Neurological effects from meningitis
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This document discusses the impact of meningitis on the brain and an overview of neurorehabilitation for children with neurological sequelae from meningitis. It provides details on the pathophysiology of meningitis and how it can cause brain damage. The document also presents clinical evidence from cases of meningitis, including outcomes and the incidence of post-meningitic hydrocephalus requiring shunt surgery. It concludes with an overview of neurorehabilitation services and a proposed model for a regional pediatric neurorehabilitation network.
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Neurological effects from meningitis
- 1. Impact of meningitis on the brain and an overview of neurorehabilitation for children with neurological sequelae Dr Peta Sharples MRF Meningitis Symposium July 2010
- 4. Aetiology of Non-traumatic coma n = 328 Admissions to BRHC PICU 1997-2001
- 5. Non-traumatic coma in relation to age n = 328 median age = 2 years
- 7. Case Fatality Rate (CFR) related to time Source: PHLS Communicable Disease Surveillance Center & ONS p<0.05
- 8. Case Fatality Rate Source : PHLS Communicable Disease Surveillance Center & ONS Case Fatality Rate %
- 9. PATHOPHYSIOLOGY OF MENINGITIS Bacteria Cytokines IL-1 β TNF IL-6 CSF ICAM Blood Neutrophils Macrophages ELAM Neutrophils Macrophages ROS Neutrophils Microglia Albumin Albumin Oedema Swelling BBB Cytokines PGs PAF lysis Vascular obstruction Stroke CN palsies Raised ICP Infarction Brain (1) (2)
- 10. Pathogenesis of Brain Damage in meningitis
- 12. PATHOPHYSIOLOGY OF MENINGITIS Cytokines CMRO2 Vasogenic / Cytotoxic Oedema Raised ICP CBF Cerebral O2 delivery Death or disability Cellular hypoxia Anaerobic glycolysis CSF lactate Neuronal loss
- 14. Tentorial herniation Foramen magnum herniation Temporal lobe damage Brain stem compression Respiratory and/or cardiac arrest Death Raised intracranial pressure
- 17. FRONTAL (“silent”) Attention Intellect (abstraction) Executive function, flexibility Behaviour (inhibition) Higher memory functions TEMPORAL Memory (encoding, retrieval) Language Behaviour/Emotion PARIETAL Language Visual-perceptual OCCIPITAL Cortical blindness Visual field problems BRAIN STEM Wakefulness/arousal, attention Cranial nerves Motor function (spastic quadriparesis, ataxia)
- 19. Selective vulnerability of the hippocampus
- 20. THE LIMBIC MEMORY SYSTEM HIPPOCAMPUS Basal forebrain Amygdala Basal ganglia BASAL FOREBRAIN BASAL FOREBRAIN CHOLINERGIC SYSTEM LIMBIC SYSTEM
- 23. Outcome from Bacterial Meningitis in Children Admitted to a Regional PICU P Prabhakar, K Vijayakumar PJ Murphy, PM Sharples Bristol Royal Hospital for Sick Children & Frenchay Hospital
- 28. Clinical evidence of raised intracranial pressure Deep coma GCS < 8 Rapid decline in conscious level Fixed and/or unequal pupils Bradycardia and/or apnoea Bulging anterior fontanelle Hemiparesis Papilloedema Prolonged seizure Oculomotor palsy Mellor, 1992
- 31. Evidence of raised intracranial pressure Intracranial pressure monitoring 18 (5.5%) Clinical only 128 (39%) Radiological 73 (22%) Lumbar puncture 16 (5%) Post mortem 3 (1%) Total patients with raised ICP 238 (72.5%) Total patients 328
- 33. Poor outcome over time chi squared test, p = 0.027
- 35. Clinical Variables Related to Outcome in Non-traumatic Coma 1.10-22.84 0.037 5.02 CNS infection 3.41-20.95 <0.001 8.46 Raised ICP on Ix 2.69-12.12 <0.001 5.72 Inotropes 2.74-31.22 <0.001 9.26 HIE 0.95-10.63 0.061 3.17 Seizure > 30 mins 0.23-1.56 0.293 0.60 GCS < 8 95% C I P value Odds Ratio Variable
- 37. Duration between Bacterial meningitis and Shunt insertion Duration in months No. of infants n=11
- 38. Incidence of shunted hydrocephalus in infants with bacterial meningitis related to organism *Chi squared, p=0.006 * * (5/18) (3/30) (2/80) n = 157 RNSC cases
- 39. Age distribution in shunted infants 7 2 1 1 0 n = 11
- 40. Meningococcal disease n=136 2 (4%) 26 (31%) Fits 30 (57%) 68 (82%) GCS 13 43 (81%) 0 –11(3) 62 (75%) 0 – 18 (2) Inotropes Duration (Median) 61 (96%) 0 – 13 (3) 69 (83%) 0 – 25 (3) IPPV Duration (Median) 5 1 - 19 4 1 - 54 Median LOS PICU (days) Range 47 (89%) 65 (78%) Transfer 22 (1m-16y) 24 (1m-16y) Age in months (Range) Sepsis (53) Meningitis (83)
- 41. Outcome in Meningococcal Meningitis vs. Sepsis * p < 0.05 * *
- 44. OCTOBER 98 DECEMBER 98 Patient: SBA
- 55. • Bristol • Bath • Exeter • Torbay • Plymouth • Swindon SOUTH WEST REGION - GEOGRAPHY Total population 4.95 million
- 57. The “slinky” model of the phases of ABI rehabilitation BSRM & RCP Working Party, 2003 Tertiary centre Outreach team Community Services, incl. education
Editor's Notes
- Mr Chairman, ladies and gentleme. Thank you for asking me to talk to you today on the impact of meningitis on the brain and to provide an overview of neurorehabilitation for children with neurological sequelae
- The topics that I shall cover in this talk include the potential importance of meningitis as cause of neurological dysfunction, mechanisms of brain injury in meningitis, evidence for our South West study of neurological outcome from meningitis and factors contributing to this. I shall then show a couple of cases which illustrate something of the spectrum of outcome and potential problems And finally give a overview of the neurorehabilitation services required by children with neurological sequelae. . Severity of ABI is usually classified by the depth of coma, severe ABI being associated with deep coma, i.e. a Glasgow Coma Scale of 3-8, moderate ABI with a GCS of 912 and mild ABI with a GCS of 13-15.
- Meningitis is one of a number of causes of acquired brain injury or ABI in children. Traumatic brain injury remains the most common, but is followed by brain tumours and CNS infection. Meningo-encephalitis is the commonest causes of non-traumatic acute encephalopathy in children.
- The importance of meningoencephalitis as a cause of non-traumatic coma is illustrated by this slide, which shows data from 328 causes of acute non-traumatic encephalopathy admitted to the South West Regional PICI in Bristol over a five year period. Half the cases were due to CNS infection.
- Non-traumatic coma n general, and meningo-encephalitis in particular, tends to be a disease of young children, although of course sme forms for example meningococcal disease can be contracted by older children and young adults. Almost half the cases of NTC admitted to the Bristol PICU were aged less than 2 years.
- Obviously the ideal approach to meningitis is to prevent it occurring, and this is the aim of vaccination programmes. However, meningitis remains a persistent problem with a UK incidence continuing to run at approximately 1000 cases per year.
- Improvements in paediatric intensive care have led to a fall in mortality rates from meningitis. This is illustrated by this slide, which shows data from the Communicable Disease Surveillance Centre and Office for National Statistics. Over the five year period 1996-2000, there was a significant and progressive fall in the case fatality rate from menigitis due to menigococcal disease.
- A similar significant fall in case fatality rates is also seen when one look at the data for meningococcal sepsis without definite meningitis. This s shown in this slide which again shows the fall in case fatality rates for meningococcal meningitis, shown in orange, and also for meningococcaemia, shown in blue. The improvement in survival rates however, leads to increased focus upon quality of outcome in survivors, and how best to achieve good outcome. Various studies have suggested that, overall, 10-20% of survivors of meningitis are left with neurological disability.
- The mechanisms of brain damage in meningitis are still incompletely delineated, but this slide illustrates current thinking concerning the pathogenesis. Lysis of bacteria in the subarachnoid space surrounding the brain, results in the release of inflammatory mediators or cytokines, including interleukin 1 beta, Tumour Necrosis factor and interleukin 6. These in turn activate adhesion molecules, causing inflammatory cells in the blood, namely neutrophils and macrophages, to adhere to receptors on the blood-brain barrier. Inflammatory cells collecting within blood vessels can cause vessel obstruction, thus causing cerebral infarction, potentially leading to stroke or cranial nerve palsies. Cytokines also activate brain neutrophils and microglia, causing production of reactive oxygen species which damage the blood brain barrier, permitting entry of albumin and fluid into the brain with resultant oedema, swelling and raised intracranial pressure. Activated neutrophils and microglia also in turn release cytokines and other inflammatory substances such as prostoglandins and platelet activating factor, continuing the vicous cycle
- The impact of the cytokine production on nerve cells or neurons is activate a cascade of destructive molecular events, including generation of excitatory amino acids such as glutamate and asparate, free radical generation and calcium influx into neurons. These processes in turn lead to cellular energy depletion, loss of cell membrane integrity, entry of fluid into the cell, cellular lysis and neuronal death by necrosis . Inflammatory processes, including glutamate production, may also result in activation of the enzymes responsible for programmed cell death or apoptosis, which are normally suppressed in neurons, also leading to cell death by a different mechanism. In addition to overt neuronal loss and histological evidence of necrosi in the hippocampus, there have been reports of neuronal loss by apoptosis in the CNS after experimental TBI
- The skull is a closed box with little capacity ot expand, even in an infant. This means than an increase in any of the contents will rapidly lead to an increase in intracranial pressure and to a reduction in the volume of the other contents. An increase in the volume of neuronal tissue as a result of cerebral swelling caused by vasogenic oedema, secondary to blood brain barrier breakdown, and cytotoxic oedema, as a result of neuronal energy failure, will lead, initially to a compensatory reduction in CSF volume, but, rapidly thereafter to a reduction in brain blood flow.
- Reduced cerebral blood flow leading in turn to reduced oxygen delivery to the brain, causes a mismatch between cerebral metabolic needs, which may even be increased as a result of cytokine production, resultant cellular hypoxia, increased anaerobic glycolysis, with increased CSF lactate, to try and compensate for the reduction in energy production, and eventually, when anaerobic glycolysis proves insufficent to meet bran energy requirement, once again to cellular energy failure, neuronal loss and resultant death or disability. Brain swelling, in addition,
- These slides show serial CT brain scans from a patient with acute meningitis. In the early scan on the left, the ventricles of the brain and small and slit like, as a result of cerebral oedema and brain swelling. However, there is still evidence of grey-white matter differentiation and no evidence of cerebral infarction. In contrast, the later scan, shown on the right, shows rather less cerebral swelling, indicated by the ventricles having increased a little in size, but complete loss of normal grey-white matter differentiation and low density areas, especially in the occipital lobes and frontal lobes, indicating evlving cerebral infarction.
- If you have an increase in cerebral volume, whether from generalised swelling as in meningitis, a mass lesion due to a tumour, a blood clot due to a head injury, as shown on this slide, neurological damage can occur not only as a result of reduced blood flow and oxygen supply to the brain, but also as a result of the increased pressure causing brain herniation. The brain can herniate across the membrane that divides the supratentorial and infratentorial fossa, so called tentorial hernation And across the foramen magnum that separates the brain and spinal cord, Foramen magnum herniation. Tentorial herniation often involves the uncus of the temporal lobe, causing damage to the temporal lobe and also to the brain stem, against which it is compressed. Foramen magnum herniation compresses the brain stem and upper cervical cord against the rim of the foramen magnum, causing damage to descending motor pathways, brain stem cranial nerve nuclei and most importantly the brain stem respiratory and cardiac centres, and thus leading to respiratory or cardiac arrest and death.
- Inflammatory processes in meningitis can also cause raised intracranial pressure by blocking normal drainage pathways for CSF, causing ventriculomegaly with raised intracranial pressure or hydrocephalus.
- Hydrocephalus is a significant cause of childhood mortality and morbidity. Bacterial meningitis is the largest acquired cause of non-tumoural hydrocephalus. Little published population based data on the incidence of hydrocephalus after meningitis. Single hospital series suggest hydrocephalus complicates 1.7- 2.8% of episodes of bacterial meningitis in children.
- The impact in any individual patient of an acquired brain injury such as meningitis, will of course depend on which areas of the brain are involved. Damage to the frontal lobes causes difficulties with attention, intellect, executive function and the inhibitory aspects of behaviour, and higher aspects of memory function, including working memory. Damage to the temporal lobes, for example, by uncal herniation, causes problems with fundamental memory functions such as encoding and retrieval, some language and behavioural and emotional functioning. Parietal lobe damage can cause problems with language and visuo-spatial functioning. Occipital lobe damage can cause visual problems including cortical blindness or visual field defects . As we saw in the previous slide, raised intracranial pressure can result in brain stem dysfunction with problems with arousal, attention cranial nerve palsies and motor dysfunction such as spastic quadriparesis or ataxia.
- Another way of categorising deficits is according to the functional system involved. This classification from the BSRM/RCP working party document of neurorehabilitation after ABI divides defictis into physical, commnicative, cognitive and behavioural/emotional categories. Menigits can cause al of the wide range of deficits listed on this slide.
- One area of the brain that is particularly vulnerable to a number of forms of acute brain insult, including meningitis, is the hippocampus of the temporal lobe. This is illustrated in this slide, which shows a post-mortem section of the hippocampus stained with haematoxylin and eosin. Densely stained neurons, examples of which are indicated by the arrows, are necrotic neurons. In meningitis the CAI region of the hippocampus is particularly likely to the affected. The selective vulnerability of the hippocampus to acquired brain damage such as meningitis, head injury and hypoxia, is not fully understood, but suggested reasons include the fact that it contains high concentrations of both interleukin 1 beta and IL-1 beta receptors, has a high density of excitatory NMDA and non-NMDA receptors and has relatively high energy requirements.
- Damage to the hippocampus is important, not only because it plays an important role in memory function, but also because it has rich interconectios to other parts of the brain, including the temporal lobe amgydala, which is important in behavioural regulation, the basal ganglia, which are increasingly recognised to be important in cognitive functioning as well as motor control, and the basal forebrain, especially the basal forebrain cholinergic system, which is important in higher cognitive function such as executive function.
- Executive function is an umbrella term that encompasses a range of interrelated abilities that direct, guide and regulate cognitive, emotional and behavioural functions. EF is essential for aspects of living such as planning, problem solving, flexible thinking, multi-tasking, motivation, and emotional regulation Damage / dysfunction of frontal and prefrontal cortical areas often results in executive dysfunction (It is important to be aware that executive function is difficult to assess in a structured cognitive test situation, as this often does not place sufficient demand on regulatory abilities and one may need to deduce that EF is prbaby impaired from behavioural observation) Psychologists often describe the frontal lobe as the ‘control’ centre for executive functioning, this is due to the dense connectivity of this region with other brain regions. Often the artificial and structured cognitive test situation does not place sufficient demand on executive abilities, and therefore it is difficult to assess such abilities in this type of setting.
- Frontal lobes are relatively late to develop, develoment ociniung throughout childhood and young adulthood. Inhibitory function and dysfunction tends to emerge when frontal lobe development in sufficiently mature. Anatomical structure is not well developed in young children and is therefore functionally invisible to assessment. Certianly evidence to suggest that frontal lobes are late to develop (neuro and electrophisiology markers ) and inhibitory fucntoiing in an adult sense is also late to develop – markers, behavioural measures (study of WCST) and behavioural disfucntion => coincidental evidece for linking brain developmentl and behvioural function But Inhbition may not be a purely ‘frontal’ function (certainly not throughout development ) In any case different markers suggest maturity at different times – cicular reasoning Bhevioural evidence of dysinibition in young children (denckla quote)
- Having looked at the causes of neurological poor outcome in meningits we will now turn to look at some figures relating to outcome in children in the South West. Recent advances howevwer a fall in the case fatality ratio probably due to advances in pi care few data on the neuro outcome of childhood survivors of bac meningirtis potenteialy importnt since experience as head inhuy studies say that fall in mrotalituy can br associated with increase in morbidity
- This was part of a wider study of outcome in children with non-traumatic admitted to the Regional PICU in Bristol. Retrospective case notes review Aged < 16 years Admitted to the Regional PICU at Bristol Royal Hospital for Sick Children Five year period 1997 – 2001 Bacterial meningitis defined by ICD 10 codes 320 (meninigits) and 036.0 (meningococcal sepsis) Regional PICU database of all cases of severe bacterial meningitis All records of children undergoing shunt surgery for post-meningitic hydrocephalus at the RNSC Regional data of all notified cases of bacterial meningitis obtained from CDSC
- Diagnostic criteria for meningococcal disease were - Clinical diagnosis of meningococcal disease + positive blood culture or blood PCR Presence of meningitis was determined by evidence of clinical signs and symptoms of meningitis - stiff neck - bulging/tense AF - photophobia - prolonged/focal fit - +ve Kernig sign - reduced LOC - headache (prior to collapse) And/or CSF pleocytosis > 10 cell/mm 3 + CSF culture
- Information was obtained concerning: Clinical symptoms / signs Glasgow Coma Scale Systemic inflammatory response CSF findings Neurological investigations Evidence of raised intracranial pressure Treatment Outcome at hospital discharge
- Outcome was classified using a adaptation of the Seisha outcome scale, a crude functional classification of outcome, adapted in turn from the adult Glasgow Outcome Scale. Poor Died, Persistent Vegetative State Major neurological handicap and/or major developmental handicap, uncontrolled epilepsy Moderate/Mild Moderate/mild neurological and/or developmental deficit, behaviour problems, controlled epilepsy Good Resumed previous activities, no neurological deficit, no apparent change from pre-morbid school performance or personality ,
- Clinical evidence of raised intracranial pressure was based on criteria published by David Mellor in Archives of Disease in childhood in 1992. Deep coma GCS < 8 Rapid decline in conscious level Fixed and/or unequal pupils Bradycardia and/or apnoea Bulging anterior fontanelle Hemiparesis Papilloedema Prolonged seizure Oculomotor palsy
- 513 children with bacterial meningitis were notified to CDSC 129 cases (25%) of severe bacterial meningitis were admitted to Regional PICU (59 boys; 70 girls) Median age PICU cases = 1.75 yrs (range 0.03 - 16) 96 (79%) transferred from other hospitals Median LOS on PICU 4 days (1 - 24) 101 (83%) patients received IPPV Causative organism 82 (67%) meningococcus 21 (17%) pneumoccus 2 (2%) H. influenzae 13 (11%) other or unidentified
- This slide shows the Glasgow Coma core of the children at presentation to hospital. Most already had signifncantly reduced level of consciousness, which was severe on 40% of cases and moderate n 34% (severe or moderate in over three quarter of 75% of cases.
- Only a minority of children had ICP monitoring but there was evidence of raised ICP on clinical assessment or investigation in 72.5% of cases.
- In terms of outcome at hospital discharge, no data in 23 cases. Of the remaining cases, 26% had poor outcome, 15% had moderate or mild disability and 54% had apparently good outcome.
- Despite improvement in PICU leading to a fall in mortality rates over time, we did not find evidence of a consistent improvement in neurological outcome over the study period.
- The importance of raised intracranial pressure is illustrated by the finding that 8/12 (67%) children who died had brain herniation. Most children did not have folow up neuroimaging but 41% of those who did had evidence of ischaemic damage. All these cases were scaned because of neurological problems such as prolonged seizure or persistent coma.
- This slide shows the results of our analysis of factors associated with an adverse outcomen al the patients with NTC. Multiple logistic regression identified these variables as being independently associated with a significantly poor outcome: HIE-Odds ratios…etc. In this study status epilepticus did not quite achieve statistical significance as an independent predictor of poor outcome. Low GCS also did not independently predict poor outcome
- In terms of the incidence of post meningitic hydrocephalus of the 513 cases in the South West region and the 129 cases admitted tp PICU, 11 chldren required shunt surgery for hydrocephalus at the RNSC.
- Younger children were partocuarly at risk of hydrocephalus
- We also looked at outcome following meningococcal sepsis and compared this with meningocococcal meningitis. Looking t=at PICU care there was little difference in duration of ventilation or use of intropes.
- Children with menintigis were signficantly ore likely to have poor outcome or moderate/mild disablity than children clased as having with sepsis only.