Central Nervous System Infections

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Acute Bacterial Meningitis

Classic symptoms of meningitis include headache, fever, and neck stiffness. Common organisms include Streptococcus pneumoniae, Neisseria meningitis and Haemophilus influenzae.

Symptoms and clinical signs in young infants may be subtle and non-specific, including fever, lethargy, irritability, vomiting or a bulging fontanelle. Neck stiffness may not be present.

Empirical therapy should be commenced without delay.

Antimicrobial 

Ceftriaxone 2g (child 50mg/kg) IV BID

PLUS

Dexamethasone 10mg (child 0.15mg/kg) IV QID for 4 days

If immunocompromised, over 50 years old, or neonate, to cover the possibility of Listeria, ADD:

Benzylpenicillin 4 million IU (2.4g) (child 100 000 IU (60mg)/kg) IV Q4H

Alternative:

If ceftriaxone is unavailable use:

Cefotaxime 2g (child 50mg/kg) IV QID

OR

Chloramphenicol 1g (child 25mg/kg) IV QID

OR

Meropenem 2g (child 40mg/kg) IV TID

If benzylpenicillin is unavailable and patient is at risk of Listeria use:

Ampicillin 2g (child 50mg/kg) IV Q4H

(No need to add additional listeria cover if meropenem is used)

Comments and Duration of Therapy 

Perform blood cultures on all patients prior to antibiotics. Lumbar puncture should be performed for CSF protein, glucose, microscopy, and culture, wherever possible, ideally prior to antibiotics, however treatment should not be delayed if there is difficulty obtaining CSF.

Raised intracranial pressure is generally a contraindication to performing lumbar puncture. Raised intracranial pressure may cause coma or focal neurological signs. Fundoscopy and CT (to rule out a space occupying lesion) can be performed prior to lumbar puncture, if there are concerns.

CNS tuberculosis is an important differential diagnosis. If patient has chronic meningitis symptoms with persisting headache or patient is immunocompromised, also consider cryptococcal meningitis. Request Cryptococcal antigen on CSF or blood if this is suspected.

See Neonatal Meningitis in Paediatric Infections (Neonates, Infants and Children).

Meningitis following penetrating head trauma or neurosurgery

Common organisms include Staphylococcus aureus, coagulase-negative Staphylococci, and gram-negative bacilli including Pseudomonas aeruginosa.

Antimicrobial 

Meropenem 2g (child 40mg/kg) IV TID

PLUS

Vancomycin loading dose 25-30mg/kg IV, then dose according to Vancomycin dosing section.

Comments and Duration of Therapy

Perform blood cultures on all patients, obtain CSF where possible. Direct antibiotics once culture results are available.

Neisseria meningitidis Meningitis

Antimicrobial 

Ceftriaxone 2g (child 50mg/kg) IV BID

If penicillin susceptible use:

Benzylpenicillin 4 million IU (2.4g) (child 100 000 IU (60mg)/kg) IV Q4H

Alternative:

Ampicillin 2g (child 50mg/kg) Q4H

Comments and Duration of Therapy 

Duration:

Treat for 5 days.
Stop empiric dexamethasone.

Streptococcus pneumoniae Meningitis

Antimicrobial 

Ceftriaxone 2g (child 50mg/kg) IV BID

If penicillin MIC <0.125mg/L use:

Benzylpenicillin 4 million IU (2.4g) (child 100 000 IU (60mg)/kg) IV Q4H

Alternative:

Ampicillin 2g (child 50mg/kg) Q4H

If penicillin MIC >0.125mg/L AND ceftriaxone MIC 1-2mg/L, in addition to ceftriaxone ADD:

Vancomycin, dose according to Vancomycin dosing section

Comments and Duration of Therapy 

Duration:

Treat for 10-14 days
Continue dexamethasone for 5 days

Haemophilus influenzae Meningitis

Antimicrobial 

Ceftriaxone 2g (child 50mg/kg) IV BID

If penicillin susceptible use:

Benzylpenicillin 4 million IU (2.4g) (child 100 000 IU (60mg)/kg) IV Q4H

Alternative:

Ampicillin 2g (child 50mg/kg) IV Q4H

Comments and Duration of Therapy 

Duration:

Treat for 7 days
Continue dexamethasone for 5 days

Listeria monocytogenes Meningitis

Antimicrobial 

Benzylpenicillin 4 million IU (2.4g) (child 100 000 IU (60mg)/kg) IV Q4H

Alternative:

Ampicillin 2g (child 50mg/kg) IV Q4H

After 3 weeks of IV therapy, in patients who are immunocompromised give:

Co-trimoxazole (adult >60kg 320mg/1600mg; adult 40-60kg 240mg/1200mg; child >1month 6mg/kg /30mg/kg) PO BID.

Comments and Duration of Therapy 

Duration:

Treat for 3 weeks IV. After this in patients who are immunocompromised change to oral antibiotics and treat for an additional 3 weeks. In patients who are not immunocompromised stop treatment at 3 weeks if well. Stop empiric dexamethasone.

 

Streptococcus agalactiae Meningitis

Antimicrobial 

Benzylpenicillin 4 million IU (2.4g) (child 100 000 IU (60mg)/kg) IV Q4H

Alternative:

Ampicillin 2g (child 50mg/kg) IV Q4H

Comments and Duration of Therapy 

Duration:

Treat for 2 weeks IV. Extend duration to 3 weeks in complicated infection. Stop empiric dexamethasone.

Cryptococcus Meningitis

Cryptococcal meningitis should be suspected in patients who present with subacute or chronic symptoms, particularly in patients who are immunosuppressed. It can also present as an intracerebral mass.

Request Cryptococcal antigen on blood and/or CSF.

Seek Infectious Diseases review where available.

Test all patients for HIV.

See Timor-Leste Comprehensive ART Guidelines

Antimicrobial 

Induction:

Fluconazole 1200mg (child 12mg/kg) IV / PO OD

THEN

Consolidation:

Fluconazole 800mg (child 6-12mg/kg) PO OD.

THEN

Eradication:

Fluconazole 200mg - 400mg (child 6mg/kg) PO OD

In patients with Cryptococcomas:

Extend duration of induction to at least 6 weeks.
Following induction treat with fluconazole 400mg-800mg (child 6mg/kg) for 12 to 18 months.

In patients with HIV, who are asymptomatic, and have a negative CSF, but serum CrAg is positive:

Fluconazole 400mg (child 6 mg/kg) PO OD ART can be started without delay.

Continue until patient is on ART AND has a CD4 count >100 cells/microL for at least 3 months

Comments and Duration of Therapy

Raised intracranial pressure (ICP):

Daily lumbar punctures should be performed to manage raised ICP due to Cryptococcal meningitis, until the patient is asymptomatic and CSF pressure is normal (<20cm).
In symptomatic patients with CSF pressure
50cm aim to reduce intracranial pressure by 50% of the opening pressure.

There is no role for acetazolamide, or mannitol to reduce intracranial pressure in cryptococcal meningitis.

There is no role for corticosteroids to reduce intracranial pressure in cryptococcal meningitis except in the setting of IRIS or cerebral oedema surrounding a cryptococcoma.

Duration:

Induction: At least 2 weeks. Extend if no clinical improvement, or if CSF sterilization not achieved (i.e. CSF cultures still grow cryptococcus at 2 weeks).

Consolidation: At least 8 weeks. Extend if slow clinical response, CSF sterilization not achieved by 2 weeks, or ART delayed by >10 weeks.

Eradication: At least 12 months.

In HIV delay commencement of antiretroviral therapy (ART) until 2-10 weeks after antifungal therapy has started.
After 12 months fluconazole can be stopped if the patient is on ART, with a CD4 count >100 and an undetectable viral load.

Encephalitis

Encephalitis is an infection of brain tissue that presents with a level of brain dysfunction and signs of infection such as fever. In the setting of meningoencephalitis it can often be difficult to differentiate between viral and bacterial causes, particularly if there are no typical associated features. If there is uncertainty it is important to also commence empirical antibiotics early (see Acute Bacterial Meningitis in Central Nervous System Infections).

VZV encephalitis should be suspected if associated with a typical rash (see Zoster / Shingles in Skin and Soft Tissue Infections).

Antimicrobial 

Acyclovir 10mg/kg (child < 5 years 20mg/kg, 5-12 years 15mg/kg, >12 years use adult dosing) IV TID

Alternative (not preferred):

Acyclovir 400mg PO 5 times a day

Consider empiric treatment for Listeria if at risk. See Acute Bacterial Meningitis above.

Consider Toxoplasma encephalitis in immunocompromised patients. See Toxoplasma gondii in Special Infections.

Comments and Duration of Therapy

As it is difficult to differentiate clinically between viral and bacterial causes of CNS infection perform blood cultures, and lumbar puncture where safe to do so.

Many other disorders can mimic viral encephalitis and are also worth considering. This may include cerebral Toxoplasmosis (particularly if HIV positive), Tuberculosis or Anti-NMDAR encephalitis.

Many viruses such as Japanese encephalitis and Nipah virus cannot be treated with antivirals and should be managed with supportive care alone if diagnosis can be confirmed.

Duration:
If Herpes simplex (HSV) encephalitis is confirmed, or cannot be ruled out, treat with acyclovir for 14 to 21 days.

See also Dendritic corneal ulceration caused by Herpes Simplex virus in Eye Infections, Genital Herpes simplex virus in Genital Infections, Neonatal Herpes simplex prophylaxis / treatment in Paediatric Infections (Neonates, Infants and Children), and Herpes Simplex in Skin and Soft Tissue Infections

Brain abscess and Subdural Empyema

Often polymicrobial and requires surgical consultation.

Consideration of the source of spread is necessary but not always successful. Potential sources include paranasal sinusitis, otitis media, malignant otitis externa, dental infection, endocarditis, or penetrating trauma. Organisms may include anaerobes, Streptococcus and Gram-negative bacteria. Subdural empyema commonly occurs as a consequence of bacterial meningitis or frontal sinus infection.

Antimicrobial 

Ceftriaxone 2g (child 50mg/kg) IV BID

PLUS

Metronidazole 500mg (child 12.5mg/kg) IV TID

If multiple abscesses or probable haematogenous spread ADD:

Cloxacillin 2g (child 50mg/kg) IV QID

OR

If increased risk of MRSA (recent prolonged or frequent hospital admission, prior colonization with MRSA).

Vancomycin IV, dose according to Vancomycin dosing section dosing section

For brain abscess after penetrating trauma or neurosurgery treat Meningitis following penetrating head trauma or neurosurgery (for duration follow Brain abscess and Subdural Empyema)

Comments and Duration of Therapy 

Surgical drainage is required. If present, infected sinus or ear should be drained and infected bone removed where possible. Send blood cultures, and tissue for culture and TB testing. Send Cryptococcal antigen. Change antibiotics according to culture results.

Seizures are frequent and prophylactic anticonvulsants should be given

In those who are immunocompromised consider other diagnoses including Toxoplasmosis, Cryptococcosis, Nocardiosis, and TB. Malignancy should also be considered if there is no improvement with empiric therapy.

Duration:

Treat for 6-8 weeks with a minimum of 2-4 weeks IV. If used, oral antibiotics should have good CNS penetration (e.g. Co-trimoxazole, fluoroquinolones). Do not use oral beta-lactams. IV treatment should be extended if surgical drainage cannot be performed.

Tuberculoma / Tuberculous Meningitis (Adult)

Antimicrobial 

See Timor-Leste Comprehensive TB Guidelines for National Tuberculosis Program.

To standard RHZE regime add corticosteroids for 6-8 weeks.

Comments and Duration of Therapy 

Test all patients for HIV.
In patients with HIV and TB meningitis delay ART for 8 weeks after commencement of TB treatment. Monitor for IRIS

Duration:

Treat for 9-12 months
Wean corticosteroids, and stop after 6-8 weeks

Epidural abscess

Epidural abscesses are most commonly caused by Staphylococcus aureus. Tuberculosis is an important differential diagnosis in high prevalence settings like Timor-Leste.

Antimicrobial 

Cloxacillin 2g (child 50mg/kg) IV QID

PLUS

In adults only: Ceftriaxone 2g IV BID

If increased risk of MRSA (recent prolonged or frequent hospital admission, prior colonization with MRSA) ADD:

Vancomycin, dose according to Vancomycin dosing section.

Comments and Duration of Therapy

Take two sets of blood cultures prior to antibiotics.
Perform CT or MRI for diagnosis.
Change antibiotics according to culture results. If no microbiological diagnosis is obtained modify antibiotics according to the most likely cause of infection.

Duration:

Treat for at least 6 weeks, with a minimum of 2-4 weeks IV.

Neurocysticercoses

Caused by the larval stage of the pork tapeworm Taenia solium.
Patients with neurocysticercosis often present with seizures. Use of albendazole reduces long-term seizure frequency in patients with active lesions. Corticosteroids should always be administered with antiparasitic therapy. Corticosteroids should also be used in the treatment of cysticercal encephalitis.

Antimicrobial 

If antiparasitic treatment is indicated (see comments) USE:

Albendazole 7mg/kg (maximum dose 600mg) PO BID

PLUS

Dexamethasone 0.1mg/kg PO OD

OR

Prednisone 1mg/kg PO OD

(begin steroids one day before antiparasitic)

Patients should also be commenced on anti-epileptic treatment.

Comments and Duration of Therapy 

Diagnose based on consistent clinical picture and radiology (CT and/or MRI). Serologic testing is not currently available in Timor.
All patients should be evaluated for ocular cysticercosis by ophthalmology.
Only treat patients with active lesions. Patients with calcified cysts and no active cysts do not benefit from treatment. Do not give antiparasitic therapy to patients with untreated hydrocephalus, ocular cysticercosis or high cyst burden disease with diffuse cerebral oedema, as inflammation around the degenerating cysts may worsen symptoms.

Oedema surrounding active lesions may cause raised intracranial pressure; this should be managed with corticosteroids.

Duration:

Treat for 10 days

References

Chang C, Hall V, Cooper C, Grigoriadis G, Beardsley J, Sorrell T, et al. Consensus guidelines for the diagnosis and management of cryptococcus and rare yeast infections in the haematology/oncology setting, 2021. Intern Med J 2021; 51 (Suppl. 7): 118-142

Chen S, Sorrell T. Cryptococcus gattii infection: treatment. In: Kauffman C, Mitty J, editors. UpToDate [internet]. Waltham (MA): UpToDate Inc; 2019. https://www.uptodate.com/contents/cryptococcus-gattii-infection-treatment?search=cryptococcoma&source=search_result&selectedTitle=3~16&usage_type=default&display_rank=3#H16486381

Cox G, Perfect J. Cryptococcus neoformans meningoencephalitis in patients with HIV: treatment and prevention. In: Bartell J, Bogorodskaya M, editors. UpToDate [internet]. Waltham (MA): UpToDate Inc; 2021. https://www.uptodate.com/contents/cryptococcus-neoformans-meningoencephalitis-in-patients-with-hiv-treatment-and-prevention?search=cryptococcal%20meningitis&source=search_result&selectedTitle=3~79&usage_type=default&display_rank=3

Cox G, Perfect J. Cryptococcus neoformans: treatment of meningoencephalitis and disseminated infection in HIV seronegative patients. In: Kauffman C, Kaplan S, Bogorodskaya M, editors. UpToDate [internet]. Waltham (MA): UpToDate Inc; 2019. https://www.uptodate.com/contents/cryptococcus-neoformans-treatment-of-meningoencephalitis-and-disseminated-infection-in-hiv-seronegative-patients?search=cryptococcal%20meningitis&topicRef=2447&source=see_link#H1351839573

eTG complete. Central Nervous System Infections. In: Therapeutic Guidelines [digital]. Melbourne: Therapeutic Guidelines Limited; 2019. http://www.tg.org.au

Gusmao dos Santos C, Francis J, Guterres J, Janson S, Lopes N, Marr I, et al. HNGV Antibiotic guidelines writing group. Antibiotic guidelines Hospital Nacional Guideo Valadares. Timor-Leste; 2016

Kurniawan M, Suharjanti I, Pinzon R, editors. Panduan Paktik Klinis Neurologis. Indonesia: PERDOSSI; 2016

National HIV/AIDS programme Timor-Leste. Guidelines for antiretroviral therapy and management of opportunistic infections for children, adolescents and adults living with HIV. Timor-Leste: Ministerio da Saude; 2021

Ropper A, Samuels M, editors. Infection of the Nervous System (bacterial, fungal, spirochetal, parasitic) and sarcoidosis. In: Adams and Victor’s Principles of Neurology. 9th ed. New York: McGraw Hill; 2014

Samuels M, Ropper A, editors. Samuel’s Manual of Neurological Therapeutics. 8th ed. Philadelphia: Lippincot Williams and Wilkins; 2010

Scheld M, Whitley R, Marra C, editors. Infections of the central nervous system. 3rd ed. Philadelphia: Lippincot Williams and Wilkins; 2004

White C. Cysticercosis: Treatment. In: Weller P, Baron E, editors. UpToDate [internet]. Waltham (MA): UpToDate Inc; 2021. https://www.uptodate.com/contents/cysticercosis-treatment?search=neurocysticercosis&source=search_result&selectedTitle=2~24&usage_type=default&display_rank=2

Yeager C, Koffman L, Bleck T, editors. Treatment of infectious meningitis and encephalitis in neurocritical care unit. In: Nelson S, Nyquist P, editors, Neurointensive care unit: clinical practice and organization. Switzerland: Humana Press; 2020