Viral Meningitis: a real pain in            the neck!         A current review of viral meningitis.                       ...
Outline•   Background•   How big is the problem.•   What causes viral meningitis.•   What happens to people who have viral...
Meningitis• What do people think of when they think of meningitis?   – “Panic, really serious illness”   – “rash, glass te...
Meningitis• What do people think of when they think of meningitis?   – “Panic, really serious illness”   – “rash, glass te...
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                        Bacteria• Very small (10nm-300nm)      • Larger – can be seen with a• Live ...
Viral Meningitis• How big is the problem?  – 2009-2010 data     • HES 3434 cases     • HPA 260 notified cases  – Finnish s...
Viral Meningitis - causes• Lots!• Enteroviruses  – Same family as poliovirus  – Gut bug  – Can be fatal in very young chil...
• Herpesviruses  – Herpes simplex virus type 2     • Spread sexually – often asymptomatically     • Very few have current/...
• Varicella Zoster virus  – Chickenpox/Shingles  – Often occurs without rash  – Can occur at time of first infection or as...
• Arboviruses  – Arthropod Borne Viruses  – Not present in UK but are in Europe/USA  – Think of in travellers  – Toscana V...
• HIV  – Causes an “aseptic” meningitis  – Normally at time of first infection  – Can occur later in disease  – If missed ...
• Others  – Mumps  – Other herpes viruses     • EBV, CMV, HSV-1, HHV-6/7  – Parechoviruses (normally in young children onl...
Undiagnosed Meningitis• 30-40% of patients with clinical viral meningitis
Undiagnosed Meningitis• Lack of knowledge and investigations not  requested/done                     %age done            ...
Clinical Features
DemographicsAge and Gender Distribution between different aetiologies                            Median Age      %age fema...
Clinical Features• Common  –   Headache  –   Fever  –   Photophobia  –   Neck Stiffness  –   Nausea and vomiting• Less com...
Clinical Features of Different Viruses                            Headache      Photophobia                Neck Stiffness ...
Outcomes
What are the longer term outcomes for       people with viral meningitis?•Viral meningitis is often quoted as being abenig...
Individual impact• 2500-4000 individuals   – Significant impact at the individual level   – I am nowhere near being back t...
Economic sequelae• Healthcare costs• Loss of earnings • Young, fit people• Indirect costs   • Carers etc…• 1.3 billion USD...
Neuropsychological sequelaeDomain            BM (%)              VM (%)                       Control (%)                 ...
Recurrences• Mollaret’s/recurrent benign lymphocytic  meningitis• All viruses have been reported• HSV-2 by far the commonest
Recurrences       Herpes viruses – latency and reactivation• Herpes viruses are characterised by the ability to  establish...
Recurrences                 Recurrent genital HSV-2• Genital recurrences common  – Asymptomatic and symptomatic  – Asympto...
Recurrences                       Recurrent HSV-2 meningitisFinnish study   665 patients with lymphocytic meningitis      ...
Recurrences – does prevention work?101 patients with HSV-2 meningitisRandomised to Valaciclovir or placeboTreated for one ...
Research questions
Research questions•   Pathogenesis•   Diagnostics•   Treatment options•   Longer term outcomes    – Recurrences    – Econo...
Pathogenesis• Current work is very patchy  – Based on work on polio• Why do some people get recurrent disease?  – Immune d...
Diagnostics• The polymerase chain reaction has greatly  improved things• Still significant number of people not getting a ...
New approaches to diagnostics• Gene expression profiling  – gene expression                                  A - TB mening...
Treatment optionsNo proven, licensed treatments for any of the common causes ofviral meningitis                           ...
HSV-2 meningitis - to treat or not to treat• US Study (2009)       – Retrospective review of HSV-2 in CSF       – 19 cases...
Longer term outcomes• How much does viral meningitis cost the NHS  in the UK?• Are there neuropsychological consequences?
How common is it?Patients admitted with suspected meningitis who havea lumbar puncture (spinal tap)  1. Control patients  ...
Adults ≥16       Admitted to hospital with suspected                   meningitis                  Lumbar Puncture        ...
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  – Head...
Suspected                      Aseptic               BacterialControl              meningitis            Meningitis    5 x...
Improving diagnosis• Looking at genes expressed in the  host/patient  • Are their differences between  controls and mening...
Pathogenesis• HSV is so prevalent why do some people  develop meningitis and others don’t?  – Examine differences in DNA f...
Thanks• You – for listening• MRF• LBIG and Prof Solomon etc…..• Doctors and Nurses at all the sites involved in  my study•...
Viral Meningitis: A real pain in the neck by Dr Fiona McGill
Viral Meningitis: A real pain in the neck by Dr Fiona McGill
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Viral Meningitis: A real pain in the neck by Dr Fiona McGill

  1. 1. 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
  2. 2. 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.
  3. 3. 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 dont know” – “Affects small children, every parent’s nightmare, nearly always fatal” – “Headaches, rashes that don’t disappear, aversion to bright lights, vomiting and nausea” – “thats 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”
  4. 4. 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 dont know” – “Affects small children, every parent’s nightmare, nearly always fatal” – “Headaches, rashes that don’t disappear, aversion to bright lights, vomiting and nausea” – “thats 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”
  5. 5. What is meningitis?• Meningitis – Inflammation of the meninges• What are meninges? – Lining of the brain.
  6. 6. What is meningitis?• Often caused by infection – Bacteria – Viruses – Fungi, parasites, tuberculosis, HIV.......
  7. 7. What is a virus?Viruses Bacteria• Very small (10nm-300nm) • Larger – can be seen with a• Live inside cells normal microscope (1000nm)• Difficult to grow in a lab • Most grow easily given the right conditions • Can live out with cells
  8. 8. 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
  9. 9. Viral Meningitis - causes• Lots!• Enteroviruses – Same family as poliovirus – Gut bug – Can be fatal in very young children – Spread by poor hygeine – Outbreaks – Seasonal
  10. 10. • 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
  11. 11. • Varicella Zoster virus – Chickenpox/Shingles – Often occurs without rash – Can occur at time of first infection or as a reactivation
  12. 12. • 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
  13. 13. • 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
  14. 14. • Others – Mumps – Other herpes viruses • EBV, CMV, HSV-1, HHV-6/7 – Parechoviruses (normally in young children only)• Many remain without a specific bug
  15. 15. Undiagnosed Meningitis• 30-40% of patients with clinical viral meningitis
  16. 16. Undiagnosed Meningitis• Lack of knowledge and investigations not requested/done %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• Current diagnostics inadequate• New/emerging pathogens
  17. 17. Clinical Features
  18. 18. DemographicsAge and Gender Distribution between different aetiologies 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 32.5 58 38 ASM
  19. 19. Clinical Features• Common – Headache – Fever – Photophobia – Neck Stiffness – Nausea and vomiting• Less common – Rash – Myalgia – Very few have concurrent (or previous) genital lesions
  20. 20. Clinical Features of Different Viruses Headache Photophobia Neck Stiffness Fever N and/or VEnterovirus Ihekwaba et 100% 82% 77% 37.8+/-0.8 91% al (n=22) Meningitis 100% 91% 77% 67% 47% NW (n=43)VZV Ihekwaba et 76% 25% 38% 37.3+/-1.0 50% al (n=8) Meningitis 100% 60% 20% 60% 80% NW (n=5)HSV-2 Ihekwaba et 100% 63% 100% 37.8+/-0.6 100% al (n=8) Meningitis 100% 67% 56% 44% 56% NW (n=9) 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.
  21. 21. Outcomes
  22. 22. What are the longer term outcomes for people with viral meningitis?•Viral meningitis is often quoted as being abenign self-limiting illness•Doesn’t tend to maim or kill•However • individual consequences • fatigue • cost implications1 • psychosocial • evidence of poor neuropsychological outcomes2 • recurrences 1) Khetsuriani et al, Viral Meningitis associated hospitalisations in the US, 1988-1999. Neuroepidemiology. 2003; 22: 345-352 2)Schmidt et al, Neuropsychological sequelae of bacterial and viral meningitis. Brain (2006):129:333-345
  23. 23. 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 wouldnt 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.
  24. 24. 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
  25. 25. Neuropsychological sequelaeDomain BM (%) VM (%) Control (%) P valueAttention 39 42.6 20.0 NsExecutive 63.6 48.3 25.0 NsFunctionShort term 58.6 39.5 15.4 <0.01memoryVerbal learning 31 25.0 10.0 Ns Schmidt et al, Neuropsychological sequelae of bacterial and viral meningitis. Brain (2006):129:333-345
  26. 26. Recurrences• Mollaret’s/recurrent benign lymphocytic meningitis• All viruses have been reported• HSV-2 by far the commonest
  27. 27. Recurrences Herpes viruses – latency and reactivation• 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
  28. 28. Recurrences Recurrent genital HSV-2• 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
  29. 29. Recurrences Recurrent HSV-2 meningitisFinnish study 665 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 previousepisodes of meningitis 3 patients had recurrent genital herpes (8%) Prevalence of RLM 2.7/100000 Prevalence of HSV-2 ass RLM 2.2/100000 Kallio-Laine et al. Recurrent Lymphocytic Meningitis Positive for Herpes Simplex Virus Type 2. EID. 15(7) :1119-1122
  30. 30. Recurrences – does prevention work?101 patients with HSV-2 meningitisRandomised to Valaciclovir or placeboTreated for one year and followed up for a further yearRecurrent meningitis commoner in patients who took valaciclovir than inthose who were on placebo?Dose not right?unable to completely eradicate/prevent virus once it has established latency
  31. 31. Research questions
  32. 32. Research questions• Pathogenesis• Diagnostics• Treatment options• Longer term outcomes – Recurrences – Economics
  33. 33. Pathogenesis• Current work is very patchy – Based on work on polio• Why do some people get recurrent disease? – Immune defects
  34. 34. 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
  35. 35. New approaches to diagnostics• Gene expression profiling – gene expression A - TB meningitis B - Cerebral Malaria C – Bacterial meningitis Griffiths, M, Hemingway C Newton, C Levin, M; unpublished
  36. 36. Treatment optionsNo proven, licensed treatments for any of the common causes ofviral meningitis – ?Aciclovir• Enterovirus – Pleconaril • HIV • Reduced symptoms by a – Antiretrovirals day or so • Others • Potential for interactions – Supportive deemed too high for clinical – ?steroids benefit, never licensed – ?immunoglobulin – ?immunoglobulin• Herpes viruses
  37. 37. 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
  38. 38. Longer term outcomes• How much does viral meningitis cost the NHS in the UK?• Are there neuropsychological consequences?
  39. 39. How common is it?Patients admitted with suspected meningitis who havea lumbar puncture (spinal tap) 1. Control patients  Symptoms of meningitis, normal lumbar puncture findings. 2. Meningitis  Viral, bacterial, other....
  40. 40. Adults ≥16 Admitted to hospital with suspected meningitis Lumbar Puncture Aseptic Suspected Control meningitis Bacterial (ASM) Meningitis (SBM) Viral Othersmeningitis TB
  41. 41. How common is it?• C.30 hospitals in the North of England
  42. 42. What happens to people with viral meningitis?• Follow-up with questionnaires for a year after admission – Headaches – Quality of life – Brain functioning – Economics
  43. 43. Suspected Aseptic BacterialControl meningitis Meningitis 5 x questionnaires at 6, 12, 24 and 48 weeks
  44. 44. 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
  45. 45. 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
  46. 46. 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?
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