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Introduction

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Introduction

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    1. Lecture was prepared by Dr. Emily Martin et al.Lecture was prepared by Dr. Emily Martin et al.

    2. Introduction Infections of the CNS are among the most devastating infectious diseases Cause death and disability worldwide Often present as medical emergencies Early, appropriate care is critical to reducing morbidity and mortality

    3. CNS Development

    4. CNS Development 2 wks: Neural plate forms from ectoderm Neural tube completed by day 26-28 3-4 wks: Hemispheres form Pons/medulla develop at 3-7.5 wks 8-18 wks: Neuronal proliferation Up to 200,000 new neurons per minute > 25 wks: Arborization, synaptogenesis, apoptosis, neural connectivity 30 wks - adolescence: Continuing myelination I would like to just briefly review CNS development and anatomy before we get started, this is from chapter 51 of Rogers. Remember that neuro development begins at 2 wks gestation when the neural plate is formed from ectoderm. By 2-4 weeks hemispheres have formed. During this time different regions of the brain begin to develop at different rates, generally the forebrain develops more slowly than the hindbrain. In particular the pons and medulla develop early in gestation at 3-7 weeks. Neuronal proliferation is at its highest rates from 8-18 weeks. Formation of synaptic connections, apoptosis, and arborization begin around 25 weeks, then myelination ramps up closer to 35 weeks and continues through adolescence.I would like to just briefly review CNS development and anatomy before we get started, this is from chapter 51 of Rogers. Remember that neuro development begins at 2 wks gestation when the neural plate is formed from ectoderm. By 2-4 weeks hemispheres have formed. During this time different regions of the brain begin to develop at different rates, generally the forebrain develops more slowly than the hindbrain. In particular the pons and medulla develop early in gestation at 3-7 weeks. Neuronal proliferation is at its highest rates from 8-18 weeks. Formation of synaptic connections, apoptosis, and arborization begin around 25 weeks, then myelination ramps up closer to 35 weeks and continues through adolescence.

    5. CNS Development The mature human brain will have 10 billion neurons Most are formed during the period of rapid proliferation (8-18 wks) Very little neurogenesis after birth 70% of developing neurons will die by apoptosis during development Bcl-2, Apaf1, cystein-protease caspase Pathways are upregulated during development Newborn brain more prone to injury-related PCD The mature human brain will eventually have 10 billion neurons, during the period of neuronal proliferation from 8-18 weeks they are produced at a rate of 200 000 per minute, although after birth there will be very little neurogenesis. Neuronal cell type and number is regulated by programmed cell death during CNS development, it is estimated that as many as 70% of developing neurons die by various apoptotic pathways. The principle regulators of PCD are Bcl-2, Apaf1, and cysteine-protease caspase family. Since these pathways are up-regulated during the embryonic period the post-natal but still developing CNS may be more prone to injury-related PCD than the adult brain, particularly in the newborn period. The mature human brain will eventually have 10 billion neurons, during the period of neuronal proliferation from 8-18 weeks they are produced at a rate of 200 000 per minute, although after birth there will be very little neurogenesis. Neuronal cell type and number is regulated by programmed cell death during CNS development, it is estimated that as many as 70% of developing neurons die by various apoptotic pathways. The principle regulators of PCD are Bcl-2, Apaf1, and cysteine-protease caspase family. Since these pathways are up-regulated during the embryonic period the post-natal but still developing CNS may be more prone to injury-related PCD than the adult brain, particularly in the newborn period.

    6. Blood-Brain Barrier The BBB functions to isolate the brain and blood compartments, to selectively transport metabolites, ions, and molecules, and metabolize or modify brain- or blood-borne substances. The mature BBB consists of endothelial cells connected by tight junctions, supportive pericytes, basal lamina, and astrocyte feet. The BBB is impermeable to hydrophilic molecules. Glucose enters via the glucose transporter-1 (figure), and water passes through aquaporin-4 channels.The BBB functions to isolate the brain and blood compartments, to selectively transport metabolites, ions, and molecules, and metabolize or modify brain- or blood-borne substances. The mature BBB consists of endothelial cells connected by tight junctions, supportive pericytes, basal lamina, and astrocyte feet. The BBB is impermeable to hydrophilic molecules. Glucose enters via the glucose transporter-1 (figure), and water passes through aquaporin-4 channels.

    7. Blood-Brain Barrier There is debate over whether the infant BBB is leaky Tight junctions in mature BBB form a true zona occludens Agree that permeability of macromolecules in the same as in adults BBB has both static and dynamic properties Astrocyte feet have lots of control Impermeable to ions, proteins, osmolar agents Osmotic (not oncotic) gradients are critical to water movement through aquaporin channels

    8. Pathogenesis Pathogens must first gain access to CNS to cause disease Subarachnoid space (meningitis) CNS parenchyma (encephalitis, myelitis, abscess) Most are spread through the bloodstream May also occur through direct spread Adjacent structures (otitis, sinusitis, dental abscess) Shunt infections Skull fractures

    9. Clinical Syndromes So Rogers describes several syndromes of clinical presentation for the variety of CNS infections we are going to discuss. The main features of CNS infections are fever, headache, and altered mental status. Focal neurologic signs may or may not be present. Remember that these symptoms are very similar to non-infectious causes of CNS pathology.So Rogers describes several syndromes of clinical presentation for the variety of CNS infections we are going to discuss. The main features of CNS infections are fever, headache, and altered mental status. Focal neurologic signs may or may not be present. Remember that these symptoms are very similar to non-infectious causes of CNS pathology.

    10. Diagnosis Thorough history and physical exam are very important! Note chronicity of symptoms, comorbid conditions, preceding illnesses, VP shunt Travel, surgery, trauma, sick contacts, insect bites, animal contact, sexual activity Lab evaluation: CBC, CMP, CPR, UA, blood culture CSF: opening pressure, cultures, cytology Fungal, AFB, mycobacterial cx if appropriate CSF gram stain, PCR, antigen testing, serology Other studies: Imaging, EEG, biopsy, I&D So according to Rogers, someone should probably do a thorough H&P. Consider an ID consult!So according to Rogers, someone should probably do a thorough H&P. Consider an ID consult!

    11. CSF Findings

    12. General Management Neurologic evaluation Meningeal signs Severity of coma Neuro exam (focal deficits, cranial nerves, bulbar tone) Increased ICP Other sites of infection or injury Otitis, sinusitis, PNA Rashes or skin lesions Trauma Of course begin with ABCs and primary survey. The secondary survey should include particular attention to the neurologic exam, including meningeal signs, severity of coma, and evidence of focal neurologic deficits or increased ICP. Also note whether there are other sources of infection (otitis, sinusitis, PNA, rashes, trauma).Of course begin with ABCs and primary survey. The secondary survey should include particular attention to the neurologic exam, including meningeal signs, severity of coma, and evidence of focal neurologic deficits or increased ICP. Also note whether there are other sources of infection (otitis, sinusitis, PNA, rashes, trauma).

    13. General Management Consider intubation if GCS <8 or bulbar hypotonia Take care to minimize ICP spikes Consider thiopental, propofol, ketamine (becoming more accepted for high ICP), lidocaine Modified RSI, avoid overventilation Get antibiotics going early and at high doses! Cardiovascular support as needed

    14. General Management Consider ICP monitoring for moderate to severe ICP elevation Level of consciousness correlates well with decreased cerebral perfusion M&M are inversely related to CPP Control seizures with benzodiazepenes About 50% of patients with seizures progress to status Status is hard to treat and has poor outcome Occasionally we will have to consider ICP monitoring for the sickest of kids with meningitis. High ICP limites cerebral perfusion, especially to the subcortical white matter. Level of consciousness correlates well with cerebral perfusion. Morbidity and mortality are inversely related to CPP. Dont be stingy with the benzos for seizures. Half of these kids who have seizures will progress to refractory status epilepticus, which is particulary difficult to treat and associated with a poor outcome.Occasionally we will have to consider ICP monitoring for the sickest of kids with meningitis. High ICP limites cerebral perfusion, especially to the subcortical white matter. Level of consciousness correlates well with cerebral perfusion. Morbidity and mortality are inversely related to CPP. Dont be stingy with the benzos for seizures. Half of these kids who have seizures will progress to refractory status epilepticus, which is particulary difficult to treat and associated with a poor outcome.

    15. General Management Electrolyte and fluid derangements are common At risk for diabetes insipidus Do not fluid restrict empirically Prospective RCT by Singhi et al found no outcome improvement with fluid restriction vs. maintenance Correct hyponatremia slowly over 36-48 hrs 3% if necessary for seizures Also at risk for hypokalemia GI losses, hemodilution, osmotherapy, diuretics, sepsis

    16. Bacterial Meningitis Etiology, Pathophysiology, Diagnosis, Treatment, Outcome

    17. Bacterial Meningitis: Etiology *There are 3 main bacterial meningeal pathogens: Haemophilus influenzae Neisseria meningitidis Streptococcus pneumoniae *Incidence varies by region and age.

    18. Haemophilus influenzae Small GN, pleomorphic, coccobacilli H. flu type B causes almost ALL invasive disease Nontypeable Hib can rarely cause meningitis. Incidence of Hib decreased by 97% after vaccine H. Flu is a gram negative, pleomorphic, coccobacillus. Hib causes almost all invasive H flu disease worldwide. Nontypeable H.flu rarely causes meningitis, often associated with immune globulin deficiencies. The incidence of invasive Hib disease decreased by 97% from 1987-1997 with the introduction of the conjugate vaccine, while incidence of strep pneumo and neisseria meningitis have remained stable.H. Flu is a gram negative, pleomorphic, coccobacillus. Hib causes almost all invasive H flu disease worldwide. Nontypeable H.flu rarely causes meningitis, often associated with immune globulin deficiencies. The incidence of invasive Hib disease decreased by 97% from 1987-1997 with the introduction of the conjugate vaccine, while incidence of strep pneumo and neisseria meningitis have remained stable.

    19. Neisseria meningitidis - GN diplococci - Serotypes A,B,C,Y, and W135 cause most invasive disease. - Virulence depends on: Capsular polysaccharide LPS(endotoxin) Pili IgA protease ompS gene Neisseria are kidney-shaped GN diplococci. Only encapsulated isolates cause invasive disease. Serotypes A, B,C, Y, and W135 cause most CNS disease. B and C are the most common in north america. Virulence depends on many factors.Neisseria are kidney-shaped GN diplococci. Only encapsulated isolates cause invasive disease. Serotypes A, B,C, Y, and W135 cause most CNS disease. B and C are the most common in north america. Virulence depends on many factors.

    20. Streptococcus pneumoniae * Small, non-motile GPC in pairs or chains. * 8 serotypes cause 90% of invasive disease. 1, 4, 6, 9, 14, 18, 19 & 23 * Virulence depends on capsular polysaccharides * Associated with CSF leak (skull fractures), asplenia, HIV, cochlear implants Strep pnemo are small, non-motile GPC in pairs or chains. 8 serotypes cause 90% of invasive disease and virulence depends on capsular polysaccharides. Children with basilar or cribriform fractures and CSF leak are at risk for pneumococcal meningitis, also associated with asplenia and HIV. Cochlear implants increase risk of pneumococcal meningitis by 30%.Strep pnemo are small, non-motile GPC in pairs or chains. 8 serotypes cause 90% of invasive disease and virulence depends on capsular polysaccharides. Children with basilar or cribriform fractures and CSF leak are at risk for pneumococcal meningitis, also associated with asplenia and HIV. Cochlear implants increase risk of pneumococcal meningitis by 30%.

    21. Other Pathogens: GN bacilli Neonatal GN sepsis/meningitis is most commonly due to E.coli K1 capsular polysaccharide antigen is a marker of neurovirulence Outside of neonates, GN meningitis is often nosocomial Associated with GI infections, head trauma, NS procedures, immune deficiency Klebsiella, Salmonella, Enterobacter, and Pseudomonas We had a patient who developed Klebsiella meningitis after her hemispherectomy a few months.We had a patient who developed Klebsiella meningitis after her hemispherectomy a few months.

    22. Klebsiella Ventriculitis/Abscess I think everyone took care of this patient between November and January, an infant with hemi-megaloenephaly and IVH who had intractable seizures. She went to the OR for a hemispherectomy. She developed a klebsiella wound infection, which spread to form these abscesses and ventriculitis.I think everyone took care of this patient between November and January, an infant with hemi-megaloenephaly and IVH who had intractable seizures. She went to the OR for a hemispherectomy. She developed a klebsiella wound infection, which spread to form these abscesses and ventriculitis.

    23. Other Pathogens: GBS Still a common cause of invasive neonatal disease Six main serotypes: Type III causes most neonatal meningitis Incidence is down in developed countries due to screening and treatment of pregnant women

    24. GBS Meningitis with Infarcts This is an infant we had in the unit recently with GBS meningitis. This is her MRI, which showed infarction of the entire left hemisphere and most of the right, sparing only a little of the r temporal and occipital lobes. She also had some scattered hemorrhages and a superior sagittal sinus and vein of Galen thrombosis.This is an infant we had in the unit recently with GBS meningitis. This is her MRI, which showed infarction of the entire left hemisphere and most of the right, sparing only a little of the r temporal and occipital lobes. She also had some scattered hemorrhages and a superior sagittal sinus and vein of Galen thrombosis.

    25. Other Pathogens: Listeria Listeria monocytogenes is a Gram positive rod and still an important cause of neonatal sepsis Can also be seen in older children with cellular immune deficiencies Associated with maternal consumption of unpasteurized cheese or contaminated meats

    26. Other Pathogens: Anaerobes * Anaerobic meningitis occurs in only in certain conditions Rupture of brain abscess Chronic otitis, mastoiditis, sinusitis Head trauma, NS procedures Congenital dural defects GI infections, suppurative pharyngitis CSF shunts Immune suppression * Includes Bacteroides fragilis, Fusobacterium spp., Clostridum spp

    27. Pathogenesis Development of bacterial meningitis progresses through 5 major steps (ignore the 10 steps in the picture). First there is bacterial colonization of the nasopharynx by adhesion to mucosa. The method of adhesion depends on the bacteria. Neisseria for example uses fimbriae on the cell wall, and strep pneumo uses surface adhesion proteins. Secretory IgA usually prevents this from happening, but organisms can secrete endopeptidases that cleave the IgA. Second, there is mucosal invasion and penetration into the bloodstream. H.flu for example can pass between epithelial cells and neisseria can pass through them into the blood stream. Viral upper respiratory infections can also help facilitate the process. Once in the bloodstream the bacterias polysaccharide capsule protects is from host defenses: circulating abs, complement, phagocytosis. The bacteria begin to muliply and cross the BBB. The same mechanisms that helped the bacteria cross the muscosal epilthelium assist in crossing the BBB, also it is thought that there needs to be a critical magnitude of bacteria. Usually this occurs through the endothelium of the choroid plexus and cerebral capillaries into the ventricular fluid. Once in the CSF they continue to multipy and cell wall fragments and LPS trigger an inflammatory response in the CNS, via cytokines IL-1b, IL-6, and TNF. This triggers a cascade of inflammatory mediators and results in increased permeability of the BBB, attraction of leukocytes from the blood, and CSF pleocytosis. From here there is resultant cerebral edema, deragements of cerebral metabolism, and neuronal damage. Development of bacterial meningitis progresses through 5 major steps (ignore the 10 steps in the picture). First there is bacterial colonization of the nasopharynx by adhesion to mucosa. The method of adhesion depends on the bacteria. Neisseria for example uses fimbriae on the cell wall, and strep pneumo uses surface adhesion proteins. Secretory IgA usually prevents this from happening, but organisms can secrete endopeptidases that cleave the IgA. Second, there is mucosal invasion and penetration into the bloodstream. H.flu for example can pass between epithelial cells and neisseria can pass through them into the blood stream. Viral upper respiratory infections can also help facilitate the process. Once in the bloodstream the bacterias polysaccharide capsule protects is from host defenses: circulating abs, complement, phagocytosis. The bacteria begin to muliply and cross the BBB. The same mechanisms that helped the bacteria cross the muscosal epilthelium assist in crossing the BBB, also it is thought that there needs to be a critical magnitude of bacteria. Usually this occurs through the endothelium of the choroid plexus and cerebral capillaries into the ventricular fluid. Once in the CSF they continue to multipy and cell wall fragments and LPS trigger an inflammatory response in the CNS, via cytokines IL-1b, IL-6, and TNF. This triggers a cascade of inflammatory mediators and results in increased permeability of the BBB, attraction of leukocytes from the blood, and CSF pleocytosis. From here there is resultant cerebral edema, deragements of cerebral metabolism, and neuronal damage.

    28. Pathophysiology * With acute CNS infection there is loss of autoregulation: Early increase in CBF, followed later by a decrease At risk for global cerebral hypoperfusion * Focal hypoperfusion can result from vasculitis leading to ischemia Can occlude large vessels: carotid, MCA, ACA * Cerebral edema can be vasogenic, cytotoxic, or interstitial Interstitial edema is the main cause of obstructive hydrocephalous in meningitis Due to these changes and the significant inflammatory response there is eventually loss of autoregulation. First this results in an increase in CBF, presumably due to the vasodilatory effects of NO released in the inflammatory cascade. In the later phase of meningitis the CBF decreases, due to vasospasm. With the loss of autoregulation the CBF becomes dependent on the systemic BP, which can result in global cerebral hypoperfusion in the event of a drop in SBP. Also, focal hypoperfusion can occur due to vasculitis of the arteries crossing the inflammed subarachnoid space, which can cause ischemia and permanent neurologic sequelae. This can be so severe as to occlude the intracranial carotid, MCA, or ACA. Resulting cerebral edema can be vasogenic, cytotoxic, or interstitial. Due to these changes and the significant inflammatory response there is eventually loss of autoregulation. First this results in an increase in CBF, presumably due to the vasodilatory effects of NO released in the inflammatory cascade. In the later phase of meningitis the CBF decreases, due to vasospasm. With the loss of autoregulation the CBF becomes dependent on the systemic BP, which can result in global cerebral hypoperfusion in the event of a drop in SBP. Also, focal hypoperfusion can occur due to vasculitis of the arteries crossing the inflammed subarachnoid space, which can cause ischemia and permanent neurologic sequelae. This can be so severe as to occlude the intracranial carotid, MCA, or ACA. Resulting cerebral edema can be vasogenic, cytotoxic, or interstitial.

    29. Cerebral Edema Vasogenic occurs with increased permeability of the BBB, allowing larger molecules and serum to cross into the parenchyma. Cytotoxic occurs due to an increase in intracellular water due to loss of cellular homeostasis and increased cell membrane permeability. Interstitial edema is a result of increased CSF volume, which may be due to increased production from increased blood flow through the choroid plexus or decreased resorbtion due to increased resistance across the arachnoid villi. Interstitial edema is the main cause of obstructive hydrocephalous in meningitis. Of course all of these factors lead to increased ICP, which is bad. Vasogenic occurs with increased permeability of the BBB, allowing larger molecules and serum to cross into the parenchyma. Cytotoxic occurs due to an increase in intracellular water due to loss of cellular homeostasis and increased cell membrane permeability. Interstitial edema is a result of increased CSF volume, which may be due to increased production from increased blood flow through the choroid plexus or decreased resorbtion due to increased resistance across the arachnoid villi. Interstitial edema is the main cause of obstructive hydrocephalous in meningitis. Of course all of these factors lead to increased ICP, which is bad.

    30. Clinical Presentation Depends on the age of the patient and the offending organism Generally more abrupt onset than viral Infants have a variable presentation Fever, poor feeding, lethargy, irritability, high-pitched cry, full fontanelle Older children may have acute onset of fever, HA, vomiting, photophobia, and altered mental status +/- Kernig or Brudzinski sign

    31. Clinical Presentation *Seizures may be the presenting feature in nearly 1 in 6 children Have a low index of suspicion with seizures + fever *Papilledema is uncommon at presentation *Focal signs can be found in 14% of cases Sudural epyema, cortical infarction, cerebritis *Rashes are not uncommon Petechial or purpuric rash highly suggests meningococcemia

    32. Diagnosis * Definitive diagnosis is by analysis and culture of the CSF LP should be done at earliest opportunity Do not delay antibiotics may alter culture and gram stain but chemistry or cells * WAIT on the LP if: Evidence of raised ICP (pupil changes, cushings, kussmaul pattern, deep coma), focal neuro exam, resp/CV instability, coagulopathy Get a head CT if there is focality or question about diagnosis A definitive diagnosis of bacterial meningitis is made by analysis and culture of the CSF. If there is clinical suspicion of meningitis, the LP should be done at the earliest opportunity. Do not delay the administration of antibiotics if the LP will be delayed. Dont do an LP on a child who has evidence of increased ICP (pupillary changes, cushings triad, Kussmaul respiations, deep coma), focal neuro exam, cardio-respiratory instability, or coagulopathy. There has been considerable controversy over the safety of LPs in children with CNS infections due to the risk of herniation. They are not typically recommended, but get one if there is focality on exam, doubt about the diagnosis (? Trauma), or if there is concern for a mass lesion or abscess. Most CTs in bacterial meningitis are normal, and remember that head CTs do not measure pressure, they do not rule out high ICP.A definitive diagnosis of bacterial meningitis is made by analysis and culture of the CSF. If there is clinical suspicion of meningitis, the LP should be done at the earliest opportunity. Do not delay the administration of antibiotics if the LP will be delayed. Dont do an LP on a child who has evidence of increased ICP (pupillary changes, cushings triad, Kussmaul respiations, deep coma), focal neuro exam, cardio-respiratory instability, or coagulopathy. There has been considerable controversy over the safety of LPs in children with CNS infections due to the risk of herniation. They are not typically recommended, but get one if there is focality on exam, doubt about the diagnosis (? Trauma), or if there is concern for a mass lesion or abscess. Most CTs in bacterial meningitis are normal, and remember that head CTs do not measure pressure, they do not rule out high ICP.

    33. Diagnosis CSF findings include high opening pressure, pleocytosis, low glucose, and high protein Cloudy CSF with high opening pressure is diagnostic Glucose ratio of 0.4 is 80% sensitive and 98% specific CSF WBC (predicted) = CSF RBC x (blood WBC/blood RBC) Observed CSF WBC/ predicted <0.01 and WBC/RBC ratio of <0.01 are 100% reliable in ruling out bacterial meningitis

    34. Diagnosis Gram stains are quick, cheap, and accurate 90% strep, 86% H. flu, 75% neisseria, 30% Listeria CSF culture will be positive in the majority of untreated cases Empiric diagnosis can be made if: CSF WBC > 300, with >60% polys Glucose < 50% of serum Absolute glucose < 30 Gram stains are quick, cheap, and accurate, depending on the organism. It has been suggested that in the absence of other tests, an empiric diagnosis of bacterial meningitis can be made if the CSF has > 300 cells with 60% polys, CSF glucose < 50% of serum, or absolute glucose < 30Gram stains are quick, cheap, and accurate, depending on the organism. It has been suggested that in the absence of other tests, an empiric diagnosis of bacterial meningitis can be made if the CSF has > 300 cells with 60% polys, CSF glucose < 50% of serum, or absolute glucose < 30

    35. Diagnosis: Viral vs. Bacterial * Latex agglutination Helpful in partially treated meningitis Specific but not that sensitive Strep pneumo 96% specific, 70 -100 % sensitive * PCRs are available for neisseria and pneumococcus Both are sensitive and specific DNA load correlates with mortality for neisseria Very expensive * CRP may be helpful but only if very high or very low * Peripheral WBC, CSF lactate, limulus amebocyte lysate, procalcitonin, and various cytokines are up in the air If the diagnosis is still unclear (culture negative, cells indeterminate), and you are trying to decide between viral and bacterial there are some other optional tests.If the diagnosis is still unclear (culture negative, cells indeterminate), and you are trying to decide between viral and bacterial there are some other optional tests.

    36. Complications Raised ICP Seizures Subdural empyema Infarcts Cerebritis Brain abscess Hydrocephalous, ventriculitis Cranial nerve involvement Sensorineural hearing loss Here are some complications of bacterial meningitis, a few of which have already been mentioned. We have already talked about raised ICP. In one series cerebral herniation was seen on autopsy in 30% of children who died of meningitis. Seizures that occur early and stop in 1-3 days are typically due to cortical irritation. At the end of abx if EEG is normal they can be tapered off AEDs. If seizures arose later, like from an infarction, they may need AEDs longer. Subdural effusions are fairly common, especially in Hib. Usually they do not require intervention unless there is persistent fever, focality, or evidence of rising ICP. Subdural empyema requires drainage. Infarcts and cerebritis occur when there is involvement of the blood vessels or direct spread of infection from the SA space to the brain. They made lead to abscesses and are associated with a poor outcome. Ventriculitis typically occurs in neonates and infants, may require prolonged antibiotics, or even intraventricular administration of abx. Cranial nerves 3, 6, and 8 can be damaged either directly or due to increased ICP. Sensorineural deafness is the most common complication occurs in 5 30 % of cases, especially in pneumococcal. It may be transient or permanent, and is associated with low CSF glucose and use of ototoxic abx. The spread of primary meningitis to other areas causing pneumonia, pericarditis, arthritis, or osteo is rare. Here are some complications of bacterial meningitis, a few of which have already been mentioned. We have already talked about raised ICP. In one series cerebral herniation was seen on autopsy in 30% of children who died of meningitis. Seizures that occur early and stop in 1-3 days are typically due to cortical irritation. At the end of abx if EEG is normal they can be tapered off AEDs. If seizures arose later, like from an infarction, they may need AEDs longer. Subdural effusions are fairly common, especially in Hib. Usually they do not require intervention unless there is persistent fever, focality, or evidence of rising ICP. Subdural empyema requires drainage. Infarcts and cerebritis occur when there is involvement of the blood vessels or direct spread of infection from the SA space to the brain. They made lead to abscesses and are associated with a poor outcome. Ventriculitis typically occurs in neonates and infants, may require prolonged antibiotics, or even intraventricular administration of abx. Cranial nerves 3, 6, and 8 can be damaged either directly or due to increased ICP. Sensorineural deafness is the most common complication occurs in 5 30 % of cases, especially in pneumococcal. It may be transient or permanent, and is associated with low CSF glucose and use of ototoxic abx. The spread of primary meningitis to other areas causing pneumonia, pericarditis, arthritis, or osteo is rare.

    37. Treatment: By Age Once bacterial meningitis is suspected, treatment should be instituted without delay. CSF, blood, urine, and other cultures should be obtained first if there is time, but dont delay abx. Initial therapy should be broad enough to cover likely organisms based on age or predisposing conditions. Here is a table from Rogers with recommended empiric therapy based on age. Note that vanc is included in the groups that are at risk for strep pneumo, due to emerging resistance to cephalosporins. Once a specific pathogen has been identified, therapy can be tailored appropriately. IV delivery is preferred, but IM is ok if an IV cant be obtained immediately. Once bacterial meningitis is suspected, treatment should be instituted without delay. CSF, blood, urine, and other cultures should be obtained first if there is time, but dont delay abx. Initial therapy should be broad enough to cover likely organisms based on age or predisposing conditions. Here is a table from Rogers with recommended empiric therapy based on age. Note that vanc is included in the groups that are at risk for strep pneumo, due to emerging resistance to cephalosporins. Once a specific pathogen has been identified, therapy can be tailored appropriately. IV delivery is preferred, but IM is ok if an IV cant be obtained immediately.

    38. Treatment: Head Trauma Here are recommended empiric therapies for patients with head trauma or some kind of compromise of the subarachnoid space.Here are recommended empiric therapies for patients with head trauma or some kind of compromise of the subarachnoid space.

    39. Duration of Therapy Duration of antibiotic therapy depends on the isolated organism.Duration of antibiotic therapy depends on the isolated organism.

    40. Other Considerations In developing countries, ampicillin and chloramphenicol are sometimes used due to the high cost of cephalosporins Increasing resistance of H.flu to ampicillin, but it is via B-lactamase production Remember that strep and meningococcus resistance is by alteration of penicillin binding proteins Meropenem and newer fluoroquinolones are as effective as cephalosporins, but still are not 1st line Meropenem is good for ESBLs In developing countries ampicillin and chloramphenicol are sometimes used due to the high cost of cephalosporins. But there is increasing resistance of H.flu to ampicillin. Let me mention briefly that we do need to keep mechanisms of antibiotic resistance in mind, if only for the boards. Meropenem and newer fluoroquinolones (gati, moxi, and trovafloxacin) have been found to be as effective as cephalosporins for meningitis, but these are still not considered first line agents. Meropenem in particular can be used for ESBLs. In developing countries ampicillin and chloramphenicol are sometimes used due to the high cost of cephalosporins. But there is increasing resistance of H.flu to ampicillin. Let me mention briefly that we do need to keep mechanisms of antibiotic resistance in mind, if only for the boards. Meropenem and newer fluoroquinolones (gati, moxi, and trovafloxacin) have been found to be as effective as cephalosporins for meningitis, but these are still not considered first line agents. Meropenem in particular can be used for ESBLs.

    41. Other Considerations With treatment CSF culture and Gram stain will become negative in 24-48 hours Glucose will normalize in 72 hours Cells and protein take days Fever may persist for 7-10 days (H.flu), but beyond this consider other factors Thrombophlebitis, spread of infection, empyema, drug fever A recurrence of fever may also indicate a complication or a secondary nosocomial infection

    42. Do we need a repeat LP? Repeat LPs are not routinely necessary if the patient gets better and is afebrile EXCEPT for neonatal GN meningitis Consider repeat LP in these situations: No clinical improvement after 3-4 days of abx NEW focal neuro signs, AMS, or increased ICP Initial culture had resistant/weird bugs and no improvement after 24-48 hrs of appropriate therapy

    43. Should we give steroids? * Inflammatory cascade in bacterial meningitis leads to tissue damage and can worsen neurologic sequelae Antibiotics make this worse * Steroids can decrease inflammation, ICP, cerebral edema, and CSF outflow obstruction * Dexamethasone given to patients with H.flu or pneumococcal meningitis has shown benefit * The AAP recommends its use in H.flu meningitis 0.4 mg/kg q12h x 2 days * Adult guys give it when strep pneumo is suspected Consider adding rifampin? * The benefits of steroids have NOT been established in neonatal meningitis Rogers has a whole paragraph about steroids but in the end doesnt say yes or no. So the inflammatory cascade triggered in patients with bacterial meningitis leads to tissue damage and worse neurologic sequelae. This response is exaggerated by the bacterial lysis and endotoxin release resulting from administration of antibiotics. Steroids can stem this effect and decrease ICP, cerebral edema, and CSF outflow obstruction. Dexamethasone has been shown to be beneficial when given prior to or with the first dose of antibiotics in patients with H.flu or pneumococcal meningitis, in a systematic review. Currently the AAP recommends dexamethasone only for H.flu meningitis. There is concern among the ID folks that dexamethasone decreases the CSF penetration of antibiotics (particularly vanc), although this does not seem to be case with highly resistant pneumococci when you use both vanc and a 3rd gen cephalosporin, but keep it in mind. The recommendation in adults is to give it you suspect strep pneumo, and consider adding rifampin. These findings have not been established in neonates. Rogers has a whole paragraph about steroids but in the end doesnt say yes or no. So the inflammatory cascade triggered in patients with bacterial meningitis leads to tissue damage and worse neurologic sequelae. This response is exaggerated by the bacterial lysis and endotoxin release resulting from administration of antibiotics. Steroids can stem this effect and decrease ICP, cerebral edema, and CSF outflow obstruction. Dexamethasone has been shown to be beneficial when given prior to or with the first dose of antibiotics in patients with H.flu or pneumococcal meningitis, in a systematic review. Currently the AAP recommends dexamethasone only for H.flu meningitis. There is concern among the ID folks that dexamethasone decreases the CSF penetration of antibiotics (particularly vanc), although this does not seem to be case with highly resistant pneumococci when you use both vanc and a 3rd gen cephalosporin, but keep it in mind. The recommendation in adults is to give it you suspect strep pneumo, and consider adding rifampin. These findings have not been established in neonates.

    44. Prognosis Mortality continues to be as high as 15-20% Coma, raised ICP, seizures, and shock are significant predictors of morbidity and mortality Neurologic sequelae are common Hydrocephalous, spasticity, vision/hearing loss, cognitive defects, developmental delay

    45. Prevention Isolation is necessary for H.flu and Neisseria for the first 24 hours of treament Rifampin prophylaxis is indicated for household contacts of H.flu if any of them is unvaccinated and <4yrs old Rifampin is also recommended for household and daycare contacts of Neisseria Single oral dose of cipro or azithro is ok for adults

    46. Prevention H.flu vaccine is awesome and has virtually eliminated H.flu meningitis in developed countries Heptavalent pneumococcus vaccine is good too Dont forget kids with asplenia, nephrotic syndome, sickle cell, and cochlear implants need 23-valent Quadrivalent meningococcal vaccine (A, C, Y, W135) is recommended for high risk kids > 2 yrs and college students/military

    47. 47 TITLE INFORMATION

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