Viral Meningitis: A real pain in the neck by Dr Fiona McGill

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  • 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. 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. 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. 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. What is meningitis?• Meningitis – Inflammation of the meninges• What are meninges? – Lining of the brain.
  • 6. What is meningitis?• Often caused by infection – Bacteria – Viruses – Fungi, parasites, tuberculosis, HIV.......
  • 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. 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. 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. • 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. • Varicella Zoster virus – Chickenpox/Shingles – Often occurs without rash – Can occur at time of first infection or as a reactivation
  • 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. • 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. • 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. Undiagnosed Meningitis• 30-40% of patients with clinical viral meningitis
  • 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. Clinical Features
  • 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. Clinical Features• Common – Headache – Fever – Photophobia – Neck Stiffness – Nausea and vomiting• Less common – Rash – Myalgia – Very few have concurrent (or previous) genital lesions
  • 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. Outcomes
  • 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. 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. 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. 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. Recurrences• Mollaret’s/recurrent benign lymphocytic meningitis• All viruses have been reported• HSV-2 by far the commonest
  • 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. 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. 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. 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. Research questions
  • 32. Research questions• Pathogenesis• Diagnostics• Treatment options• Longer term outcomes – Recurrences – Economics
  • 33. Pathogenesis• Current work is very patchy – Based on work on polio• Why do some people get recurrent disease? – Immune defects
  • 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. 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. 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. 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. Longer term outcomes• How much does viral meningitis cost the NHS in the UK?• Are there neuropsychological consequences?
  • 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. Adults ≥16 Admitted to hospital with suspected meningitis Lumbar Puncture Aseptic Suspected Control meningitis Bacterial (ASM) Meningitis (SBM) Viral Othersmeningitis TB
  • 41. How common is it?• C.30 hospitals in the North of England
  • 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. Suspected Aseptic BacterialControl meningitis Meningitis 5 x questionnaires at 6, 12, 24 and 48 weeks
  • 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. 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. 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?