Viral Meningitis: A real pain in the neck by Dr Fiona McGill
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Transcript of Viral Meningitis: A real pain in the neck by Dr Fiona McGill
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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
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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.
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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”
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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”
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What is meningitis?
• Meningitis– Inflammation of the meninges
• What are meninges?– Lining of the brain.
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What is meningitis?
• Often caused by infection– Bacteria
– Viruses
– Fungi, parasites, tuberculosis, HIV.......
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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
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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
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Viral Meningitis - causes
• Lots! • Enteroviruses– Same family as poliovirus– Gut bug– Can be fatal in very young children– Spread by poor hygeine– Outbreaks– Seasonal
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• 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
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• Varicella Zoster virus– Chickenpox/Shingles– Often occurs without rash– Can occur at time of first infection or as a
reactivation
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• 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
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• 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
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• Others– Mumps – Other herpes viruses• EBV, CMV, HSV-1, HHV-6/7
– Parechoviruses (normally in young children only)
• Many remain without a specific bug
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Undiagnosed Meningitis• 30-40% of patients with clinical viral meningitis
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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
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Clinical Features
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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
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Clinical Features
• Common– Headache– Fever– Photophobia– Neck Stiffness– Nausea and vomiting
• Less common– Rash– Myalgia– Very few have concurrent (or previous) genital lesions
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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.
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Outcomes
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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
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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.
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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
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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
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Recurrences
• Mollaret’s/recurrent benign lymphocytic meningitis
• All viruses have been reported• HSV-2 by far the commonest
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• 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
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• 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
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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
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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
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Research questions
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Research questions
• Pathogenesis• Diagnostics• Treatment options• Longer term outcomes– Recurrences– Economics
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Pathogenesis
• Current work is very patchy– Based on work on polio
• Why do some people get recurrent disease?– Immune defects
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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
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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
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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
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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
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Longer term outcomes
• How much does viral meningitis cost the NHS in the UK?
• Are there neuropsychological consequences?
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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)
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Adults ≥16
Admitted to hospital with suspected meningitis
Lumbar Puncture
ControlAseptic
meningitis (ASM)
Suspected Bacterial
Meningitis (SBM)
Viral meningitis TB Others
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How common is it?
• C.30 hospitals in the North of England
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What happens to people with viral meningitis?
• Follow-up with questionnaires for a year after admission
– Headaches– Quality of life– Brain functioning– Economics
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ControlAseptic
meningitis
Suspected Bacterial
Meningitis
5 x questionnaires at 6, 12, 24 and 48 weeks
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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
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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
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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?