central nervous system infections Flashcards
CSF
The brain and spinal cord are suspended in the skull and vertebrae in cerebrospinal fluid (CSF), which acts as a “shock absorber”.
-Approximately 85% of the CSF is produced by the choroid plexus of the third, fourth, and lateral ventricles.
-CSF volume within the CNS is related to the age of the patient: Infants: 40 to 60 ml, Older children: 60 to 100 ml, Adults: 110 to 160 ml
-Normally, 550 ml of CSF is produced daily. The CSF typically resides in the subarachnoid space and flows unidirectionally downward through the spinal canal.
Normal characteristics of CSF:
-Clear fluid
-Protein concentration less than 50 mg/dl
-Glucose concentration = 50 to 66% of serum
-pH 7.4
-WBCs = fewer than 5 white blood cells per ml of CSF**
meinges
In addition, the brain and spinal cord are ensheathed by a protective covering known as the meninges.
-The meninges are made up of three separate membranes:
—Dura mater – a tough outer membrane that directly adheres to the skull (periosteum and vertebral column)
—SUBDURAL SPACE – between the dura mater and the arachnoid
—Arachnoid - middle meningeal layer between the dura mater and
the pia mater
—SUBARACHNOID SPACE – between the arachnoid and the pia mater; contains the CSF; meningitis = infection of subarachnoid space*
—Pia mater – the innermost, thin membrane layer of the meninges that closely adheres to the contours of the brain
BBB and BCSFB
Blood Brain Barrier (BBB) and Blood-CSF Barrier (BCSFB)
- Two distinct natural barriers exist within the CNS to regulate the exchange of drugs and endogenous compounds between the blood, brain, and CSF to maintain homeostasis.
- The relative impermeability of these barriers to immunoglobulin, complement, and antimicrobial agents plays an important role in the pathogenesis and treatment of CNS infections.
- The BBB consists of tightly joined capillary endothelial cells** (within brain parenchyma) that separate the blood from the interstitial fluid of the brain.
- –The tight junctions produce a barrier similar to that of a continuous lipid bilayer – drugs enter brain tissue by direct passage through capillary endothelial cells.***
- –Surface area of the BBB is > 5,000 times larger than that of the BCSFB.
- The BCSFB consists of tightly fused ependymal cells** (specialized epithelium) lining the ventricular side of the choroid plexus.
- Ependymal cells act as an active transport system to restrict the diffusion of substances (drugs, chemicals) into the CSF, and may serve as a barrier to antibiotic penetration.*****
- –Active transport systems are saturable.
- –In the presence of inflammation (meningitis), the active transport system of the ependymal cells is inhibited, allowing penetration of some antibiotics into the CSF.
Antibiotic Characteristics that Influence CSF/CNS Penetration (Ability to Cross Blood-Brain and Blood-CSF Barriers)
Lipid solubility → highly lipid-soluble compounds penetrate more readily
- Degree of ionization (dependent on pKa and pH of environment) → only antibiotics that are nonionized at physiologic or pathologic pH are capable of diffusion
- Protein binding → only free drug can penetrate
- Molecular weight → agents with low molecular weights can penetrate easier
- Meningeal inflammation →penetration of some antibiotics into the CSF is increased when the meninges are inflamed due to damage of the tight junctions between capillary endothelial cells and impairment of active transport pumps. As healing occurs, access of non-lipophilic antibiotics to CSF decreases.
therapeutic CSF concentrations with or without meningeal inflammation
Acyclovir* Linezolid* Chloramphenicol* Metronidazole* Minocycline Fluconazole Flucytosine* Pyrazinamide Foscarnet Rifampin* Ganciclovir* Trimethoprim-sulfamethoxazole Isoniazid Voriconazole
therapeutic CSF concentrations with meningeal inflammation
Ampicillin* Imipenem Aztreonam* Meropenem* Cefepime* Nafcillin* Cefotaxime* Penicillin G* Ceftazidime* Piperacillin* Ceftriaxone* Pyrimethamine Cefuroxime* Quinupristin/dalfopristin Colistin* Ticarcillin* Ethambutol Vancomycin* Problems with CSF penetration may be overcome by the direct instillation of the antibiotic by intrathecal, intracisternal, or intraventricular administration (rare).
therapeutic concentration NOT achieved with or without meningeal inflammation
Aminoglycosides 2nd generation cephalosporins* Amphotericin B Clindamycin β-lactamase inhibitors Doxycycline 1st generation cephalosporins Itraconazole Problems with CSF penetration may be overcome by the direct instillation of the antibiotic by intrathecal, intracisternal, or intraventricular administration (rare).
epidemiology of acute bacterial meningitis
Worldwide, bacterial meningitis is a very important disease, with over 1.2 million cases and 135,000 deaths annually.
In the United States, the incidence of acute bacterial meningitis is approximately 3 cases per 100,000 persons per year.
-Meningitis is generally a disease of the very young and the very old, with infants older than 1 month of age and children less than 4 years of age at highest risk for acute bacterial meningitis.
Overall mortality rates for patients with meningitis are 2 to 30% depending on age of the patient, infecting organism, mental status on presentation, and the presence of seizures.
-Despite advances in medical care and the introduction of new, more potent and broad-spectrum antibiotics, the overall mortality rate for acute bacterial meningitis has not changed.
acute bacterial meningitis pathogenesis
Meningitis is the inflammation of the meninges caused by the presence of a pathogen in the subarachnoid space. Once bacteria gain entry into the CSF, host defenses are inadequate to contain the infection and bacteria replicate rapidly.***
Bacteria can gain access into the CSF and subarachnoid space through a number of different mechanisms: Hematogenous spread, coniguous spread from a parameningeal focus, direct inoculation of the bacteria into the CNS/CSF during head trauma or neurosurgery
hematogenous spread
most common mechanism where an organism from the bloodstream gains access into the subarachnoid space
The critical first step is nasopharyngeal colonization of the host. Pathogens adhere to the epithelial surface of the nasopharynx and enter the intravascular space (bloodstream) after phagocytosis.
-Fimbriae (pili) → N. meningitidis
-Bacterial capsule (S. pneumoniae, H. influenzae, N. meningitidis) → inhibits neutrophilic phagocytosis and resists complement-mediated bactericidal activity
-Secretion of IgA proteases (S. pneumoniae, H. influenzae, N. meningitidis) → cleave secretory IgA at the mucosal surface → enhance colonization
Capsular polysaccharides activate an alternate complement pathway as host defense mechanism→ patients unable to activate this pathway (e.g., asplenic, sickle cell) are at increased risk of meningitis caused by encapsulated organisms
Eventually, organisms multiply to sufficient numbers that allow invasion of the BBB and BCSFB (continuous exposure of CNS/CSF to large bacterial inoculum; production of capsule surrounding the bacteria making it resistant to phagocytosis, etc).
contiguous spread from a parameningeal focus
untreated or uncontrolled sinusitis or otitis media leads to bacterial drainage via the veins in the CNS, or erosion of the bacteria through the bony structures into the CNS/CSF.
neurologic sequelae of acute bacterial meningitis
30 to 50% of patients who survive bacterial meningitis develop neurologic sequelae such as seizures, sensorineural hearing loss, cerebral edema, and hydrocephalus depending on the infecting organism (highest risk with S. pneumoniae). Neuronal injury and irreversible focal or diffuse brain damage results from activation of host inflammatory pathways in response to the infection.
etiology of acute bacterial meningitis
Meningitis is primarily acquired in the community; however, meningitis can also be acquired nosocomially in certain patient types.
The microbiology of bacterial meningitis varies depending on the age of the patient and the presence of underlying conditions (e.g. recent head trauma, neurosurgery, etc.).
acute bacterial meningitis most likely causative pathogen
HSN
H. influenzae, Strep pneumo, N. meningitidis
H. infuenzae is prevented by Hib vaccine
H. influenzae acute bacterial meningitis
Since the introduction of Hib vaccine in 1980, a > 90% decrease has been observed in the incidence of invasive H. influenzae type b disease in children less than 5 years - a vaccine-preventable disease!***
-Prior to 1985, H. influenzae accounted for up to 45% of all cases of meningitis in children in the US compared to only 7% in 1995.
In children > 3 years old and adults, meningitis due to H. influenzae may indicate a parameningeal focus of infection (middle ear infection, paranasal sinus infection, CSF leak).
Neurologic sequelae develop in 35% of patients (e.g., seizures, deafness, mental retardation).
Lowest case fatality rates = 3 to 6%.
Coma and seizures observed early in the course of infection
Neisseria meningitdis acute bacterial meningitis
Predominant pathogen in children and young adults; can occur in clusters** (college dorms, high schools, military).
Most cases occur in the winter and spring, and the source is usually an asymptomatic carrier (spread by person-to-person contact).
5 serogroups are primarily responsible: A, B, C, Y, W-135.**
May be rapidly progressive; overall mortality rate is 3 to 13%.**
Meningococcemia – a systemic reaction characterized by a petechial or purpuric rash** (> 50%); fever; arthritis; disseminated intravascular coagulation (DIC) with widespread thrombosis; and hearing loss (10.5%) due to damage of sensory nerves.
strep pneumo acute bacterial meningitis
The most frequent cause of bacterial meningitis, especially in children and adults older than 30 years of age.
Highest case fatality rate = 19 to 26%.**
Risk factors: pneumonia, endocarditis, CSF leak secondary to head trauma, anatomic or functional asplenia, alcoholism, sickle cell disease, bone marrow transplant, uncontrolled sinusitis/otitis media/mastoiditis.
Commonly associated with decreased sensorium and neurologic sequelae (> 50% in adults) including seizures, facial palsy, visual field defects, hemiparesis, hearing impairment or loss (31%), focal neurologic deficits, learning disabilities, and mental retardation.
gram-negative bacilli acute bacterial meningitis
Increasing in incidence as a cause of bacterial meningitis over the last 20 years in both adults and children - is now the 4th leading cause of bacterial meningitis.
Predisposing factors include congenital defects of the CNS, penetrating head trauma, previous neurosurgery, use of antibiotics with Gram positive activity preoperatively in neurosurgical cases, diabetes, urinary tract infections in neonates or the elderly, and malignancy.
Elderly debilitated patients are at increased risk, where the classical signs and symptoms of meningitis may be subtle.
listeria monocytogenes acute bacterial meningitis
Causative organism in approximately 2% of cases; incidence peaks in summer and early fall.
Case fatality rate ≈ 15%
Primarily affects neonates, alcoholics, immunocompromised adults (e.g., HIV infection, transplant, etc.), and older adults/elderly (>50 years old).
Transmission usually involves colonization of the patient’s GI tract with the organism → sources include contaminated cole slaw, unpasteurized milk, cheese, ready-to-eat foods, lunchmeat, raw beef and poultry
clinical presentation of acute bacterial meningitis
On initial presentation, it is often difficult to differentiate between bacterial, viral, fungal, or tuberculous meningitis.
The clinical signs and symptoms** of acute bacterial meningitis are variable and
dependent on the patient’s age:
Adults – present with classic symptoms that are abrupt** in onset: Fever, Nuchal rigidity (stiff neck), Severe headache (“worst headache of my life”), Altered mental status, Nausea and vomiting, Kernig’s, Brudzinski’s sign, photophobia, Cranial nerve palsies, Seizures, focal neurologic deficits (later)
Young infants – may present with only nonspecific symptoms; Fever, Vomiting, Irritability, High-pitched crying, Altered sleep patterns, Decreased oral intake, Seizures, Bulging fontanelle
Children – more CNS-specific clinical presentation; Changes in activity level, Confusion, Somnolence, lethargy, Seizures
Elderly – lack the typical clinical signs and symptoms of infection; Low-grade fever, Change in mental status (drowsiness, lethargy), Nuchal rigidity (may be hard to detect due to cervical arthritis)
CSF examination for diagnosis of acute bacterial meningitis
3 tubes of CSF are obtained via lumbar puncture (LP) as soon as the diagnosis of meningitis is suspected.
-An elevated opening pressure* (> 200-500mm H2O) is often observed due to cerebral edema, intracranial suppurative infection, or hydrocephalus.
In patients presenting with papilledema, new-onset seizures (within one week), focal neurologic deficits (signifying a space-occupying lesion), history of CNS disease (stroke, mass lesion, focal infection), and impaired consciousness, a CT scan or MRI of the brain may be performed BEFORE the LP (do not delay initiation of antibiotic therapy while waiting for results).
The CSF is evaluated for chemistry* (chemical composition), hematology* (presence of WBCs), and microbiology* (Gram stain and culture)
-Chemistry Results
—CSF characteristics - usually cloudy
—Glucose concentrations less than 50% of simultaneous serum glucose concentrations (under 40 mg/dl) suggest bacterial meningitis* and values under 30 mg/dl are suggestive of bacterial, fungal, or TB meningitis → due to ↑ glycolysis of brain cells adjacent to CSF and inhibition of membrane transport system
—Protein ≥ 100 mg/dl suggests bacterial meningitis
Hematology Results:
—WBC count > 400 WBCs/mm3 suggests bacterial meningitis
—WBC Differential with a predominance of neutrophils (> 50%) suggest bacterial meningitis
Microbiology Results
-Gram stain of centrifuged sediment – most rapid
—Usually positive* in acute bacterial meningitis
—May be negative in partially-treated meningitis or nonbacterial meningitis
Culture and susceptibility testing - usually positive
Additional studies:
—Latex fixation, latex agglutination, or ELISA to detect S. pneumoniae, N. meningitidis, and H. influenzae
—Biofire PCR Meningitis/Encephalitis panel
—Acid-fast stain, AFB culture, PCR → M. tuberculosis
—PCR for Herpes simplex, Enterovirus, West Nile Virus, etc.
—Cryptococcal antigen, India ink stain, fungal culture → Cryptococcus neoformans
components of bacterial CSF fluid
WBC: 400-5000
differential: over 80% PMNs
Protein: 100-500
Glucose: less than 1/2 serum
