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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?