Management of Intracranial Infections

• Intracranial infections include MENINGITIS, ENCEPHALITIS, VENTRICULITIS, CEREBRAL ABSCESS, EPIDURAL ABSCESS, SUBDURAL EMPYEMA and present almost always to the emergency room.
• These conditions often require admission to an ICU and they have significant morbidity and mortality.
• These could be community-acquired, nosocomial, or could follow neurosurgical procedures (craniotomy, VP shunting, invasive neuromonitoring techniques).
• Reducing morbidity and mortality is critically dependent on rapid diagnosis and timely initiation of appropriate antimicrobial therapy.

• Various organisms have been implicated in CNS infections:
  • Bacteria
  • Viruses
  • Protozoa
  • Helminthes
  • Prion

Acute Bacterial Meningitis

• Neonates: Group B streptococcus, E. coli
• 4-12 weeks: Group B streptococcus, Listeria monocytogenes
• 3 months-5 years: H. Influenzae, S. pneumoniae, N. meningitidis
• Older than 5 years: S. pneumoniae, N. meningitidis
• Hospital acquired/post neurosurgical: Staph aureus, mixed infection

Acute Community Acquired Viral Meningitis

• Enteroviruses - most common
• Adenovirus
• Arbovirus
• Herpes Simplex virus
• Varicella Zoster virus

Encephalitis

• Encephalitis is an acute inflammation of the brain parenchyma, and it is most commonly caused by viruses such as mumps, herpes simplex virus (HSV), cytomegalovirus (CMV), varicella zoster virus (VZV), enteroviruses, togaviruses (eastern and western equine viruses), and lymphocytic choriomeningitis virus. Other recently emerged viral encephalitis include; West Nile virus (WNV - the most common arboviral encephalitis in the US transmitted by mosquitoes) and monkeypox in North America, and Chandipura viruses in the developed world.
• An increase in encephalitis caused by CMV, Epstein-Barr virus (EBV), and human herpes virus (HHV-6) has occurred because of an increase in immuno-compromised states, including HIV, organ transplantation, and cancer chemotherapy.
• Other microorganisms that can cause encephalitis include protozoa, such as Toxoplasma gondii, and bacteria, such as Listeria monocytogenes and Mycobacterium tuberculosis.

Ventriculitis

• It often complicates meningitis but it can occur as a primary process.
• It is frequently associated with the presence of a CSF shunt, external ventricular drainage (EVD), or other intracranial device.
• The risk of developing a ventriculitis or meningitis with an EVD in place is 10-15% (and up to 40%).
• The most common pathogens involved in EVD and CSF shunt infections are gram-positive organisms, such as Staphylococcus epidermidis and Staphylococcus aureus.
• As many as 25% of infections, however, are caused by gram-negative organisms, such as E. coli, Klebsiella spp., Acinetobacter, and Pseudomonas spp.
• These organisms should be suspected in patients with a ventriculo-peritoneal shunt, as a result of contamination of the peritoneal end of the catheter.

Cranial Epidural Abscess

• The most common infectious etiologies include streptococci, staphylococci, and anaerobes, and infections are often polymicrobial.

Subdural Abscess

• Unlike the epidural space, the subdural space is less restrictive, resulting in a wider spread of empyema, which can cause inflammation of the brain parenchyma (when it breaches the subarachnoid space), edema, mass effect, elevated intracranial pressure (ICP), septic thrombophlebitis, and venous infarction.
• Subdural empyema is associated with a much more complicated course and worse outcome when compared with epidural abscess.

Pathogenesis

• Infective microorganisms reach and establish themselves in the CNS via one of the following means:
  • Direct Spread
    • From infected contiguous structures such as the scalp, nasal cavity, paranasal sinuses, middle ear, and dental apparatus.
    • This is facilitated by retrograde spread through valveless emissary veins.
  • Haematogenous Spread
    • Also described as “metastatic” spread, if there is an abscess already established elsewhere in the body.
    • Examples include congenital cyanotic heart disease (with right to left shunt), osteomyelitis.
  • Direct Inoculation
    • Following trauma or surgical interventions.

• Invasive infections of the CNS begin with entry of bacteria into the subarachnoid space (or brain parenchyma).
• Bacteria responsible for meningitis attach to the nasopharyngeal epithelium and are nearly all capable of secreting IgA proteases that prevent their destruction and allow them to traverse the epithelium and invade the intravascular space. Interactions between the bacterial capsular polysaccharide coat and complement regulatory proteins protect pathogenic bacteria from the complement system, increasing their ability to cross the blood-brain barrier (BBB) and enter the cerebrospinal fluid (CSF).
• The CNS is an area of impaired host resistance.
• Within the CNS, a relatively low concentration of immunoglobulin and weak complement-mediated host defenses enables bacterial replication. Because levels of complements, immunoglobulins, and polymorphonuclear leukocytes are lower in the CSF than the serum, opsonic activity is inferior, mandating the use of bactericidal as opposed to bacteriostatic agents.

Pathophysiology of Cerebral Abscess

• There are four stages in abscess formation following brain parenchymal inoculation:
  • Early Cerebritis (Day 1-3)
  • Late Cerebritis (Day 4-9)
  • Early Capsule Formation (Day 10-14)
  • Late Capsule Formation (Beyond day 14)

• Inoculation of bacteria into brain parenchyma results in focal inflammation and edema (early cerebritis) which develops in the first 1-3 days. Typically, there is neutrophil accumulation, edema, and some tissue necrosis. Astrocytes and microglia are activated early on, and this activation persists afterward.
• The area of cerebritis expands and a necrotic center develops (late cerebritis) on days 4 to 9. Macrophages and lymphocytes predominate in the infiltrate.
• The early capsule stage is characterized by the development of a capsule that is vascularized and ring enhancing on CT scan on days 10-14.
• In the late capsule stage, the host immune response causes the capsule to wall off, and there is destruction of some surrounding healthy brain tissue in an attempt to sequester the infection.

Bacterial Meningitis

• Symptoms: Sensitivity
  • Fever - 85%
  • Neck pain/stiffness - 70%
  • Altered mental status - 67%
  • Headaches - 50%
  • Nausea and vomiting - 30%
  • Photophobia
• Highlighted features constitute the classic triad found in 40-45% of cases. About 95% of cases have at least two of the first four symptoms.

Other symptoms include:

• Focal neurologic deficits/nerve palsies including gaze palsies caused by hydrocephalus
• Seizures, 5-28% of cases (indicates cortical irritation, which may be caused by a cortically based complication, e.g., empyema, stroke, or venous thrombosis)
• Coma, from cerebral edema and herniation in the fulminant type
• Multiple cerebral infarcts secondary to vasculitis
• Septic shock (22%)

Other manifestations of meningitis may provide clues to the causative organism:

• Petechial or purpural rash in meningococcal meningitis
• Ataxia and labyrinthitis in Haemophilus influenzae meningitis

Tuberculous Meningitis

• Cough, weight loss, night sweats, and cranial nerve deficits in TBM
• Visual impairment or blindness
• Painful ophthalmoplegia

Viral Encephalitis

• Clinical presentation often includes a prodrome with fever, headache, myalgia, and mild respiratory infection. Altered consciousness with focal neurologic deficits may follow, as well as seizures.
• Specific viruses can have characteristic presentations, such as parotitis associated with mumps and herpetic rash with herpes simplex encephalitis (HSE). Diplopia, dysarthria, and ataxia can be seen in immunocompromised patients with brainstem HSE.

Herpes Simplex Encephalitis (HSE)

• HSE is the most important form of treatable encephalitis. It has a predilection for the temporal and orbitofrontal lobes and results in a clinical picture of altered consciousness, memory loss, personality change, and confusion or olfactory hallucinations, following a prodrome of headache and fever.

Brain Abscess, Epidural, and Subdural Empyema

• Intracerebral/Brain Abscess:
  • Spread from contiguous structures/post-op incision sites – direct and via valve-less veins (face, sinuses, ear infections)
  • Focal neurologic symptoms & signs: aphasia, paralysis, gait disturbances
  • Classical triad of fever, headaches, neurologic deficit is present only in 25%
  • Fever is less common than in meningitis

Pott’s Puffy Tumor

• Frontal bone osteomyelitis with sub-periosteal abscess
• Spread from frontal sinusitis, contiguous structures, intracranial abscess
• Fluctuant, tender scalp swelling with erythema
• Described by Percival Pott in 1760

• CSF Analysis through LP, Ventricular tap, or shunt tap
• Avoid LP if raised ICP is suspected (coning!!!)

• CSF Biochemistry (protein and glucose)
• CSF Microscopy, Culture, Sensitivity (MCS)
• CSF AAFB and Lowenstein Jensen medium culture (Tuberculous meningitis)
• CSF Indian ink test (Fungal Meningitis)

CSF Parameter	Normal	Bacterial	Viral
Opening pressure (mm H2O)	60-180	200-500	<250
WBC (/mm³)	<5	>1000	50-1000
WBC differential	-	Neutrophils	Lymphocytes
Glucose (mg/dL)	45-80	<40	>40
CSF: Blood glucose ratio	>0.6	<0.4	>0.6
Protein (mg/dL)	-	100-500	<200

• Neuroimaging: Brain CT Scan or MRI with contrast (may also reveal sinusitis/mastoiditis)
• CT or MR venography should be considered to diagnose complicating cerebral venous sinus thrombosis
• Early cerebritis stage
• Acute inflammatory infiltrate with visible bacteria on Gram stain and marked edema surrounding the lesion.
• No contrast enhancement
• late cerebritis stage
• The center of the lesion becomes necrotic,
• macrophages and fibroblasts invade the periphery.
• proliferate blood vessel surrounding lesion
• early capsule formation
• The center of the lesion becomes necrotic,
• macrophages and fibroblasts invade the periphery.
• proliferate blood vessel surrounding lesion
• late capsule formation
• the collagenous capsule was complete circumferentially
• increased in density and thickness
• inner inflammatory layer
• middle collagenous layer
• outer gliotic layer

• Blood cultures in the presence of meningitis are positive in up to 50% of cases, and a touch preparation of the rash in meningococcal meningitis yields a positive Gram’s stain in 70% of cases.
• Serum Electrolytes: Hyponatremia caused by syndrome of inappropriate antidiuretic hormone (SIADH) is common in both meningitis and encephalitis.

• Aggressive treatment
• May need ICU care
• Antibiotic
• Steroid
• +/- anticonvulsant
• Drain abscess

Meningitis

• Start antibiotics empirically. A knowledge of prevalent and most likely causative organism is necessary.
• Antibiotic doses are higher for CNS infections (meningitic doses).

Host	Pathogens	Preferred Abx (see dosing table)	Alternative for serious PCN allergy, i.e., anaphylaxis (ID)
Immunocompetent, age < 50*	S. pneumonia, H. influenzae	Ceftriaxone PLUS Vancomycin	Vancomycin PLUS Meropenem
Immunocompetent, age > 50*	S. pneumonia, Listeria monocytogenes, N. meningitidis, H. influenzae Group B streptococcus	Ceftriaxone PLUS Ampicillin	Vancomycin PLUS Meropenem OR TMP/SMX PLUS Meropenem
Immunocompromised*	S. pneumonia, N. meningiditis, H. influenzae, Listeria	Vancomycin PLUS Cefepime PLUS Ampicillin	Vancomycin PLUS Meropenem PLUS TMP/SMX
Post-neurosurgery or penetrating head trauma	S. pneumo (if CSF leak) H. influenzae, Staphylococci (MRSA, CoNS), Gram-negatives	Vancomycin PLUS EITHER Cefepime OR Meropenem	Vancomycin PLUS Meropenem
Infected Shunt	S. aureus, CoNS, P. acnes, gram-negatives (rare)	Vancomycin PLUS Cefepime	Vancomycin PLUS Meropenem

• In patients with HIV infection, non-bacterial causes of meningitis must be considered, particularly cryptococcal meningitis.

Recommended Doses of Select Antimicrobial Agents for Treatment of Meningitis in Adults with Normal Renal and Hepatic Function

• Ampicillin 2 g q4h
• Aztreonam 2 g q6h
• Cefepime 2 g q8h
• Ceftriaxone 2 g q12h
• Ciprofloxacin 400 mg q8h
• Meropenem 2 g q8h
• Metronidazole 500 mg q6h

Duration of Antibiotic therapy

• S. pneumoniae: 10-14 days
• N. meningiditis, H. influenzae: 7 days
• Listeria: 21 days
• Gram-negative bacilli: 21 days

Viral Encephalitis

• Less virulent than bacterial meningitis
• Usually self-limiting (supportive management)
• HSV, VZV: Acyclovir 10 mg/kg IV q8h for 14-21 days

Brain/Epidural/Subdural Abscess

• Antibiotics, drainage +/- anticonvulsant, steroids
• Antibiotics should be adjusted based on culture results.
• Anaerobic coverage should ALWAYS continue even if none is grown.
• IV antibiotics for 2 weeks and oral for 6 weeks

Use of Dexamethasone

• Addition of dexamethasone is recommended in all adult patients with suspected pneumococcal meningitis.
• Dose: 0.15 mg/kg IV q6h for 2-4 days

• The management of patients who have CNS infections is challenging.
• Antimicrobial therapy and source control are keys in management.
• Early management is paramount.
• Long-term antimicrobial treatment.