JC WCS 22

JC WCS 22

FEVER + CONFUSION

Meningitis, Encephalitis, Suppurative Brain Infection
Suggested references

Davidson's Principles and Practice of Medicine. Edited by C Haslett, ER Chilvers, JAA
Hunter, NA Boon. Eighteenth Edition, Churchill Livingstone
Neurology in Practice. Edited by YL Yu, JKY Fong, SL Ho. Second Edition, Hong Kong
University Press

General points

Very common and important neurological problems in hospital
High mortality and morbidity if treatment delayed
Formulate a working diagnosis urgently and start empirical treatment without delay
Early lumbar puncture if without contraindication
Quick septic workup including a blood culture before commencement of antibiotics (otherwise culture will not yield any org)
High dose parenteral antibiotics (cefotaxime, ceftriaxone, meropenem, penicillin); intrathecal administration seldom required (locally dose v high and may induce chemical irritation - adhesion and fibrosis - neurol complications on their own)
PO route not effective, nausea + vomiting common in CNS infections
Oral chloramphenical, cotrimoxazole, and metronidazole with good CSF penetration (not usu used in beginning, unless anaerobes, Pt has penicillin allergy)
Corticosteroid controversial; useful in childhood meningitis (recent NEJM articles shows corticosteroid useful in meningitis). Corticosteroid is a potent immunosuppressant, so no immune system to fight infection - therefore not for infection, for inflam (eg. Autoimmune, demyelinating), not to be used alone. When using bactericidal ABX, inflam activated by dead bacteria. Therefore corticosteroids + bactericidal used together recommended by some authorities
Close liaison with clinical microbiologist, neurologist, neurosurgeon, and paediatrician
Look for the primary infective focus (original source) or else Pt will re-present (eg. Sinusitis, chronic lung infec'n)
Regular monitoring of neurological status and vital signs
Consider prophylactic or therapeutic anti-epileptic therapy

Approach to a patient with fever and confusion

Must consider CNS infection
DDx: systemic infection with toxic or metabolic encephalopathy (coincidental or complicating the systemic infection), connective disease with CNS involvement (multi-organ involvement: eg. Skin, jt, CNS if preference for small BV)
Note: pure meningitis does not usu cause confusion (therefore, consider meningitis plus complications)
History of travel (acute vs. chronic, indigenous vs. exotic infec'n, eg. Dengue fever was exotic, now endemic), systemic infection, chronic illness (prone to infection of any type), immunisation (esp. Paed Pt b/c if completed course, then chance of a particular infec'n lower)
Pt factors: age of patient, immunological status, onset and duration of symptoms, progression or deterioration, previous treatment history (esp. ABX - aseptic meningitis)
Cardinal features of CNS infection: fever (maybe not in elderly), higher mental functions (usu incl. in Hx taking - succinct Hx then higher mental func'ns intact), focal neurological signs (asym/ unilat findings), neck stiffness, Kernig's sign, general physical examination (hints of primary focus of infec'n, general state of Pt)
Investigations: septic workup (collecting specimen and send to lab - eg. Urine, sputum, blood, NP/ throat swab), CXR (focus, pneum?), CBC with DC (neutrophilia indicates bacterial, lymphocytes for chronic), clotting time (adequate for LP?), biochemistry (metabolic encephalopathy; if major electrolyte imbalances, may not indicate primary CNS prob), blood gases (prob breathing due to CNS effects; or type 1/2 resp failure causing confusion), toxicology screen (alcohol, soft, hard drugs leading to intoxicated test), CT/MRI brain (CT usu not needed if suspect focal neurol prob, but CT for safety, in case SOL does not cause focal neurol signs), LP & CSF analysis, EEG (abn = encephalopathic condition)
Empirical treatment without delay; monitor response to treatment
Underlying predisposing factors

Lumbar puncture (LP) & cerebrospinal fluid (CSF) interpretation

CSF production, circulation, absorption, functions
Absorption: across arachnoid villi by a valve-like mechanism; press-dep; resistance to CSF outflow determines the CSF pressure
If prob in circ or absorption, hydrocephalus likely to occur b/c feedback to production absent (b/c usu press-dep)
Func: mech support, protective water jacket, regulating ionic composition, immunological isolation, removal of metabolites, protection from sudden pressure changes (equivalent of lymph in rest of body)
Normal CSF findings: clear, colourless, odourless; opening pressure 8-12 cm (6 to 20 cm water) (intracranial pressure), normal fluctuations with respiration; 0-5 (usu 2 or less) lymphocytes per microlitre; 0.15-0.45 g/L total protein [70 to 90 = plasma pro level; with infection there is leakage of BBB so pro inside CSF rises]; 0.08- 0.25 g/L albumin [40 to 55]; 2.5-4.0 mmol/L glucose [5 to 7; glucose transporters mean glucose usu 60% of blood glucose, b/c glucose is major fuel of brain]; IgG < 15% of total CSF protein
Diagnostic and therapeutic indications of LP (drug instillation, contrast injection/ myelogram, CSF removal in normal pressure hydrocephalus/ benign hypertension)
Contraindications of LP: suspected mass lesion in the brain or spinal cord (do not want to accentuate pressure gradient -> movt of brain struc -> herniation)
(neuroimaging); raised CSF pressure; focal neurological signs; fluctuating conscious level (not sure if there is a mass); spinal block (CSF below spinal block is not reflective of changes in brain); coagulopathies (subdural haematoma that will compress SC); local suppuration (spread infection to CNS); local congenital lesions (cannot puncture through spina bifida meningocele)
Complications: headache, dry tap, subdural haematoma, aneursymal subarachnoid haemorrhage, brain herniation
Analysis: opening pressure, routine microscopy protein, glucose (plus blood glucose), Gram smear, culture and sensitivity, AFB smear and culture, fungal smear and culture, Indian ink, serological tests (incl. cryptococcal Ag, viral Ab), PCR for DNA (M. TB, HSV)
Pattern #1 (pyogenic meningitis): turbid CSF (lots of cells), increased ICP, neutrophilic pleocytosis (500-20,000 in contrast to <5), elevated protein (>0.45 g/L), reduced glucose (<50% of blood glucose b/c bact + neutrophils consume glucose), and positive Gram smear (pyogenic infection, can also be seen in early TB/ fungal infection)
Pattern #2 (chronic meningitis): clear or slightly turbid CSF (less cells), increased ICP, lymphocytic or mixed pleocytosis (10-500/mm3), mildly elevated protein (could also be markedly elevated dep on org), reduced sugar, and negative Gram smear; due to TB meningitis, fungal meningitis partially treated pyogenic meningitis (not high dose, not bactericidal t/f some penetration of CSF controlling part of infection but infection still going on), and malig meningitis(lymphoma, leukaemia, carcinomatosis)

Pattern #3 (aseptic meningitis): lymphocytic pleocytosis, similar to Pattern 2 but glucose is normal; due to viral meningoencephalitis

Meningitis

Inflammation of the leptomeninges: infection (bacterial, viral, fungal, protozoal), neoplastic infiltration, irritation by drugs, contrast medium & blood
Meningism = symptoms of meningeal irritation without actual inflammation
Can be quite alert
Must consider if suspect CNS without focal neurol signs
Local spread from nearby structures (sinuses, middle ear, mastoid, orbit, nasopharynx)
Direct spread via skull or meningeal defect (head injury and neurosurgery)
Haematogenous spread from distant septic foci (lung abscess, pneumonia, infection endocarditis, septicaemia, bacteriaemia)
Causative bacteria according to probability and age of patient (common bacteria: N meningitidis, Strep pneum, Strep suis - occupational risk for those working with pork such as butcher and housewife, H influenza type b)
Bacteria in neonates: Gram -ve org (E Coli) Group B streptococcus, Listeria monocytogenes - from delivery tract, neonates imm-comp
Bacteria in infants: H influenzae, meningococcus, pneumococcus, salmonella
Bact in children + young adults: meningococcus, pneumococcus
Bact in older adults: pneumoccocus
Bact in elderly: Pneumococcus, Gram -ve org, Listeria monocytogenes
Common and less common viral causes; important fungal or protozoal organisms
Common viruses: Coxsackie A + B, Poliovirus, Echo viruses, Enteroviruses types 68-72 (faecal-oral route, young children, warm climates, poor hygiene)

Less common viruses: Mumps, EBV, Lymphochorionic bisuse, Measles, Influenza, Herpes
Important fungal org: Cryptococcus neoformans, Candida, Aspergillus
Important protozoa: Plasmodium falciparum (cerebral org), free living amoeba (esp. living near lake, river)
Non-specific clinical features: fever, chills, malaise, lethargy, nausea, vomiting, photophobia
Meningeal irritation: neck stiffness and Kernig's sign; bulging anterior fontanelle
Neurological features: global and focal
Diagnosis: clinical features + LP & CSF findings
CT/MRI: normal, increased meningeal enhancement
Meningeal adhesions (obstructive hydrocephalus, increased ICP, CN palsies)
Arteritis or thrombophlebitis (cerebral infarction)
Intellectual impairment, MR, cerebral palsy
Seizure and epilepsy, local spread of infection (cerebritis, cerebral abscess, subdural effusion. Empyema)
Complications: obstructive hydrocephalus, cranial nerve palsies, cerebral infarction, intellectual impairment, mental retardation or cerebral palsy, seizure and epilepsy, cerebral abscess, subdural effusion/empyema, SIADH
Empirical treatment for bacterial meningitis: benzylpenicillin plus a third generation cephalosporin (e.g. cefotaxime)
Empirical Tx for bact meningitis: 3rd gen cephalosporins (cefotaxime 2g [children 50 mg/kg] IV Q6h of ceftriaxone 2g [children 50 mg/kg] IV Q12h) plus broad spectrum penicillin
American Academy of Paediatrics Red Book (Report of the Committee on Infectious Diseases) recommends combination therapy with vancomycin and cefotaxime or ceftriaxone to be administered initially to all children older than 1 month with definite or probable bacterial meningitis because of the increased prevalence of penicillin, cefotaxime, and ceftriaxone-resistant S. pneumoniae. Some experts, however, recommend that vancomycin need not be used if compelling evidence indicates that the cause is an organism other than S. pneumoniae

Modify the regimen if needed when the organism and its sensitivity are known
Response to treatment is expected within a few days (if not, check Dx, check ABX)
Neurosurgery for hydrocephalus: relieve hydrocephalus via temporally CSF diversion; obtain CSF for diagnosis; permanent CSF diversion (shunting)

Encephalitis

Inflammation of the brain parenchyma; mostly viral
Usually with aseptic meningitis; myelitis may occur
Acute viral encephalitis: (1) epidemic: Jap B encephalitis, dengue fever, influenza; (2) sporadic: HSV type I, enterovirus (Coxsackie, ECHO, Polio), Herpes (CMV, VZV, EBV), Mumps, Measles, Rubella, Adenovirus, Lymphochorinionic, Rabies, HIV; non-viral infectious (Rickettsia (Typhus, Scrub typhus, Rocky mountain spotted fever), Plasmodium falciparum, Toxoplasma gondii, Trypanosomiasis, Strongyloides stercoralis meningoencephalitis; post-infective encephalitis (acute disseminated encaphlomyelitis, ADEM), common viral infections (measles, chickenpox, childhood exanthemata, mumps, rubella) or vaccinations (rabies, smallpox, influenza, pertussis), hypersensitivity reaction to myelin; chronic infective encephalitis (slow virus - prion disease eg. CJD), progressive multifocal leucoencephalopathy (papovavirus), subacute sclerosing panencephalitis (measles)
Features of cerebritis (epileptic seizures, myoclonus, chorea or athetosis limb weakness, visual changes, memory impairment aphasia, agnosia, confusion, delirium, drowsiness, stupor, coma, psychiatric manifestations); features of increased ICP from cerebral oedema
Non-specific systemic symptoms (fever, viral syndrome, headache, nausea, general malaise
Differential diagnosis: complicated bacterial meningitis with cerebral oedema or cerebral venous thrombosis; toxic encephalopathy due to septicaemia and other febrile illnesses, or overdose of drug and toxin; metabolic encephalopathy caused by hypoglycaemia, organ failure, electrolyte disturbances
Diagnosis: CT or MRI of the brain + LP & CSF analysis + EEG
CT usually normal; MRI may reveal abnormalities in grey or white matter
EEG: diffuse slow waves ± spike activities, but may be focal (eg. Periodic lateralising epileptiform discharges from one or both temporal lobes) in herpes encephalitis
Paired sera (acute and convalescent) for viral titres; urine, faeces, and throat swab for viral culture
Brain biopsy is seldom performed these days
Empirical treatment: acyclovir (only HSV)

SLIDE: axial CT showing hypodensity over right medial temporal love and saggital T1W MRI showing hypointensity over right temporal lobe
SLIDE: T2W at level of midbrain or 3rd ventricle showing hyperintensity over the right and left temporal lobes

Brain abscess

Local spread: paranasal sinuses, middle ear, mastoids, orbit, cavernous sinus, scalp
Direct spread: skull or meningeal defect; haematogenous spread: distant focus
Features of increased ICP; non-specific systemic upset due to infection
Focal deficits depending on the site of the abscess; seizures (up to 30%); EEG
Usually mixed aerobic and anaerobic organisms
Aerobic and microaerophilic bact: strep milleri, pneumoccous, staph aureus, enterobacteriae etc
Diagnosis: CT head (plain and contrast) or MRI brain; avoid LP
Microbiological work-up: blood cultures, aspirated pus for smear and culture
Look for underlying septic foci using CXR, echocardiogram, X-rays of the paranasal sinuses, skull X-rays, and examination of the ear, nose and throat
EEG: give focal slow wave related to abscess
MRI T1W shows ring, T2W plus gadolinium shows enhancing ring (white)
Empirical treatment: benzylpenicillin plus cefotaxime plus metronidazole
Treatment for at least 6 weeks
Abscesses complicating skull injury or neurosurgical procedures need high dose cloxacillin or fusidic acid to cover Staphylococcus aureus
Neurosurgery is usually not required for small and multiple abscesses

Close monitoring of the clinical status with serial CT head
Neurosurgery in abscess/empyema: drainage to establish diagnosis/ bacteriology (if no response to Tx); decrease mass effect (if very large abscess)
Neurosurgical approach: stereotactic guided aspiration; ultrasound guided aspiration; craniotomy and excision of abscess cavity
Antiepileptic medications

Chemoprophylaxis and immunoprophylaxis of contacts
Meningococcal meningitis

Chemoprophylaxis: rifampicin 10 mg/kg (maximum 600 mg/day) twice daily for 4 days (5 mg/kg twice per day for infants < 1 month old); not for pregnant female; for all household contacts, other contacts of oropharyngeal secretions, close contacts in a child care facility, and recent close contacts in camps; alternative: ceftriaxone 2 g (children: 50 mg/kg) IMI once
Immunoprophylaxis: meningococcal vaccine recommended in health officials under special circumstances (boost immune system so do not dev infection)

Haemophilus influenzae type b Meningitis

Chemoprophylaxis: rifampicin 20 mg/kg (maximum 600 mg/day) daily for 4 days (10 mg/kg/day for infants < 1 month old); not for pregnant female; for the index case and all household contacts; for all close contacts (including staff) who are not fully vaccinated if the index case attends a child care facility with other children under 2 years old for > 18 h per week; alternative: ceftriaxone 1 g (children: 50 mg/kg) IMI daily for 2 days
Immunoprophylaxis: Haemophilus influenzae type b (Hib) vaccine after recovery if the index case is under 2 years old and for unvaccinated contacts under 5 years old

CNS infection in immunocompromised hosts

New or reactivation of latent infection
Haematogenous spread is usual (lack of defence in circulating blood)
Unusual infection (eg. TB, fungal, Aspergillus, protozoal) or unusual presentations of common infections (lack of body defence)
Plus/minus fever, headache, with or without meningism, altered mental state, focal sign, and meningism
Lower threshold to consider LP
Empirical therapy of likely org in adequate doses
Asplenism (pneumococcal meningitis): post-splenectomy, sickle cell anaemia, coeliac disease (spleen important for encapsulated bact like pneumococcus)
Humoral immundeficiency states (bact and viral infections); hypogammaglobulinaemia, chronic lymphocytic leukaemia, or myeloma
Complement deficiency (meningococcal infection): congenital complement deficiency, active SLE (complement imp for lysing bacteria)
Neutropenia (bact + fungal): aplastic anaemia, chemo, extensive rad, org from skin, GIT, RT
Cell-mediated imm-def (virus, fungus, parasite, mycobact)