CONTENTS
- Infectious disease history
- Clinical syndromes
- Blood tests to consider
- Lumbar puncture (LP)
- Specific risk groups
- Other related topics
- Podcast
- Questions & discussion
- Pitfalls
- Travel history?
- Sexual history?
- Substance use history?
- Contact with mosquitoes, ticks, or animals?
- Sick contacts?
- Recent infections, for example:
- Sinusitis, otitis, or dental infection?
- Endocarditis or bloodstream infection?
- Iatrogenic:
- Recent CNS procedures?
- Any indwelling hardware/devices?
- Recent skin lesions, for example:
- Herpes zoster, including several months prior?
- Target-shaped rash of Lyme disease?
- Immune status:
- Known HIV, or HIV risk factors?
- Malignancy, transplantation, or immunosuppressive medications?
- Duration of illness.
Some types of infection tend to present with characteristic clinical syndromes. These are explored in other chapters, including:
- Meningitis and encephalitis.
- Limbic encephalitis.
- Basal ganglia involvement.
- Brainstem encephalitis.
- Cerebellitis.
- Anterior horn of spinal cord.
- Blood cultures.
- HIV serology. (The CDC recommends screening patients as part of routine care; more on this here).
- PCR for tick-borne illnesses (e.g., anaplasmosis/ehrlichiosis; selection may depend on geographic location).📖
- C-reactive protein (CRP).
- If a fungal infection is suspected:
- Galactomannan and beta-D-glucan.
- Antigen testing for specific fungi (e.g., Histoplasma urine antigen; Blastomyces urine antigen; serum cryptococcal antigen).
- Autoimmune evaluation:
- Serum autoimmune encephalitis panel. (Some antibodies are easier to find in the CSF, whereas others are easier to find in the serum.)
- Serum testing for oligoclonal bands.
- Serum albumin and IgG level.
- Antinuclear antibody (ANA) with reflex extractable nuclear antigen autoantibodies (ENA) panel.
CSF labs for all patients with suspected infection:
- ✅ Cell count with differential.
- ✅ Protein.
- ✅ Glucose.
- ✅ CSF lactate level.
- ✅ Gram stain & bacterial culture.
- ✅ PCR for HSV and VZV.
- ❗️ Hold additional fluid for further tests PRN.
additional CSF labs to consider may include:
- Additional tests for infectious diseases:
- Cryptococcal antigen.
- Fungal culture.
- AFB (Acid-fast bacilli) culture and smear.
- PCR tests for additional viruses (e.g., JC virus; Enterovirus; West Nile virus).
- May-October: West Nile virus IgM, EEE (eastern equine encephalitis) antibody panel.
- PCR microarray if available (e.g., BioFire). CSF may be sent to Mayo Clinic for a meningitis/encephalitis panel (Test ID: CSFME).
- Additional autoimmune tests:
- Additional tests for malignancy:
- Cytology and/or flow cytometry.
obtain an opening pressure
- The opening pressure is potentially very helpful in this scenario and should be measured. In a supine position, the opening pressure will equal the patient's intracranial pressure (ICP). This can be converted from cm water to mm mercury using the following formula:
- ICP in mm = 0.7(Opening pressure in cm water).
- Opening pressure cannot be calculated in a patient who is sitting up.
- Further discussion of elevated intracranial pressure here: 📖
technique of performing lumbar puncture
- Obese patients with impalpable landmarks may require ultrasound-guided lumbar puncture with a long LP needle (videos of this are here and here).
CSF results can be categorized into patterns as shown below. This is obviously a gross oversimplification of reality. For example, the malignant/fungal pattern contains a diverse range of pathologies that can manifest with broadly varying CSF patterns. Nonetheless, general pattern recognition may be a useful initial approach to abnormal results.
normal CSF findings & some caveats
- White count: <5/uL.
- The normal cell count is 0-5 lymphocytes or monocytes per uL. Rarely a neutrophil (aka, polymorphonuclear cell) may be seen, but two or more should be considered abnormal.(Louis 2021)
- ⚠️ Cytopenias (e.g., neutropenia) or severe immunosuppression may cause pleocytosis to be absent in situations where it would be expected.(30273244)
- Differential: ~70% lymphocytes, ~30% monocytes, rare neutrophils or eosinophils.(33788511)
- ⚠️ Bacterial meningitis may cause a lymphocytic predominance in <10% of patients.(33788511)
- ⚠️ Viral meningitis or encephalitis may initially cause a neutrophilic pleocytosis that later transitions to a lymphocytic pleocytosis, but the cell count is rarely >1,000 white blood cells/mm3.(34623095) Low CSF lactate level 📖 may help identify the presence of viral infection in patients with neutrophilic predominance.
- Protein: <50-60 mg/dL 📖
- Glucose: >40-50% serum level, or >40 mg/dL (2.2 mM) 📖
- Lactate: 1.2-2.4 mM 📖
bacterial pattern
- CSF findings:
- White count: ⬆️⬆️ often 1,000-5,000/uL (>100,000/uL suggests rupture of an abscess into ventricles).
- Differential: Usually neutrophilic.
- Protein: ⬆️⬆️ ~80-500 mg/dL.
- Glucose: Usually decreased.
- Lactate: >3.5 mM. 📖
- Causes of CSF bacterial pattern:
- (1) Early meningeal response to any acute, aggressive meningeal infection:
- Most often: bacterial meningitis.
- This can occur with other types of infection (e.g., tuberculosis, fungal, viral including HSV, naegleria fowleri).
- (2) Parameningeal focus of infection (brain abscess, subdural empyema, epidural abscess).
- (1) Early meningeal response to any acute, aggressive meningeal infection:
- Differential diagnosis: Other causes of neutrophilic CSF:
- Additional comments:
- Some features are strongly suggestive of bacterial infection if present, as compared with viral infection (perhaps with >99% specificity):(2810603; 33788511)
- Glucose <34 mg/dL (<1.9 mM).
- Protein >220 mg/dL.
- CSF WBC count >2,000/uL.
- CSF neutrophil count >1,180/uL.
- In borderline cases, it may be helpful to repeat a lumbar puncture later on. Some patients may have an early neutrophilic response to a virus that later shifts to a lymphocyte-predominant pattern. CSF lactate measurement may likewise be useful in this situation.
- Some features are strongly suggestive of bacterial infection if present, as compared with viral infection (perhaps with >99% specificity):(2810603; 33788511)
viral pattern
- CSF findings:
- White count: Usually ⬆️, but <1,000/uL.
- Differential: Lymphocytic (but neutrophils may initially predominate).
- Protein: Often ⬆️, ~30-200 mg/dL.
- Glucose: Normal (but may be low in HSV, CMV, LCMV, enteroviruses, West Nile virus, eastern equine encephalitis, or mumps).
- Lactate: <3.5 mM. 📖
- Differential diagnosis is broad, including:
- Viral meningitis, encephalitis, or meningoencephalitis, especially:
- Enteroviruses are most common (e.g., coxsackieviruses, echoviruses).
- Herpesviruses (HSV, VZV).
- Arboviruses (e.g., West Nile Virus).
- Acute HIV.
- Partially treated bacterial meningitis.
- Endocarditis.
- Spirochetes (leptospirosis, Lyme 📖, syphilis).
- Rickettsia (Rocky Mountain spotted fever, ehrlichiosis).
- Drug-induced aseptic meningitis. 📖
- Paraneoplastic or postinfectious encephalomyelitis.
- Active demyelinating disease (e.g., ADEM (acute disseminated encephalomyelitis) 📖, most types of autoimmune myelitis 📖).
- Autoimmune (lupus, Behcet disease, Vogt-Koyanagi-Harada syndrome).
- Viral meningitis, encephalitis, or meningoencephalitis, especially:
- 🔑 A viral pattern doesn't mean that the patient has just “some virus” and thus requires no specific therapy. Diseases that deserve special attention here to avoid missing them: HSV, Lyme, syphilis, and HIV.
malignant/fungal pattern
- CSF findings:
- White count: ⬆️, usually <1,000/uL.
- Differential: Usually lymphocytic.
- Protein: ⬆️⬆️ ~80-500 mg/dL.
- Glucose: Often decreased.
- Lactate: May be increased, depending on the etiology. 📖
- Differential diagnosis includes:
- Malignancy (leptomeningeal carcinomatosis 📖).
- Tuberculosis 📖.
- Fungal meningitis 📖.
- Listeriosis.
- Selected viral pathogens that can cause hypoglycemia:
- WNV (West Nile virus), EEE (eastern equine encephalitis).
- HSV, CMV.
- LCMV (lymphocytic choriomeningitis virus).
- Mumps.
- Spirochetes (syphilis, or rarely lyme).
- Inflammatory:
- Neurosarcoidosis (~20% of patients have low glucose).
- Lupus cerebritis (~10% of patients have low glucose).
- CNS vasculitis.
- See further discussion of CSF hypoglycemia below: 📖
correction of erythrocyte count in a traumatic lumbar puncture
- Traumatic lumbar puncture will cause an increase in protein, RBCs, WBCs, and lactate. The ratio of elevation of these components should equal that present in the blood. As general rules of thumb:
- The WBC count will be elevated by 1 WBC for every 500-1,500 RBCs.(33788511) Sources disagree somewhat, but as a rough approximation, 1 WBC for every 750 RBCs may be reasonable (among patients with relatively normal RBC count).(Louis 2021)
- Protein will increase by ~1 mg/dL for every 1,000 RBCs (but these determinations must be made in the same CSF tube).(Mandell 2020)
- An online calculator may also be used to estimate the number of WBCs in the CSF prior to contamination with peripheral blood.
elevated CSF erythrocytes
- Causes of elevation include: traumatic tap, intracranial hemorrhage, Listeria, Naegleria fowleri, HSV or any other viral encephalitis that causes cortical tissue necrosis, leptospirosis, anthrax, tuberculous meningitis.
- 💡 Red blood cells themselves may decrease glucose and increase lactate levels. For correction of WBC and protein levels in a traumatic tap, see the section above.📖
CSF eosinophilia may suggest:
- Parasitic infection (e.g., neurocysticercosis, toxoplasmosis).
- Fungal infections (especially coccidioidomycosis).
- Rickettsial infection (e.g., Rocky Mountain spotted fever).
- Drug-induced meningitis or foreign material in the CNS (e.g., ventriculoperitoneal shunts).
- CNS vasculitis (e.g., granulomatosis with polyangiitis, polyarteritis nodosa).
- Hypereosinophilic syndrome.
- Malignancy (e.g., leukemia, lymphoma, primary CNS tumor).
- Neuromyelitis optica spectrum disorders.
normal protein level
- Normal protein level is below ~50-60 mg/dL.
- Normal protein levels tend to increase with age. Therefore, for patients >50 years old, the upper limit of normal should be 60 mg/dL.
- Mild elevation of CSF protein is nonspecific, occurring in a wide variety of CNS pathologies.
albuminocytological dissociation
- Albuminocytological dissociation may be defined as an elevated CSF protein despite normal leukocyte count (<5/uL) and erythrocyte count (<50/uL).
- Pathophysiological mechanisms for albuminocytological dissociation include:
- Intrathecal production of proteins (e.g., IgG).
- Blood-brain barrier dysfunction, or blood-nerve barrier dysfunction.
- Obstruction of CSF flow, or reduced CSF flow.
- About a third of patients may display some albuminocytological dissociation if elevated protein is defined simply as >45 mg/dL. However, if an age-adjusted cutoff is used for the protein level, this rate may decrease to ~7%.(30765408)
- Causes of albuminocytological dissociation are numerous, including most often:(30765408)
- Polyneuropathy (e.g., Guillain-Barre syndrome).
- Seizures.
- Intra-axial or extra-axial tumors.
- Encephalitis, inflammatory white matter disease, or myelopathy.
- Major stroke.
- Systemic infection without meningitis.
- Hydrocephalus or CNS shunt.
- PRES (posterior reversible encephalopathy syndrome).
- Benign headache.
- Following a CNS infection, protein may remain elevated for months (after other parameters have normalized).
causes of marked protein elevation (>500 mg/dL) include:
- Infection (especially bacterial).
- Guillain-Barre syndrome.
- ICANS (immune effector cell–associated neurotoxicity syndrome) due to CAR-T therapy. Protein may be >1,000 mg/dL.(33391257)
- Subarachnoid fluid block (Froin's syndrome) is likely if the protein is >1,000 mg/dL. Profoundly elevated protein may cause the CSF to clot.(Mandell 2020)
hypoglycorrhachia (low CSF glucose)
- This is often defined as either <40-50% of the serum glucose, or <40 mg/dL (<2.2 mM).
- 🔑 Hyperglycemia can mask the presence of abnormally low CSF glucose levels. Compare the CSF glucose with the serum glucose to help avoid missing abnormally low CSF glucose.
- CSF glucose levels equilibrate with blood levels within under an hour. Ideally, a blood glucose level should be measured within ~30-45 minutes of the lumbar puncture.(35665717)
causes of low CSF glucose include:(34623095; 34030191, Louis 2021)
- Infection:
- Bacteria.
- Tuberculosis.
- Fungi.
- Spirochetes (syphilis, Lyme).
- Selected viruses (mumps virus, HSV, CMV, lymphocytic choriomeningitis virus, West Nile virus, Enterovirus, eastern equine encephalitis).
- Parasitic infection.
- Malignancy:
- Leptomeningeal carcinomatosis (~40% of patients).
- CNS lymphoma (~10% of patients).
- Inflammatory conditions:
- Neurosarcoidosis (~20% of patients).
- Lupus cerebritis (~10% of patients).
- Subarachnoid hemorrhage (usually 4-8 days after ictus).
basics
- CSF lactate reflects lactate production within the central nervous system (lactate doesn't transport readily from the blood into the CSF).
- CSF lactate is generally utilized for the diagnosis of bacterial meningitis. However, there are numerous potential causes of elevated CSF lactate, so this value must always be interpreted within clinical context.
causes of elevated lactate (32404406)
- Bacterial meningitis:
- Lactate may be especially helpful following neurosurgery or external ventricular drain placement, which may alter the baseline CSF chemistries.
- Lactate is elevated in Listeria meningitis, which can be helpful because Listeria meningitis may occasionally cause an ambiguous pattern of conventional CSF results. (17509430)
- Other CNS infections:
- Tuberculous meningitis.
- Fungal meningitis.
- Seizures (especially status epilepticus and focal seizures with loss of consciousness).
- Stroke, SAH (subarachnoid hemorrhage).
- TBI (traumatic brain injury).
- Malignancy.
- Anoxic brain injury or hypoglycemic coma.
- Inherited metabolic disorders (especially mitochondrial disorders).
- Artificially elevated lactate values:
- Erythrocytes in the CSF sample.
- Delayed sample processing (with CSF sample left at room temperature).
role of CSF lactate in the diagnosis of bacterial meningitis
- Head-to-head comparisons reveal that lactate outperforms conventional CSF parameters for differentiation of viral versus bacterial infection. For example:
- Lactate measurement is recommended by meningitis guidelines from France, Europe, and the United Kingdom.(31402154, 26845731, 27062097)
- From an evidence-based medicine standpoint, lactate should be utilized more broadly in the evaluation for bacterial meningitis.
interpretation of the CSF lactate value
- Normal CSF lactate:
- A normal CSF lactate may be regarded as 1.2-2.1 mM(32404406) or 1.3-2.4 mM.(33788511)
- A normal CSF lactate level supports the decision to discontinue antibacterial therapies. This may be especially helpful in cases where the CSF parameters are ambiguous (e.g., early viral infection with a neutrophilic predominance may falsely raise concern for bacterial meningitis, leading to inappropriate antibacterial therapy).
- Lactate values in community-acquired bacterial meningitis:
- The optimal cutoff for diagnosing bacterial meningitis might be >3.5 mM or >3.8 mM. A lactate cutoff >3.5 mM has a sensitivity of 96-99% and a specificity of 88-94% for bacterial meningitis if obtained before antibiotic therapy begins.(32404406) However, bacterial meningitis has been reported with values as low as 3.2 mM.(31402154)
- ⚠️ Lactate may be reduced among patients who were previously treated with antibiotics (partially treated meningitis).(Nelson, 2020) However, a single dose of antibiotic prior to lumbar puncture is unlikely to affect the lactate value.(29490540)
- One general schema for interpreting lactate values in differentiating viral versus bacterial meningitis: 📄 (22203753)
- Lactate <3 mM suggests viral meningitis.
- Lactate 3-6 mM suggests partially treated bacterial meningitis.
- Lactate >6 mM suggests acute bacterial meningitis.
If basic CSF labs are concerning for infection, a PCR microarray such as BioFire may be ordered (if available). These microarrays test for multiple targets at once, with a rapid turnaround time. Targets include H. influenzae, Listeria, N. meningitidis, S. pneumoniae, CMV, HSV, VZV, and cryptococcus. Data below refer to BioFire, but it's likely that similar issues may apply to other microarray assays.(31760115, Marra 2022)
targets for CNS biofire
- Bacteria:
- Streptococcus pneumoniae.
- Haemophilus influenzae.
- Neisseria meningitidis.
- Listeria monocytogenes.
- Streptococcus agalactiae (Group B streptococcus).
- Escherichia coli K1.
- Viruses:
- HSV-1/2 (but sensitivity is limited, so a standard HSV-1/2 PCR should be sent).
- VZV.
- Enterovirus.
- HHV-6.
- CMV.
- Human parechovirus.
- Fungi:
- Cryptococcus neoformans / Cryptococcus gatii (but sensitivity is limited, so cryptococcal antigen should also be sent if there is concern for these pathogens).
sensitivity
- Overall sensitivity is favorable (e.g., ~90%).
- False-negative results may occur due to HSV-1/2, Cryptococcus, Enterovirus, or Listeria. Another cause of false-negative results is nosocomial meningitis (e.g., following neurosurgery), since the BioFire array isn't designed to look for nosocomial pathogens.
- Depending on the clinical scenario, the BioFire array may need to be supplemented with specific tests (e.g., dedicated PCR for HSV-1/2; cryptococcal antigen).
specificity
- Specificity is overall high (e.g., ~97%).
- False-positive results may occur due to Streptococcus pneumoniae or Streptococcus agalactiae.
- Positive results from some viral PCRs may be difficult to interpret in terms of invasive infection versus latent infection (e.g., CMV, HHV-6). These issues are discussed further in the sections on these individual pathogens.
basics
- Lumbar puncture carries a risk of spinal hematoma which may cause catastrophic spinal cord compression. The absolute risk of a clinically significant hematoma is unknown. The literature contains only 35 reports of spinal hematoma, but this is undoubtedly an underreported event.(30154234)
- Available evidence is not sufficiently robust to create any hard and fast rules. Thus, the risk vs. benefit calculus should be considered for each individual patient. Nonetheless, some general guidelines are helpful. The material below is based on a guideline by the Association of British Neurologists that specifically addresses lumbar puncture.(30154234) 📄
- 💡 It is important to consider the totality of any individual patient's coagulopathies. For example, neither a platelet count of 55,000, nor use of aspirin, nor severe uremia are contraindications to a lumbar puncture. However, the combination of all three risk factors should give the practitioner some pause.
coagulopathies
- Target a platelet count of >40,000.(30154234)
- Target an INR 1.4 or lower.(30154234)
- Coagulation testing is not necessarily required in a patient with no personal/family history of bleeding, no anticoagulant medications, no liver or renal failure, and no known hematologic disorder.(30154234) Most critically ill patients will have coagulation studies available, so this isn't usually an issue. However, in a patient who emergently requires a lumbar puncture it may be reasonable to proceed without checking coagulation studies, if the above criteria are met (especially if the platelet count is known but the INR is unknown).
medications that inhibit coagulation
- Above are the time intervals that medications should ideally be held prior to lumbar puncture.(30154234)
- ⚠️ Be careful about patients with renal dysfunction. For example, acute renal failure may cause accumulation of direct oral anticoagulants, which may linger for several days (well after many practitioners may have forgotten that the patient was originally on them).
- In urgent/emergent situations, it may be necessary to actively reverse certain coagulopathies (e.g., using prothrombin complex concentrates to reverse warfarin). Anticoagulant reversal is discussed further here: 📖
- Recent publications have suggested that antiplatelet agents may not cause a clinically significant risk of hematoma.(29573815, 31378231) If urgent lumbar puncture is clinically necessary, it may be reasonable to carefully perform it despite the presence of antiplatelet agents. If it is unclear whether the patient was compliant with antiplatelet therapy, platelet functional assays could be considered to evaluate this (discussed further here: 📖).
The infectious and noninfectious complications following organ transplantation vary depending on timing after transplant. Below is a rough guide to common neurological complications.(30273244)
first month after transplantation
- Infectious complications:
- CMV.
- HHV6 (bone marrow transplantation).
- Aspergillus.
- Toxoplasmosis.
- Candida (from intravenous catheters).
- Nosocomial bacterial infection.
- Noninfectious complications:
- Metabolic delirium.
- Seizures.
- PRES (often related to tacrolimus or cyclosporine).
- Parkinsonism (amphotericin B).
- Intracranial hemorrhage due to thrombocytopenia.
- Engraftment syndrome (bone marrow transplantation).
1-6 months after transplantation
- Infectious complications:
- Aspergillus.
- HSV.
- VZV.
- PML.
- EBV (causing post-transplantation lymphoproliferative disorder).
- Toxoplasmosis.
- HHV6 (bone marrow transplantation).
- Cryptococcus neoformans.
- Tuberculosis.
- Noninfectious complications:
- Acute disseminated encephalomyelitis (ADEM).
- Immune reconstitution inflammatory syndrome (IRIS).
- Graft versus host disease (GVHD).
6 months after transplantation
- Infectious complications:
- VZV.
- CMV.
- PML (progressive multifocal leukoencephalopathy, due to JC virus).
- EBV (causing post-transplantation lymphoproliferative disorder).
- Aspergillus.
- Mucor.
- Noninfectious complications:
- Secondary malignancy.
- Disease relapse.
- Demyelination.
- Immune reconstitution inflammatory syndrome (IRIS).
- Graft versus host disease (polymyositis, myasthenia, chronic inflammatory demyelinating polyradiculopathy).
HIV-associated neurologic disorders (34623100)
- Cerebrovascular disease:
- Vasculitis/vasculopathy related to VZV, syphilis, tuberculosis, cryptococcal meningitis.
- Meningitis:
- Acute HIV seroconversion.
- Cryptococcus neoformans (CD4 <100/mm3).
- Tuberculosis (CD4 <100/mm3).
- Neurosyphilis (any CD4 count).
- Encephalitis:
- HIV encephalitis.
- HIV-associated dementia.
- CD8+ encephalitis.
- CMV (CD4 <50-100/mm3).
- HHV6.
- HSV.
- VZV.
- Intracranial mass or focal lesion:
- PML (progressive multifocal leukoencephalopathy) (CD4 <200/mm3).
- Toxoplasmosis (CD4 <100-200/mm3).
- Primary CNS lymphoma (CD4 <50-100/mm3).
- Tuberculoma.
- Cryptococcoma (CD4 <100-200/mm3).
- Endemic mycoses.
- Nocardia abscess.
- Inflammatory processes (may be more common with CD4 > 200)
- ADEM (acute disseminated encephalomyelitis) in acute HIV seroconversion.
- AIDP (Acute inflammatory demyelinating polyneuropathy, a form of Guillain-Barre syndrome).
- Myelitis:
- Transverse myelitis in acute HIV seroconversion.
- HIV-associated vacuolar myelopathy.
- Opportunistic infections: CMV, VZV, rarely toxoplasmosis.
HIV-associated neurocognitive disorders (HAND)
- Epidemiology:
- Primary risk factors are lack of treatment and low CD4 count.
- Clinical features:
- Chronic cognitive dysfunction ranges from mild to severe (HIV-associated dementia).
- Deficits may include impaired executive function and attention, memory, incoordination, and tremor.
- Laboratory studies:
- CSF may be bland, or it may show a mild lymphocytic pleocytosis (up to 20 WBC/mm3) with mildly elevated protein.
- ⚠️ When performing a lumbar puncture in patients with HIV, lymphocytic pleocytosis up to 20 WBC/mm3 and mild protein elevation may be seen in the absence of any acute infection.(34623100)
- Imaging:
HIV-associated vacuolar myelopathy
- This occurs late in the disease course of advanced AIDS. However, this may rarely occur among patients with well-controlled HIV, due to poor penetration of retroviral therapy across the CSF (“CSF viral escape”).
- The pathologic finding is white matter vacuolization of the posterior and lateral columns, most often in the thoracic spine. Clinically this causes spastic paraparesis and sensory ataxia, as well as urinary incontinence.(34010967)
- HIV-associated vacuolar myopathy is typically a gradual, smoldering process. Especially among patients presenting with an acutely progressive myelopathy, HIV-associated vacuolar myopathy should be considered as a diagnosis of exclusion.(34010967)
- Treatment involves antiretroviral therapy for HIV. For patients already being treated for HIV, transition to antiretrovirals that penetrate the CSF better may be considered.
Various immunosuppressive medications increase the risk of specific infections. Below is a rough guide to common infectious complications from selected medications.(30273244; 34623105)
general principles:
- Immunosuppressive effects may last for weeks to months after medication discontinuation, so a history of recent immunosuppressive medication use is essential. In some cases, discontinuation of the immunosuppressive medication may precipitate immune reconstitution – leading to clinical worsening.
- Lymphopenia may be caused by some agents, and this may correlate with greater degrees of immunosuppression.
associations with specific agents
- Alemtuzumab (targets CD52, causing profound depletion of T- and B-cells):
- VZV, HSV, CMV, TB, Listeria, Nocardia, PML.
- Azathioprine (purine analogue, antimetabolite):
- EBV-associated primary CNS lymphoma, CMV, PML.
- Brentuximab (targets CD30):
- PML.
- Calcineurin inhibitors (cyclosporine, everolimus, sirolimus, tacrolimus):
- Viruses: CMV, EBV (with associated primary CNS lymphoma), HHV6, HSV, PML, lymphocytic choriomeningitis virus (LCMV), VZV, West Nile virus, BK virus.
- Tuberculosis, Listeria, Nocardia, Toxoplasmosis.
- Aspergillus, Candida spp., Cryptococcus neoformans, Histoplasma capsulatum.
- Cyclophosphamide (alkylating agent):
- PML, Nocardia, Cryptococcus neoformans.
- Dimethyl fumarate (Nrf2 upregulation)
- PML (especially in patients with lymphopenia), VZV.
- Eculizumab (targets C5 complement)
- Neisseria meningitidis
- Fingolimod (downregulates Sphingosine-1 phosphate)
- VZV, HSV, PML, Cryptococcus, Listeria.
- Fludarabine (antimetabolite, purine analogue)
- PML.
- Ibrutinib (Bruton tyrosine kinase inhibitor)
- PML.
- Leflunomide (pyrimidine synthesis inhibitor)
- TB, PML.
- Methotrexate (folate analogue inhibitor)
- Toxoplasmosis, PML, EBV (with associated primary CNS lymphoma).
- Mycophenolate mofetil (inosine 5′-monophosphate dehydrogenase inhibitor)
- Toxoplasmosis, PML, EBV-associated lymphoma.
- Natalizumab (targets alpha-4 integrin)
- The primary concern is often PML, which may occur up to six months after discontinuing natalizumab.
- VZV, HSV.
- Ocrelizumab (targets CD20, depletes B-cells)
- Same as rituximab (See below)
- Rituximab (targets CD20, depletes B-cells)
- Viruses: CMV, VZV, West Nile virus, PML, Enterovirus, primary CNS lymphoma.
- Cryptococcus neoformans, Toxoplasmosis.
- Ruxolitinib (Janus kinase inhibitor)
- Toxoplasmosis, PML.
- Steroid (broad range of activity)
- Wide range of infectious agents, including pyogenic bacteria, Listeria monocytogenes, tuberculosis, herpesviruses, fungal infections, and some parasites.(34623105)
- Teriflunomide (pyrimidine synthesis inhibitor)
- TB, PML.
- TNF inhibitors (adalimumab, etanercept, golimumab, infliximab).
- HSV, VZV, PML.
- Listeria, tuberculosis, Nocardia.
- Aspergillus, Candida, Cryptococcus, Histoplasmosis.
clinical presentation
- Clinical presentation may be indistinguishable from meningitis (potentially including meningismus, fever, headache, nausea/vomiting, arthralgia, myalgia, rash, and sometimes papilledema).
- Features of meningitis usually begin within a week of drug initiation. However, in patients with prior sensitization, symptoms can begin within hours.
- After withdrawal of the drug, symptoms resolve within a few days.
- 💡 A clue may be recurrent episodes of meningitis that are otherwise unexplained.
causative medications (29364542)
- NSAIDs (especially ibuprofen).
- Antimicrobials:
- Most notably: trimethoprim-sulfamethoxazole.
- Also reported due to amoxicillin, cephalosporins, rifampin, and valacyclovir.
- Intravenous immunoglobulins (IVIG).
- Anti-seizure medications (lamotrigine > carbamazepine).
- Monoclonal antibodies.
- Others: Allopurinol, azathioprine, cytarabine.
CSF studies
- There is usually an elevation of white blood cells, ranging from hundreds to thousands (mean of 300/uL). Typically neutrophils predominate, but elevated lymphocytes or eosinophils may also occur. (29364542)
- Protein is generally elevated.
- Glucose levels remain normal.
- Lactate level should be normal.
management
- The causative drug should be discontinued. Clinical resolution should follow within days.
- There is no role for steroid.
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- Incorrectly assuming that any neurological abnormality reflects an opportunistic infection (bear in mind that immunosuppression doesn't provide protection against other disorders, such as ischemic stroke).
Guide to emoji hyperlinks
- = Link to online calculator.
- = Link to Medscape monograph about a drug.
- = Link to IBCC section about a drug.
- = Link to IBCC section covering that topic.
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