptoms– In the longer term - consequences

• What are the outstanding unanswered questions.

Meningitis• What do people think of when they think of meningitis?

– “Panic, really serious illness”– “rash, glass test, projectile vomiting, sore neck, dislike of bright light,

scary bananas”– “Aaaaaaaaaaaaaagh!”– “inflammation of the stuff round the brain, membrane? I don't know”– “Affects small children, every parent’s nightmare, nearly always fatal”– “Headaches, rashes that don’t disappear, aversion to bright lights,

vomiting and nausea”– “that's not good. Then the test u r supposed to do with the glass for

blotchy skin, high temperature, difficulty breathing, vomiting possibly”– “'serious' and mainly of kids/young people, the glass test”– “It is extremely dangerous, can kill”– “Scary, serious, unpredictable, rash”– “serious illness, rash, glass test”

Meningitis• What do people think of when they think of meningitis?

– “Panic, really serious illness”– “rash, glass test, projectile vomiting, sore neck, dislike of bright light,

scary bananas”– “Aaaaaaaaaaaaaagh!”– “inflammation of the stuff round the brain, membrane? I don't know”– “Affects small children, every parent’s nightmare, nearly always fatal”– “Headaches, rashes that don’t disappear, aversion to bright lights,

vomiting and nausea”– “that's not good. Then the test u r supposed to do with the glass for

blotchy skin, high temperature, difficulty breathing, vomiting possibly”– “'serious' and mainly of kids/young people, the glass test”– “It is extremely dangerous, can kill”– “Scary, serious, unpredictable, rash”– “serious illness, rash, glass test”

What is meningitis?

• Meningitis– Inflammation of the meninges

• What are meninges?– Lining of the brain.

What is meningitis?

• Often caused by infection– Bacteria

– Viruses

– Fungi, parasites, tuberculosis, HIV.......

What is a virus?

Viruses• Very small (10nm-300nm)• Live inside cells• Difficult to grow in a lab

Bacteria• Larger – can be seen with a

normal microscope (1000nm)

• Most grow easily given the right conditions

• Can live out with cells

Viral Meningitis

• How big is the problem?– 2009-2010 data

• HES 3434 cases• HPA 260 notified cases

– Finnish study• 7.6/100,000 (adults)

– 50% of all meningitis related hospital admissions

• c. 2500 – 4000 cases a year in the UK

Viral Meningitis - causes

• Lots! • Enteroviruses– Same family as poliovirus– Gut bug– Can be fatal in very young children– Spread by poor hygeine– Outbreaks– Seasonal

• Herpesviruses– Herpes simplex virus type 2• Spread sexually – often asymptomatically• Very few have current/history of genital disease• Amount of people infected worldwide with HSV-2 is

increasing• Can recur (most don’t!)• Can occur with a first infection, or several years after

infection

• Varicella Zoster virus– Chickenpox/Shingles– Often occurs without rash– Can occur at time of first infection or as a

reactivation

• Arboviruses– Arthropod Borne Viruses– Not present in UK but are in Europe/USA– Think of in travellers– Toscana Virus, West Nile Virus, Tick Borne

Encephalitis

• HIV– Causes an “aseptic” meningitis– Normally at time of first infection– Can occur later in disease– If missed may mean patient not diagnosed until

have advanced disease or ‘AIDS’– 30% of patients diagnosed with HIV could have

been diagnosed earlier

• Others– Mumps – Other herpes viruses• EBV, CMV, HSV-1, HHV-6/7

– Parechoviruses (normally in young children only)

• Many remain without a specific bug

Undiagnosed Meningitis• 30-40% of patients with clinical viral meningitis

Undiagnosed Meningitis• Lack of knowledge and investigations not

requested/done

• Current diagnostics inadequate• New/emerging pathogens

%age done

HSV-1 PCR (n=100) 92

HSV-2 PCR 92

EV PCR 89

VZV PCR 82

Parecho PCR 64

HIV ag/ab (n= 37) 41

Clinical Features

Median Age %age female n

Control 37 67.4 92

ASM 32.5 62.7 102

SBM 59.5 35.7 28

Encephalitis 47.5 60 10

Median Age %age female N

Enterovirus 30 65.1 43

HSV-2 43 78 9

VZV 40 60 5

Unknown ASM

32.5 58 38

Age and Gender Distribution between different aetiologies

Demographics

Clinical Features

• Common– Headache– Fever– Photophobia– Neck Stiffness– Nausea and vomiting

• Less common– Rash– Myalgia– Very few have concurrent (or previous) genital lesions

Headache Photophobia Neck Stiffness Fever N and/or V

Enterovirus Ihekwaba et al (n=22)

100% 82% 77% 37.8+/-0.8 91%

Meningitis NW (n=43)

100% 91% 77% 67% 47%

VZV Ihekwaba et al (n=8)

76% 25% 38% 37.3+/-1.0 50%

Meningitis NW (n=5)

100% 60% 20% 60% 80%

HSV-2 Ihekwaba et al (n=8)

100% 63% 100% 37.8+/-0.6 100%

Meningitis NW (n=9)

100% 67% 56% 44% 56%

Clinical Features of Different Viruses

Ihekwaba UK, Kudesia G, McKendrick M. Clinical Features of viral Meningitis in Adults: significant differences in Cerebrospinal Fluid Findings among Herpes Simplex Virus, Varicella Zoster Virus and Enterovirus Infections. CID 2008:47. 783-789.

Outcomes

What are the longer term outcomes for people with viral meningitis?

•Viral meningitis is often quoted as being a benign self-limiting illness•Doesn’t tend to maim or kill•However• individual consequences• fatigue• cost implications1

• psychosocial• evidence of poor neuropsychological

outcomes2

• recurrences1) Khetsuriani et al, Viral Meningitis associated hospitalisations in the US, 1988-1999. Neuroepidemiology. 2003; 22: 345-3522)Schmidt et al, Neuropsychological sequelae of bacterial and viral meningitis. Brain (2006):129:333-345

Individual impact

• 2500-4000 individuals– Significant impact at the individual level– I am nowhere near being back to normal and anticipate it being months until I am.

– Since being home I have found it hard to concentrate, had memory loss, muffled ears, sleep apnoea, racing heart, shooting pains down my legs, loss of co-ordination, sore and stiff neck and back, speech problems, shakes, photophobia on occasion, tics and twitches and felt depressed.

– It lasted for only a week but I can honestly say that was the worst seven days of my life. I wouldn't wish meningitis on my worst enemy.

– I had never felt so unwell.

– it was the scariest thing I have ever had to experience

– I now have really bad headaches and my back is always sore with shooting pains through it.

Economic sequelae

• Healthcare costs• Loss of earnings• Young, fit people

• Indirect costs• Carers etc…

• 1.3 billion USD over a 5 year period

Khetsuriani et al, Viral Meningitis associated hospitalisations in the US, 1988-1999. Neuroepidemiology. 2003; 22: 345-352

Neuropsychological sequelae

Domain BM (%) VM (%) Control (%) P value

Attention 39 42.6 20.0 Ns

Executive Function

63.6 48.3 25.0 Ns

Short term memory

58.6 39.5 15.4 <0.01

Verbal learning 31 25.0 10.0 Ns

Schmidt et al, Neuropsychological sequelae of bacterial and viral meningitis. Brain (2006):129:333-345

Recurrences

• Mollaret’s/recurrent benign lymphocytic meningitis

• All viruses have been reported• HSV-2 by far the commonest

• Herpes viruses are characterised by the ability to establish latency– Remains present in the host– No active replication– Always retain ability to reactivate

• Reactivation– Triggers– Associated with immune status– More frequently with HSV than VZV (normally only once)– Normally asymptomatic

RecurrencesHerpes viruses – latency and reactivation

• Genital recurrences common– Asymptomatic and symptomatic– Asymptomatic more common– Infection with HSV-2 globally is rising– Infection with HSV-2 significantly increases risk of

HIV infection– Antivirals reduces clinical disease and detectable

genital shedding but don’t reduce transmission or HIV acquisition

Recurrences Recurrent genital HSV-2

Finnish study665 patients with lymphocytic meningitis

37 had recurrent meningitis (5.6%)28 had HSV-2 in CSF (76%)

27-30% of pts with HSV-2 in CSF had previous episodes of meningitis

3 patients had recurrent genital herpes (8%)Prevalence of RLM 2.7/100000Prevalence of HSV-2 ass RLM 2.2/100000

Recurrences Recurrent HSV-2 meningitis

Kallio-Laine et al. Recurrent Lymphocytic Meningitis Positive for Herpes Simplex Virus Type 2. EID. 15(7) :1119-1122

Recurrences – does prevention work?

101 patients with HSV-2 meningitisRandomised to Valaciclovir or placeboTreated for one year and followed up for a further year

Recurrent meningitis commoner in patients who took valaciclovir than in those who were on placebo

?Dose not right?unable to completely eradicate/prevent virus once it has established latency

Research questions

Research questions

• Pathogenesis• Diagnostics• Treatment options• Longer term outcomes– Recurrences– Economics

Pathogenesis

• Current work is very patchy– Based on work on polio

• Why do some people get recurrent disease?– Immune defects

Diagnostics

• The polymerase chain reaction has greatly improved things

• Still significant number of people not getting a diagnosis– Requires education– New approach

• Gene expression profiling

New approaches to diagnostics

• Gene expression profiling– gene expression

A - TB meningitisB - Cerebral MalariaC – Bacterial meningitis

Griffiths, M, Hemingway C Newton, C Levin, M; unpublished

Treatment options

• Enterovirus– Pleconaril

• Reduced symptoms by a day or so

• Potential for interactions deemed too high for clinical benefit, never licensed

– ?immunoglobulin• Herpes viruses

– ?Aciclovir

• HIV– Antiretrovirals

• Others– Supportive– ?steroids– ?immunoglobulin

No proven, licensed treatments for any of the common causes of viral meningitis

HSV-2 meningitis - to treat or not to treat

• US Study (2009)– Retrospective review of HSV-2 in CSF– 19 cases of meningitis, 74% female, only 2 had history of prior

genital herpes, one had concurrent herpes– Treatment variable

– None to 21 days of IV Aciclovir and everything in between.

• Need for a properly conducted trial

Longer term outcomes

• How much does viral meningitis cost the NHS in the UK?

• Are there neuropsychological consequences?

How common is it?

1. Control patients Symptoms of meningitis, normal lumbar puncture

findings.2. Meningitis

Viral, bacterial, other....

Patients admitted with suspected meningitis who have a lumbar puncture (spinal tap)

Adults ≥16

Admitted to hospital with suspected meningitis

Lumbar Puncture

ControlAseptic

meningitis (ASM)

Suspected Bacterial

Meningitis (SBM)

Viral meningitis TB Others

How common is it?

• C.30 hospitals in the North of England

What happens to people with viral meningitis?

• Follow-up with questionnaires for a year after admission

– Headaches– Quality of life– Brain functioning– Economics

ControlAseptic

meningitis

Suspected Bacterial

Meningitis

5 x questionnaires at 6, 12, 24 and 48 weeks

Improving diagnosis

• Looking at genes expressed in the host/patient• Are their differences between controls and meningitis?• Are they different between patients who have

viruses and those who have bacteria?• Are they different between different viruses?• Blood and spinal fluid

c/o M.Griffiths

Pathogenesis

• HSV is so prevalent why do some people develop meningitis and others don’t?– Examine differences in DNA from pts with

meningitis and those without– Both patient and viral/bacterial DNA– Compare differences in pathogen DNA from

different sites e.g. CSF and genital

Thanks

• You – for listening• MRF• LBIG and Prof Solomon etc…..• Doctors and Nurses at all the sites involved in

my study• All the patients in the study

Any questions?