IDA-CNS Infections PDF

Case history: A 59 yrs old obese lady with poorly controlled diabetes, had high fever for 1 day. Next day morning she was found to be unarousable and was brought to a hospital. She has taken her usual oral hypoglycaemic medication and atorvastatin in the previous night and had her dinner...

Case history: A 59 yrs old obese lady with poorly controlled diabetes, had high fever for 1 day. Next day morning she was found to be unarousable and was brought to a hospital. She has taken her usual oral hypoglycaemic medication and atorvastatin in the previous night and had her dinner as well. No history of fits. On examination, she was febrile (38.40C)her GCS was 6/15 (M-3, V-2, E-1), pulse rate 116/min, BP 120/70, respiratory rate 20/min, lungs - clear, heart – dual rhythm and no murmurs. She had neck stiffness. No focal neurological deficit. CBS – 280 mg/dl 1  What is the differential diagnosis? Meningitis or encephalitis? Diabetic keto acidosis? Hyperglycemic hyperosmolar nonketotic coma Stroke ? 2  Differential diagnosis Diabetic keto acidosis? Patient is not dyspnoeic. CBS not very high. Hyperglycemic hyperosmolar nonketotic coma In HHNC, blood sugar is very high. Stroke ? No focal weakness. Fever +. 3  Differential diagnosis Meningitis/encephalitis Should be the first in the list of differential diagnosis. What is in favour? – History of fever – History of diabetes (poorly controlled) – Neck stiffness Why should it be considered first? – Dangerous. Patients can deteriorate rapidly. – Early diagnosis and treatment is essential to prevent complications and death. – A medical emergency. 4 CNS Infections: An Overview IDA- Microbiology 5  Learning Objectives Classify cerebral infections in children and adults Describe the pathophysiology of CNS infections List aetiologies of CNS infections including acute and chronic infections Describe the clinical presentation of CNS infections in children and adults List the investigation required to diagnose CNS infections Outline the immediate management of acute CNS infections List the emerging and reemerging CNS infections 6 Defense Mechanisms List the subtypes of hepatitis infection. Classify and wwwwwwww 7 Defense Mechanisms… 8 Classification of cerebral infections Meningitis Infected by various – Acute bacterial agents meningitis (pyogenic – Viruses meningitis) – Bacteria – Aseptic meningitis – Fungi – Shunt associated – Protozoa meningitis – Helminthes – Chronic meningitis Encephalitis – HSV, JE, Enteroviral Brain abscess 9  Meningitis Inflammation of the meninges Bacterial meningitis is more severe but less common than viral meningitis Acute bacterial meningitis is a life threatening infection needing urgent specific treatment A medical emergency 10 Pathophysiology of meningitis Source of Infection Bacteraemia – spread via blood from distant foci of infection Contiguous infection – sinusitis, otitis media, dental abscess Trauma/ surgery on head – compound fracture, craniotomy Ventricular drain/ CSF shunts/ lumbar puncture Immune deficiency – HIV/AIDS, Immunosuppresive treatment, Alcohol abuse, Diabetes mellitus 11 Pathogenesis of Bacterial Meningitis Nasophryngeal colonization 1. Smoking and concurrent viral infection are predisposing factors 2. Pathogens secrete IgA proteases to break down secretary IgA Invasion of respiratory mucosal epithelium (Local invasion) Bacteremia Evade complement activation and phagocytosis by means of polysaccharide capsule Enters CSF and multiplies Once in the CSF the low levels of antibodies (Blood: CSF – 800:1) Low complement components allow the bacterial infection to flourish Low white blood cells Inflammation of the meninges 12 Pathogenesis of Bacterial Meningitis Bacterial infection thus leads to – Increased permeability of the blood-brain barrier – Cerebral oedema – Presence of bacterial toxins in the CSF Causing – Cerebral hypoxia – Exudates that extend throughout the CSF May damage cranial nerves Block CSF drainage pathways causing obstructive hydrocephalus 13 Aetiological Agents-According to Age Age Causative organisms 50 years Streptococcus pneumoniae Neisseria meningitides Listeria monocytogenes Aerobic gram-negative bacilli 14 Aetiological Agents-According to Risk Factors Risk factor Causative organisms Immunocompromis Streptococcus pneumoniae ed state Neisseria meningitides Listeria monocytogenes Aerobic gram-negative bacilli (including Pseudomonas aeruginosa) Basilar skull Streptococcus pneumoniae fracture Haemophilus influenza Group A β-haemolytic streptococci Head trauma; after Staphylococcus aureus neurosurgery Coagulase negative staphylococci (specially Staphylococcus epidermidis) Aerobic gram-negative bacilli (including Pseudomonas aeruginosa) 15  Streptococcus pneumoniae Gram positive diplo- cocci Mortality 20-30% High incidence in children with cochlear implants Serious infection in patients with various underlying conditions especially, splenectomy or asplenic states 16  Neisseria meningitidis Gram negative intracellular diplococci Serogroups A, B, C, and W135 account for most cases Overall mortality rate of 3% - 13% Not common in Sri Lanka Annual outbreaks of meningococcal meningitis occur in the sub-Saharan meningitis belt 17  Haemophilus influenzae type b (Hib) Pleomorphic Gram- negative bacilli The overall mortality rate is 3% to 7% The number of cases of H. influenzae type b meningitis since the introduction of vaccination has decreased by more than 90% 18 Clinical Presentation of Meningitis Acute meningitis – Syndrome characterized by onset of meningeal irritation over the course of hours up to few days Chronic meningitis – Insidious onset (weeks to months) Tuberculous meningitis Fungal meningitis Syphilitic meningitis – Patients are often immunocompromised 19 Clinical Features of Meningitis Fever Neck stiffness Classic triad Altered consciousness (40-50% patients) Headache Vomiting Inability to tolerate bright light (photophobia) 20 Clinical Features of Meningitis ctd. Kernig’s sign (pain when leg is raised with the knee flexed to a 90-degree) Brudzinski's sign. Severe neck stiffness causes a patient's hips and knees to flex when the neck is flexed. Focal neurological signs Convulsions Sometimes rash 21 Meningococcal Septicaemia- Waterhouse- Friderichsen Syndrome Purpuric skin rash Bilateral adrenal haemorrhage 22 Morphology Gross Meningeal vessels are engorged Brain- Purulent exudate over the surface H. influenzae – basal Pneumococcal – cerebral convexities near sagittal sinus Tracts of pus follow the blood vessels 23  Microscopy – Neutrophils predominantly around blood vessels, in subarachnoid space If untreated, inflammatory cells infiltrate meningeal veins and enter into brain parenchyma Hemorrhagic cerebral infarctions due to vasculitis and thrombosis 24 25  Pyogenic Aseptic Tuberculous meningitis meningitis meningitis Appearance Turbid or frankly purulent Pressure Increased Cells Neutrophils (10- 10,000/uL) Protein Raised Glucose Markedly reduced Other Gram stain +/- Culture 26  Acute focal suppurative infections A brain abscess is a localized focus of necrosis of brain tissue with accompanying inflammation, usually caused by a bacterial infection 27 A 43-year-old woman has had a headache and fever for the past 2 weeks following a severe respiratory tract infection accompanying bronchiectasis. On physical examination, her temperature is 38.3° C. There is decreased vision in the left half of her visual fields. CT scan of the head shows a sharply demarcated, 3-cm, ring- enhancing lesion in the right occipital region. A Cerebral abscess B Glioblastoma C Metastatic carcinoma D Multiple sclerosis E Subacute infarction 28  Viral Meningitis Commonest type of meningitis -commonly seen in children Milder disease than bacterial meningitis Complete recovery generally occurs Causative organisms ⁻ Enteroviruses -Coxsackie, Echo ⁻ Mumps virus ⁻ Herpes simplex viruses type 1 and 2 ⁻ Varicella zoster virus - may cause meningitis during reactivation ⁻ HIV -especially during seroconversion ⁻ Lymphocytic choriomeningitis - zoonotic transmission by urine of rodents 29  Acute aseptic meningitis Acute aseptic meningitis is a clinical term used for an absence of organisms by bacterial culture in a patient with manifestations of meningitis. Generally viral in origin, but may be due to some bacteria, rickettsial or autoimmune in origin Common viral aetiologies are Enterovirus (80% of cases) Aetiological agents can be identified in a minority of the cases with the help of sensitive detection methods 30  Morphology No distinct microscopic features except for brain swelling Mild to moderate infiltration of lymphocytes in leptomeninges Usually self-limited infection and are treated symptomatically 31  Chronic Meningitis Tuberculous Meningitis Caused by Mycobacterium tuberculosis Chronic/sub acute meningitis Insidious onset and can be associated with focal neurological signs Apart from meningitis can also cause tuberculomas Diagnosis: – CSF: Acid fast stain – TB culture – TB PCR 32  Fungal Meningitis Causative organisms – Cryptococcus neoformans The most common cause of fungal meningitis Majority of patients are immunocompromised – Histoplasma capsulatum (histoplasmosis) Seen in previously healthy or immunocompromised patients – Coccidioides immitis (coccidioidomycosis) Seen in endemic areas – Candida species (candidiasis) Chronic meningitis is rare; seen in patients with disseminated candidiasis 33  Cryptococcus neoformans Associated with soil contaminated with pigeon droppings or eucalyptus trees and decaying wood A neurotrophic fungus Predisposing factors – HIV/AIDS – Organ transplant recipients – Cancer patients Yeast is inhaled into the lungs and disseminate Diagnosis – CSF: India ink stain, fungal culture – Ag detection in blood – Serology 34  What to do when meningitis is suspected? Stabilization Blood for culture and ABST FBC, CRP, RBS, LFT, RFT. Immediate commencement of IV antibiotics CT scan – if indicated Lumbar puncture and CSF examination – preferably before starting antibiotics 35  Microbiological Diagnosis of Meningitis CSF (obtained by lumbar puncture) – Full report – Gram stain (or other staining methods) – Culture and ABST – Bacterial antigen detection Latex agglutination for the detection of S. pneumoniae, N. meningitides, H. influenzae type b, group B streptococci & E. coli High specificity but low sensitivity, hence negative results do not rule out bacterial meningitis Blood culture and ABST Specimens from skin lesions - Neisseria meningitidis 36 Other Investigations If TB meningitis is suspected – CSF direct smear for AFB – TB culture and ABST – TB PCR If fungal meningitis is suspected – CSF direct smear for India ink - to detect capsulated yeasts in cryptococcal meningitis – Fungal culture In viral meningitis – CSF full report – PCR – Serology: blood and CSF 37  Lumbar puncture (LP) Is a commonly performed procedure that involves obtaining and sampling cerebrospinal fluid from the spinal cord. It is the gold standard diagnostic procedure in the diagnosis of meningitis, subarachnoid hemorrhage, and certain neurological disorders. It is also used in the measurement of intracranial pressure and administration of medications or diagnostic agents 38  Lumbar Puncture for CSF Analysis A sterile procedure CSF is withdrawn from the subarachnoid space (L3-4 or L4-5) Using these landmarks will avoid inadvertent damage to the conus medullaris, which typically terminates at L1. 39 The order in which the spinal needle will traverse the lumbar spine is as follows: Skin Subcutaneous tissue Supraspinous ligament Interspinous ligament Ligamentum flavum Epidural space Dura Arachnoid Subarachnoid space 40  CSF sample collection Sample is collected into 4 tubes: CSF sugar Microbiological investigations ie. Culture and ABST, smear for AFB. Full report ie. Cytology, protein, Store one sample for other tests (eg Viral studies) 41 Contraindications to performing a LP Skin infection near or at the site of lumbar puncture needle insertion, Central nervous system (CNS) lesion or spinal mass leading to increased intracranial pressure, Platelet count less than 20,000 mm3 (ideally the platelet count should be greater than 50,000 mm3), Use of unfiltrated heparin or low-molecular-weight heparin in the past 24 hours, coagulopathies (i.e., hemophilia, von Willebrand disease) Vertebral trauma. (Consensus guidelines for lumbar puncture in patients with neurological diseases. Alzheimers Dement (Amst). 2017; 8: 111– 126.) 42 Indications for neuroimaging (CT scan) before doing a LP Patients should not have neuroimaging before their LP unless there is a clinical indication suggestive of brain shift Focal neurological signs (To exclude significant brain swelling and shift that may predispose to cerebral herniation post LP) Presence of papilloedema (inability to view the fundus is not a contraindication to LP, especially in patients who have had a short duration of symptoms) Continuous or uncontrolled seizures GCS≤12 (LP without prior neuroimaging may be safe at levels below this) (The UK joint specialist societies guideline on the diagnosis and management of acute meningitis and meningococcal sepsis in immunocompetent adults) 43  Normal CSF Gross appearance: clear and colourless Glucose: 40–80 mg/dL (2/3 of blood glucose) Total protein: 15–45 mg/dL Leucocytes (WBC): -0–5/µL (adults and children) -up to 19/µL in infants -up to 30/µL (new borns) Red blood cell count: normally, none unless a traumatic tap 44 Characteristic CSF Changes in CNS Infections Condition Cell type Cell count Glucose Protein Gram stain Normal Mononuclear Up to 5 40–80 15–45 (cells/mm3) mg/dL mg/dL Viral Lymphocytes 10-2000 normal slightly - elevated Bacterial Polymorphs 1000-5000 low elevated + (pyogenic) Tuberculous polym/lymph/ 50-5000 low highly +/- mixed elevated Fungal Lymphocytes 50-500 low elevated +/- 45  Microbiological Basis of Treatment of Meningitis Principles of antimicrobial therapy Antibiotic therapy should be intravenous Choosing the type of antibiotic 1. ability to penetrate the CSF 2. activity in purulent CSF 3. bactericidal activity 4. concentration in CSF (PK/PD) Duration – depends on the organism 46  Empirical Treatment for Bacterial Meningitis Age Commonest organisms Suggestions for empirical Antimicrobial therapy < 3 months Group B Strep., E. coli, Listeria Ampicillin/C.penicillin + monocytogenes Cefotaxime/Ceftriaxone 3 months - 18 years S. pneumoniae, H. influenzae, N. Cefotaxime/Ceftriaxone meningitidis 18 - 50 years S.pneumoniae, N. meningitidis Cefotaxime/Ceftriaxone > 50 years N.meningitidis Cefotaxime/Ceftriaxone S. pneumoniae +/-Ampicillin L.monocytogenes Gram negative rods CNS shunts – Ventriculo E. coli, Klebsiella, Enterobacter Cefotaxime/Ceftriaxone peritoneal Meropenem CNS shunts - Ventriculoatrial S. aureus, Coagulase negative Vancomycin Staphylococci 47  Empirical Treatment Risk factor Empiric treatment Age Penicillin/ampicillin plus cefotaxime; or 65 years, alcoholics Cefotaxime/ceftriaxone plus ampicillin with or and patients with without vancomycin debilitating diseases Immunocompromised Ampicillin plus cefotaxime/ceftriaxone with or state without vancomycin Basilar skull fracture Cefotaxime/ceftriaxone with or without vancomycin Head trauma; after Vancomycin plus either ceftazidime, cefepime, or neurosurgery, CSF meropenem shunt infections 48  Prevention of Meningitis HIB vaccine (Haemophilus influenzae type b) A conjugate vaccine Included in the NPI schedule in SL Pneumococcal vaccine Polysaccharide vaccine - 23 valent Conjugate vaccines – 7, 10,13 valent For high risk groups Meningococcal vaccine Polysaccharide vaccines- bivalent (A+C), tetravalent (A,C,W 135, Y) Conjugate vaccines – Group C conjugated, tetravalent conjugated (A vaccine for Group B is not available) 49 Chemoprophylaxis Chemoprophylaxis for prevention of secondary cases among close contacts is recommended – H. influenzae type b – Meningococcal infection Pneumococcal meningitis and other types of meningitis – Chemoprophylaxis not indicated for close contacts 50  Encephalitis An acute inflammation/infection of the brain parenchyma Encephalitis is distinguished by the presence of decreased mentation (abnormal state of consciousness, with or without seizures) early in the course of disease with minimal meningeal signs 51  Routes of Acquiring the Brain Haematogenous (commonest) – Arboviruses – Enteroviruses – Bacteria – rickettsia – Fungi Neuronal retrograde dissemination – HSV – Rabies – VZV Post infectious encephalomyelitis (immune mediated) – Measles – Rubella 52 Clinical Features Neuropsychiatric symptoms – Abnormal behavior – Hallucinations – Psychosis – Personality changes – Agitation Focal neurological signs Focal seizures Altered consciousness Abrupt history of fever and headache 53  Causative Organisms Viruses Others Listeria Monocytogenes Herpes simplex virus Japanese encephalitis Rickettsial spp. West Nile virus Bartonella spp. HIV Mycoplasma pneumoniae Varicella zoster virus St. Louis encephalitis virus Toxoplasma gondii Equine encephalitis virus Several free-living 54 amebae  Herpes Simplex Encephalitis Family – Herpesviridae Serotypes - HSV-1, HSV-2 – HSV -1 –associated with mouth, eye and CNS infections – HSV -2 - more commonly but not exclusively causes genital infections Characteristic features of viruses of Herpesviridae family Latency Virus remains latent in ganglia and brain Pathogenesis – Source: herpes infected lesions – About 2/3 of cases occur due to virus reactivation in the trigeminal ganglia and are due to HSV-1 Virus is transmitted form trigeminal ganglia to the temporal lobe through the nerve fibres – The remaining 1/3 occurs as primary infection due to HSV-2 in the neonatal period It is believed that the virus enters the brain via the olfactory ganglia in primary 55 infection Herpes Simplex Virus 56 Microbiological Investigations Specimens – CSF – Blood for serology Investigations – Cerebrospinal fluid for PCR Highly sensitive and specific - test of choice – CSF full report may be helpful – Detection of specific IgM and IgG from serum 57 Treatment Parenteral acyclovir for 14 days – Duration is 21 days for immunosuppressed patients – Started empirically for encephalitis as it is lifesaving High mortality and morbidity in untreated patients 58  Japanese Encephalitis Caused by a Flavivirus transmitted in an enzootic cycle among mosquitoes and vertebrate amplifying hosts, chiefly domestic pigs and birds. Man is an accidental host Vectors: Culex mosquitoes, primarily C. tritaeniorhynchus – These species are common in rural areas where their larvae breed in ground pools and especially in flooded rice fields Seen in unvaccinated population currently Most infections are asymptomatic Clinical disease seen 1 in 300 Less than 1% of JE cases manifest as encephalitis Encephalitis usually is severe, resulting in a fatal outcome in 30% of cases and residual neuropsychiatric sequel in 30-50% of cases 59  Japanese Encephalitis Virus JE virus first isolated in Japan in 1935(1968 in Sri Lanka) Seen in Sri Lanka, mainly in paddy growing areas of the country and below an elevation of 3000 feet Shows increased incidence with the N-E monsoonal rains (November-February) 60 Microbiological Investigations Serological tests JE virus specific IgM in CSF is confirmatory – Detected as early as 3-4 days following onset of illness – Presence of antibody in the CSF confirms the virus has infected the central nervous system – A single sample of CSF is often adequate for diagnosing as 70% are positive at the time of admission JE virus specific IgM in serum Rising titres of JE specific antibodies in paired sera Molecular diagnostic tests JE specific PCR of CSF 61 Treatment No specific antiviral therapy is available for JE Treatment is mainly supportive and symptomatic 62 Prevention Vector control Protection of animal reservoirs – Pig breeding sites - away from human habitats – Use of residual insecticides - in piggeries – Vaccination of pigs Prevention of mosquito bites(mosquitoes commonly bite in the twilight hours) – Personal protective measures(Ex: long-sleeved clothes) – Use of mosquito nets – Use of mosquito repellents, coils and vaporizers Health education of people - avoid paddy fields and piggeries after dark Vaccination of humans in NPI schedule (the single most cost effective strategy for control and prevention of JE) 63  Enterovirus Encephalitis Causative agents – Enterovirus 71 – Coxackieviruses – Echoviruses – Poliovirus (rare) Pathogenesis – Transmitted by faeco oral route and infects the gut. Viraemia results in infection of the CNS Diagnosis – Organism specific PCR in CSF 64  Microbiological Diagnosis of Encephalitis 1. CSF PCR: identification of viral DNA or RNA Identification of virus specific IgM antibodies Virus isolation 2. Blood for serology Identification of virus specific IgM antibodies Determining a four fold rising titre of virus specific IgG antibodies 65  Brain Abscess A focal, intracerebral infection that begins as a localized area of infection and develops into a collection of pus in the brain surrounded by a well-vascularized capsule Predisposing factors – Chronic middle ear infection – Dental abscess – Chronic sinusitis – Congenital heart disease – Trauma to the head – Immunosuppression 66 Causative Organisms Bacterial Other organisms Streptococci (S. millerii) Cryptococcus Staphylococcus aureus neoformans Enteric Gram-negative bacilli Mycobacterium (e.g., Proteus spp., Escherichia tuberculosis coli, Klebsiella spp.) Pseudomonas spp. Anaerobes (Nocardia, Actinomyces) - Usually a polymicrobial infection 67 Clinical Features Those of a space occupying lesion Headache Vomiting Drowsiness Confusion Seizures Focal neurological signs Treatment: Drainage depending on site Antibiotics 68  Summary Acute bacterial meningitis - Streptococcus pneumoniae, Haemophilus influenzae type b, Neisseria meningitidis Chronic/subacute meningitis – TB, Cryptococcus Diagnosis CSF -Full report -Gram stain/ AFB stain/ India ink -Culture and ABST Blood culture and ABST Bacterial antigen detection PCR: TB, certain viruses Serology: blood and CSF Encephalitis Brain abscess 69 QUESTIONS…..???? 70 The 59 yrs old lady…. Lumbar puncture was done immediately Blood culture done IV C. penicillin started at high dose CSF – bacterial meningitis Blood culture – N. meningitidis Patient end up in a vegetative state and was discharged to a rehabilitation unit. 71