CONTENTS
- Listeria
- Nocardia
- Legionella
- Mycoplasma
- Tuberculosis
- Lyme
- Neurosyphilis
- Podcast
- Questions & discussion
- Pitfalls
basics
- Listeria is a bacterial pathogen which can cause meningitis, encephalitis, or meningoencephalitis. Among bacterial pathogens, Listeria is notable because it may sometimes be associated with a relatively unimpressive CSF profile. Research on Listeria is confusing to interpret, since it often pools together patients with meningitis along with those who have encephalitis (despite the latter group's probably having less dramatic CSF abnormalities). The combination of CSF analysis together with MRI scanning (as indicated, in patients with abnormal neurologic examination) may be needed to avoid missing cases of neurolisteriosis.
epidemiology
- Listeria monocytogenes is generally spread via contaminated food (e.g., soft cheeses).
- CNS infection can rarely occur in immunocompetent individuals, but there is generally a risk factor present: (Torbey, 2019)
- Age >50-55 years old. (28419853).
- Pregnancy.
- Alcoholism and/or cirrhosis.
- Malignancy (especially hematological malignancy).
- Transplantation.
- Immunosuppression (including chronic steroid, TNF-inhibitors, alemtuzumab, fingolimod).
- Risk is especially high with TNF-inhibitors.(33293366)
- Diabetes.
- Chronic renal insufficiency.
- Collagen vascular disease.
- Conditions associated with iron overload.
clinical presentation
- Patients may present with isolated meningitis, isolated encephalitis, or combined meningoencephalitis.
- (1) Meningitis presentation: The most common features are typical components of bacterial meningitis: fever (~95%), altered mental status (~75%), and headache (~65%).(34623105)
- (2) Generalized encephalitis: Clinical features may include a variety of focal neurologic deficits (e.g., hemiplegia, ataxia, tremors, seizures, or deafness).
- (3) Focal encephalitis involving the brainstem and cerebellum (rhombencephalitis):
- Presentation is classically biphasic. Initially there is a nonspecific, flu-like prodrome, which subsides spontaneously. Days or weeks later patients develop progressive asymmetric cranial nerve palsies, cerebellar signs, and an altered level of consciousness.(34623096)
- Rhombencephalitis may be uncommon, occurring in as few as 17% of patients with neurolisteriosis.(33896533)
laboratory studies
- CSF studies are generally similar to other forms of bacterial meningitis, with significant neutrophilic pleocytosis (>100 cells/mm3), reduced glucose, and elevated protein. However, abnormalities may be less dramatic.(34623105) Additionally, some patients may have a lymphocytic pleocytosis.
- CSF lactic acid levels are generally elevated, even in patients whose CSF chemistry is otherwise not dramatically abnormal.
- CSF bacterial culture and gram stain are incompletely sensitive.
- Blood cultures have a relatively high sensitivity of ~75%.(31378872)
imaging
- Normal imaging in up to half of patients.(34623105)
- Meningitis may cause leptomeningeal enhancement.
- Encephalitis:
- Abscesses may rarely occur, predominantly in the context of immunocompromise. Abscesses are ring-enhancing and diffusion-restricting, similar to other types of bacterial abscesses. They are usually solitary (~70%), but may be multifocal.(31378872)
basics
- Nocardia is a ubiquitous gram-positive rod found in soil, house dust, and decaying plant matter.
epidemiology
- About a third of Nocardia infections occur in healthy people.
- Impaired cell-mediated immunity increases susceptibility, for example:
- Chronic steroid use.
- Transplantation (especially lung transplantation).
- HIV (mostly with CD4 counts <100).
- Malignancy, chemotherapy.
- Alcoholism.
- Diabetes.
clinical presentation
- The primary site of infection is the lungs. Nocardia pneumonia is notable for its subacute/chronic nature, with waxing and waning symptoms occurring over weeks (e.g., weight loss, night sweats, fever, productive cough, pleuritic chest pain). Radiologically, the presence of nodules and/or cavitation may suggest Nocardia (rather than a more typical bacterial pneumonia).
- 80% of patients with CNS nocardiosis will have clinically apparent lung disease. Thus, the absence of lung involvement doesn't exclude nocardiosis.
- Brain involvement:
- Brain involvement occurs in ~25% of patients with pulmonary nocardiosis. However, 38% of patients with CNS infection lack infection elsewhere (“primary” CNS infection).(33549266)
- Usually this involves one or more indolent abscesses. Symptoms may include headache, focal neurologic abnormalities, fever, altered mental status, or seizures.(34623105)
- Meningitis is uncommon, but can occur if an abscess ruptures into the subarachnoid space.
- Other sites of involvement may include the skin and eye.
laboratory diagnosis
- Blood culture is almost always negative, although bacteremia may occur in profound immunocompromise.
- Sputum culture and staining may be very helpful.
- CSF is generally unhelpful (although rare cases involving nocardial meningitis may have a bacterial-type CSF profile and may grow Nocardia in culture).(34623105)
- Brain abscess aspiration is highly sensitive.
treatment
- Treatment of nocardiosis involving the brain requires a combination of antimicrobials with adequate penetration (e.g., trimethoprim-sulfamethoxazole plus imipenem, sometimes additionally with amikacin).
- Neurosurgical management may be necessary for biopsy and/or therapeutic drainage of abscesses.
basics
- Legionella is associated with severe pneumonia, which generally occurs among older or immunocompromised patients.
- Legionella has historically been associated with various neurological syndromes, but in retrospect some of these may not have been true causative relationships. Many neurologic complications (e.g., delirium) correlate with overall disease severity. Since Legionella often causes severe disease, it may be more likely to cause a variety of nonspecific neurologic complications.
1. severe pneumonia with delirium
- Overall rates of delirium appear to be similar to those of other patients with severe pneumonia.(27979685)
- Legionellosis may be associated with alcoholism, so the possibility of Wernicke's encephalopathy should also be considered.
- Management involves treatment of the pneumonia and supportive management of delirium. Further discussion of delirium here: 📖
2. specific syndromes associated with Legionella
- (a) Legionella may cause MERS (mild encephalopathy with reversible splenial lesion).(30782478, 22886060, 26631897) Further discussion of this syndrome is here: 📖
- (b) Legionella has been linked to Guillain-Barre syndrome (more on this here: 📖).
- (c) Legionella has been associated with ADEM (acute disseminated encephalomyelitis 📖).
basics
- Mycoplasma pneumoniae is an atypical bacterium that is generally associated with atypical pneumonia.
- Neurologic complications occur in ~5% of hospitalized patients with Mycoplasma pneumoniae infection. (Louis 2021)
- Neurologic effects are likely immune-mediated, rather than reflecting direct infection (aka, parainfectious or postinfectious). They often begin days to weeks following respiratory infection.(33522738)
clinical syndromes associated with Mycoplasma:
- Meningoencephalitis.
- Transverse myelitis, usually in the context of ADEM (acute disseminated encephalomyelitis).📖
- Guillain-Barre syndrome.📖
treatment
- The role of antibiotics is dubious, since neurologic conditions are often postinfectious. Management often centers around immunomodulatory therapies (e.g., steroid and/or IVIG).
- Supportive therapy is based on the clinical manifestations, for example:
basics
- Tuberculous meningitis occurs in patients who are immunocompetent, although immunosuppressed patients may have an accelerated disease course.
- Most patients have evidence of tuberculosis elsewhere, as well as within the CNS.
- Meningitis accounts for ~75% of CNS tuberculosis presentations, whereas the remaining ~25% are due to tuberculomas (space-occupying granulomas).(31964490) The following discussion focuses mostly on meningitis.
epidemiology
- Risk factors for TB acquisition include:
- Travel/migration.
- Incarceration or employment in a healthcare setting.
- Intravenous drug use.
- In adults, most infections result from reactivation of latent infection. Risk factors for reactivation include immunosuppression (e.g., HIV, malnutrition, diabetes, alcoholism, end-stage renal disease, immunosuppressive medications, older age).
clinical presentation
- Tuberculous meningitis may present as an insidious chronic meningitis, or acute fulminant meningitis.(34623101) Symptoms often follow a systemic prodrome lasting >6 days.(34623095) Clinical features may include the following:
- Meningeal symptoms: Fever (~80%), headache, neck stiffness.
- Basilar meningitis:
- Obstruction to CSF flow may cause clinical hydrocephalus (may lead to stupor and coma).
- Seizures occur in roughly a third of patients, usually >1 month after disease onset.
- Subacute myeloradiculopathy (aka, tuberculous spinal arachnoiditis) can occur, with inflammatory exudates surrounding the spinal cord and nerve roots.(33522738)
- Hyponatremia occurs in about half of patients, mostly due to SIADH (syndrome of inappropriate antidiuretic hormone secretion).(34623105)
lumbar puncture
- Basic tests:
- A lymphocytic pleocytosis is typically seen (e.g., 10-500 cells/mm3). However, more dramatic pleocytosis is also possible.(27321918) Alternatively, cell counts may rarely be normal, due to severe immunosuppression.(34623105, 34623101)
- Protein is significantly elevated (e.g., 100-500 mg/dL). Strikingly elevated protein levels may indicate spinal block.(34623097)
- CSF glucose is reduced in >80% of patients, sometimes severely. (34623101)
- Opening pressures are usually elevated.
- Specific testing:
- CSF PCR may allow for prompt diagnosis, with ~90% sensitivity (although this varies depending on the specific assay).(31964490) This is the best test for rapid diagnosis of tuberculous meningitis.
- CSF microscopy for AFB (acid-fast bacilli) has a sensitivity of ~15%.
- CSF culture has a higher sensitivity (~50%) but it's extremely slow to grow.(33896533) Nonetheless, cultures should be obtained, since it may eventually be useful to help guide antibiotic selection. Obtaining multiple specimens with high volume may increase yield.(34623097)
imaging: CT scan (31964490)
- CT may be normal initially.
- Hydrocephalus may occur, commonly also with effacement of the basal and Sylvian cisterns.(31964490)
- Contrasted CT may show enhancement of the basal leptomeninges (with or without calcifications). Precontrast basal hyperdensity may also occur.
- Infarctions may be seen.
- Tuberculomas may be seen (more on this in the section below).
imaging: MRI (31964490)
- FLAIR sequences are more sensitive than CT for detection of exudates in the basal cisterns.
- Contrast administration may reveal thick, nodular, intense enhancement along the cisterns and extending into the Sylvian fissures (figure below).
- MRI is more sensitive than CT scan for infarctions (seen in ~40% of patients, often in the periventricular or basal ganglia).(31378872)
differential diagnosis of basilar meningitis
- Infections, especially:
- Tuberculosis.
- Fungal meningitis.
- Neurosarcoidosis.
- Meningeal carcinomatosis; lymphoma.
diagnostic criteria: uniform case definition for tuberculous meningitis
- Diagnostic criteria should never be utilized rigidly. However, criteria may be useful to organize clinical and imaging data, especially for clinicians without extensive experience with tuberculous meningitis.
- To be eligible for application of these criteria, patients should have signs and symptoms of meningitis. Additionally, alternative diagnoses should be excluded (e.g., bacterial and cryptococcal meningitis).
- Criteria are listed below. For patients in whom neuroimaging is obtainable, the total score may be interpreted as follows:(34623101)
- Definite diagnosis: requires microbiological confirmation of tuberculosis.
- Probable diagnosis: Score of 12 or higher.
- Possible diagnosis: Score of 6-11.
- Clinical criteria (maximum subscore of 6)
- Symptom duration >5 days: 4 points.
- Systemic symptoms suggestive of TB (including weight loss, night sweats, or cough >2 weeks): 2 points.
- Close contact with someone with TB in the past year: 2 points.
- Focal neurologic deficit (other than cranial nerve palsies): 1 point.
- Cranial nerve palsy: 1 point.
- Altered consciousness: 1 point.
- CSF criteria (maximum subscore of 4)
- Clear appearance: 1 point.
- 10-500 cells/mm3: 1 point.
- Lymphocytic predominance: 1 point.
- Protein >100 mg/dL: 1 point.
- CSF-to-plasma glucose ratio <50%, or absolute CSF glucose <40 mg/dL: 1 point.
- Neuroimaging (maximum subscore of 6)
- Hydrocephalus: 1 point.
- Basal meningeal enhancement: 2 points.
- Tuberculoma: 2 points.
- Infarct: 1 point.
- Precontrast basal hyperdensity: 2 points.
- Evidence of TB elsewhere (maximum subscore of 4)
- Chest x-ray suggestive of active tuberculosis:
- Signs of TB: 2 points.
- Miliary TB: 4 points.
- Imaging evidence of TB outside of the central nervous system: 2 points.
- Acid-fast bacilli identified, or TB cultured from another source (e.g., sputum, lymph node): 4 points.
- Positive TB PCR from outside of the central nervous system: 4 points.
- Chest x-ray suggestive of active tuberculosis:
management
- ⚠️ Airborne isolation should be instituted, since ~40% of patients may have concurrent pulmonary tuberculosis.(27321918)
- Multidrug therapy for tuberculosis is needed (e.g., typically RIPE: rifampin, isoniazid, pyradinzmide, ethambutol).
- Adjunctive steroid is beneficial among immunocompetent patients, but it may not be safe in the context of immunosuppression (e.g., TB plus HIV). For example, dexamethasone 0.3-0.4 mg/kg per day may be used, with a gradual taper off over two months.(Ramachandran 2022)
- Hydrocephalus may require drainage (e.g., with a ventriculoperitoneal shunt).
- Aspirin has been demonstrated to reduce the risk of ischemic stroke.(34623101)
- Hyponatremia may require therapy.
- A checklist has been published that may help guide management.(31984242) It's freely available here: 📄
basics
- Tuberculomas are granulomatous reactions which develop into space-occupying lesions.(31964490) They are usually <1 cm, with 10% of lesions 1-3 cm.(34623101) One third of patients have a solitary lesion, but most have several lesions.
epidemiology
- Tuberculomas occur in 10% of patients with tuberculous meningitis.(34623101)
- They may occur as the sole manifestation of tuberculosis.
- Tuberculomas can emerge or enlarge following initiation of treatment of tuberculosis (as a feature of immune reconstitution inflammatory syndrome).
clinical presentation may include:
- Focal neurologic deficits (which vary, depending on location).
- Headache, fever.
- Seizures are common.
imaging
- Imaging findings may evolve over time, depending on the stage of the tuberculoma (table above). Differentiation from other infectious diseases (e.g., toxoplasmosis) can be challenging.
- On CT:
- Tuberculomas often appear as one or more round/lobulated hyperdensities.
- Chronic lesions may have central calcification. Central calcification surrounded by hypodensity with rim enhancement may create a “target sign.”
- Contrast may reveal punctate, ring-enhancing, or solid lesions.
- On MRI:
- Lesions may be hypointense on T2 (reflective of a solid caseating lesion) or hyperintense on T2 (reflective of a liquified lesion).
- Contrast administration causes irregular ring enhancement.
- Larger lesions with liquified cores may show restricted diffusion.
lumbar puncture
- CSF is generally normal, in the absence of simultaneous tuberculous meningitis.
treatment
- Treatment is generally similar to that of tuberculous meningitis (as discussed above). This involves initiation of a multidrug regimen against TB, often along with adjunctive steroid.
basics
- Lyme disease in the United States is generally caused by Borrelia burgdorferi. However, in Europe, Lyme disease may also be caused by other species (including Borrelia afzelii and Borrelia garinii). This may lead to somewhat different presentations among varying locales.
- Patients may report a history of known tick bite and/or circular “bull's eye” rash (erythema migrans). However, Lyme disease may occur without these signs.
- Neurological involvement occurs in 10-15% of patients with untreated Lyme disease.(31533184)
- Acute, early neurologic Lyme is the most common neurologic presentation (including meningitis, cranial neuritis, and elevated intracranial pressure). These generally occur within a few weeks to a few months after tick exposure (e.g., typically from July through September in Northern climates).(34623103) Although they are discussed separately below, these processes may actually represent different manifestations of the same underlying phenomena (e.g., cranial neuritis may result from meningeal inflammation). Antibiotic therapy for these entities is the same.
clinical manifestations
meningitis
- Meningitis is the most common form of neurological involvement. This can be the initial clinical presentation of Lyme disease.
- This presents similarly to viral meningitis (e.g., fever, headache, nuchal rigidity, photophobia).
- Headache is the most common symptom.
- Lyme meningitis tends to have more gradual onset than most viruses. Fever and meningismus may be mild or absent.(34623103)
- Features that may suggest a diagnosis of Lyme meningitis:
- Cranial neuropathy (~50% have facial nerve palsy).
- History of tick exposure or (especially) a typical rash.
- Evaluation:
- CSF evaluation is pivotal (with findings shown above).
- Lyme serology is highly sensitive (discussed further below).
- Management:
- Lyme meningitis is generally self-limiting (even without any treatment). Thus, empiric antibiotic therapy isn't necessarily required in a patient with low-suspicion for Lyme meningitis (provided that serologies will return soon).
- More on antibiotic selection below.
facial nerve (CN7) palsy
- Facial nerve palsy usually manifests several weeks to a few months after tick exposure. This is the same time-frame as meningitis, with the two often occurring together.
- Facial nerve palsy evolves over hours to a couple days. This is a lower motor neuron palsy that resembles Bell's palsy. Some patients develop bilateral facial palsy, which is more suggestive of Lyme.
- Evaluation:
- Serology is generally sensitive.
- CSF evaluation is often unnecessary. Regardless of whether Lyme meningitis is diagnosed, the treatment is the same. For a patient with negative Lyme serology, CSF could be utilized to help exclude very early Lyme infection.(34623103) Alternatively, a repeat serology could be performed after 2-4 weeks.
- The differential diagnosis of bilateral facial palsies includes: sarcoidosis, HIV infection, Guillain-Barre syndrome, and meningitis.
- Management:
- Antibiotic therapy is discussed below. Antibiotics are intended primarily to prevent other complications from Lyme disease, rather than to improve the facial nerve palsy (which is generally self-limited).
- Steroid doesn't appear beneficial for facial palsy due to Lyme. However, steroid is helpful in Bell's palsy – so empiric steroid may be indicated for patients with undifferentiated facial nerve palsy who are undergoing evaluation.
- Other cranial nerve palsies:
- Facial nerve palsy represents ~80% of all Lyme-related cranial neuropathies. However, other cranial nerves may be involved, (including CN3, CN4, CN5, CN6, and CN8).(34623103)
- Evaluation and management are generally similar to that of patients with isolated facial nerve palsy. However, patients with multiple cranial neuropathies may have a broader differential (e.g., lumbar puncture may be advisable to evaluate for basilar meningitis).
intracranial hypertension
- This seems to be relatively rare in adults.
- The clinical presentation is similar to IIH (idiopathic intracranial hypertension), including headaches, papilledema, and visual symptoms.(31533184)
- CSF evaluation shows meningitis, suggesting that intracranial hypertension may reflect a manifestation of meningitis.
- Management includes:
- (1) Antibiotic therapy for Lyme meningitis.
- (2) Management of elevated intracranial pressure may resemble the treatment of idiopathic intracranial hypertension (e.g., including the use of acetazolamide).
evaluation & management
serum testing
- (#1) Screening ELISA
- The initial screening test is an ELISA assay that evaluates for any antibodies against Lyme.
- (#2) Western blot
- If the initial ELISA is positive or borderline, western blot assays should be performed to evaluate separately for IgG and IgM antibodies against Lyme. This test is more sensitive and specific than the screening Lyme ELISA assay.
- Interpretation:
- Positive IgM in a patient with illness duration <~6 weeks supports a diagnosis of acute Lyme.(34623103) For patients with illness duration >~6 weeks, an isolated positive IgM is increasingly likely to represent a false-positive result (because IgG would be expected to be positive in the context of a true infection).
- Rarely, patients may present with acute, early neurological Lyme before seroconversion (seroconversion usually occurs within 4-6 weeks of exposure).(30921086) If the clinical presentation is highly suggestive of Lyme (e.g., facial nerve palsy), a repeat Lyme titer may be obtained after waiting for 2-4 weeks.
- An organized approach to Lyme serology is shown here:
CSF findings
- Utility of lumbar puncture:
- Lumbar puncture is predominantly relevant for patients presenting with clinical meningitis (e.g., to differentiate Lyme meningitis from other infections).
- Patients with cranial nerve palsy or intracranial hypertension have the same CSF abnormalities as patients who manifest with meningitis.
- If lumbar puncture is performed, an opening pressure should be determined to evaluate for elevated intracranial pressure (discussed further below).
- Traditional CSF labs:(29628177, 21898139)
- The overall pattern of laboratory studies fits a viral pattern (which is discussed further here: 📖 ).
- CSF leukocyte count is often ~300 (with an interquartile range of ~100-500).
- Pleocytosis is generally lymphocytic, but may also be monocytic. Some authors recommend using an elevated number of monocytes as an indicator of Lyme disease, but this doesn't seem to be evidence-based.(29628177)
- CSF protein is often mildly elevated (~150 mg/dL), but may be quite elevated.
- Glucose is generally normal.
- CSF lactate has a median value of ~2.4 mM, with an interquartile range of ~1.7-2.9. ~5% of patients may have a lactate >3.5 mM. (21898139)
- Enteroviral PCR may be useful in differentiating Lyme disease from enterovirus infection, since both infections are common in the summer and present similarly.
- Lyme IgG index:
- The Lyme IgG index evaluates for local synthesis of anti-Lyme IgG within the CSF (calculated as shown below). Synthesis of anti-Lyme IgG within the CNS is implied by an index greater than 1.3-1.5.(34623103)
- The Lyme IgG index isn't necessary for diagnosis in all cases, but might be useful in more complex situations.
- IgG index may be falsely negative within the first six weeks of symptoms.
- Unfortunately, the Lyme IgG index may remain elevated for years after infection, so it doesn't necessarily indicate active infection.(30921086)
management
- Doxycycline 💉
- This is often preferred therapy for acute neurological disease (e.g., meningitis, facial nerve palsy, or radiculoneuropathy). Doxycycline has fairly good penetration of both inflamed and uninflamed CSF. 📖
- The dose is 100 mg PO/IV BID for 14-21 days.
- Doxycycline also covers most other tick-borne illnesses (e.g., anaplasmosis and ehrlichiosis). 📖
- Ceftriaxone 💉
- May be used to treat any form of neurological disease (including encephalitis).
- The dose is 2 grams IV daily for 14-21 days.
- Penicillin G may be another option.(Louis 2021)
(Lyme encephalomyelitis)
- Although much-feared, this seems to be exceedingly rare within the United States.
- Clinical presentation may mimic multiple sclerosis, with inflammatory lesions involving the brain or spinal cord.
- Laboratory evaluation involves Lyme serology and lumbar puncture. CSF evaluation may show oligoclonal bands. Otherwise, CSF findings may be similar to those of patients with Lyme meningitis (discussed above).
- MRI may show multiple areas of T2/FLAIR hyperintensity that are contrast-enhancing. Lesions tend to be periventricular and/or subcortical, but may also be seen in the basal ganglia or brainstem.
basics
- Syphilis invades the nervous system within days of primary infection.(31577877)
- Neurosyphilis is often divided into early (1-2 years after infection) or late (manifestations which often arise 1-2 decades after infection). Contrary to traditional beliefs, the most common presentation of neurosyphilis is within a couple years of initial infection (early neurosyphilis).(34623102)
epidemiology
- Syphilis rates have been increasing over the past two decades.
- Rates are highest among men who have sex with men, but rates are increasing across all people.
- Syphilis is associated with HIV, substance use (especially methamphetamine), incarceration, and housing instability.
clinical manifestations
syphilitic meningitis
- Chronicity: may occur weeks to months after infection.
- Clinical findings may include:(31577877)
- Meningismus (e.g., headache, photophobia).
- Elevated intracranial pressure (Confusion, lethargy, nausea, vomiting).
- Seizures.
- Cranial nerve palsies (most often involving CN2, CN7, or CN8) may cause symptoms including impaired visual acuity or hearing loss.(34623102)
- Polyradiculopathy:(28351506)
- Back or neck pain.
- Sensory changes.
- Weakness, muscle atrophy.
meningovascular syphilis
- Chronicity: typically 1-10 years after infection.(31577877) This may overlap with syphilitic meningitis (often with meningovascular syphilis occuring after a prodrome of meningeal symptoms).(34623102)
- Basics: Meningitis evolves to cause vasculitis of small and medium-sized arteries. This causes strokes and various types of myelopathy.(31577877)
- Clinical findings may include:(31577877)
- (1) Meningismus, cranial nerve palsies.
- (2) Stroke
- Typically involves the middle cerebral artery distribution, but any vascular territory serving the brain or spinal cord can be involved.(34623102, 31533185)
- Syphilis testing may be considered in patients presenting with stroke and the following features: preceding meningitis, younger age, exposure history, absence of usual stroke risk factors, recurrent stroke.
- (3) Meningomyelitis with progressive myelopathy (including sphincter dysfunction).
- Radiological findings may include:
- Ischemic stroke(s) are usually the predominant imaging finding (which may be multifocal).
- Vascular imaging may show features of vasculitis (e.g., alternating segments of stenosis and dilation).
- Meningitis may occasionally be seen (e.g., increased FLAIR hyperintensity within the cortical sulci).
general paresis (aka syphilitic dementia, or dementia paralytica)
- May occur beyond a decade after infection.
- Clinical findings may include:(31577877)
- (1) Dementia.
- (2) Psychiatric syndromes, personality change, manic delusions.
- (3) Tremor, dysarthria (with halting and syllabic repetition), and rarely Parkinsonism.(31533185)
- (4) Argyll Robertson pupils in <50% of patients (unresponsiveness to light, but responsive to accommodation for near vision).
- (5) Seizures.
tabes dorsalis
- May occur beyond a decade after infection. For unclear reasons, tabes dorsalis has become less common recently.(31577877)
- Clinical findings may include:(31577877)
- (1) Severely impaired proprioception with ataxia.
- (2) Lightning pains in legs and trunk.
- (3) Argyll Robertson pupils in most patients.
- (4) Paraparesis with leg areflexia.
- (5) Bowel and bladder dysfunction.
lab tests
treponemal vs. nontreponemal tests
- Nontreponemal tests (RPR and VRDL) measure nonspecific antibodies that form and interact with synthetic cardiolipin-cholesterol-lecithin antigen complex. False-positive results may occur due to various conditions (e.g., HIV; pregnancy; autoimmune disorders; injection drug use; older age; other infections such as tuberculosis, malaria, and rickettsiae).(34623102)
- Treponemal tests include TPPA (Treponema pallidum particle agglutination assay) and FTA-ABS (fluorescent treponemal antibody absorption). These tests evaluate for the presence of anti-syphilis antibodies.
- Specificity: The advantage of treponemal tests is that they are generally more specific than nontreponemal tests. However, false-positive treponemal tests can occur due to other treponemal infections (e.g., yaws or pinta), other infections (e.g., malaria, leprosy), pregnancy, and autoimmune disease.(34623102)
- The disadvantage of treponemal tests is that they remain positive over time, reducing their utility in any patient with a known history of syphilis.
serum nontreponemal tests (VRDL or RPR)
- Sensitivity is high (~97-100%) for early neurosyphilis (with sensitivity somewhat lower with the RPR test). For late neurosyphilis, the sensitivity decreases.
- Specificity is high but imperfect (~90%). In patients with low pretest probability of having neurosyphilis, false-positive results may be common. False positive results usually have low titer (<1:8).(34623102)
- Use:
- Traditionally, this has been used as an initial screening test. However, with decreasing cost of treponemal tests, some centers are using a treponemal test for screening.
- A positive result will typically trigger reflex testing of a serum treponemal test to confirm that it is a true-positive.
serum treponemal tests (FTA-ABS)
- Sensitivity is excellent for early neurosyphilis (~100%) and late neurosyphilis (~96%).
- Specificity is good (~95%).
- Use: Perhaps the best single test to evaluate for syphilis infection.
CSF nontreponemal test (VRDL)
- Sensitivity is reduced compared to serum VRDL (~75% for early neurosyphilis, or ~50% for late neurosyphilis).
- Specificity is outstanding. In the absence of CNS malignancy or blood contamination of the CSF, the specificity for neurosyphilis may approach 100%. Thus, a positive CSF VRDL is considered diagnostic for neurosyphilis.(34623102)
CSF treponemal tests (FTA-ABS)
- Sensitivity is outstanding for early neurosyphilis (~100%) and late neurosyphilis (~99%). The test usually remains positive for life, but may occasionally turn negative following treatment for syphilis. A negative CSF treponemal test largely excludes neurosyphilis.
- Specificity is marginal (~80%). A positive result may reflect previously treated neurosyphilis, or syphilis without neurological involvement (due to entry of antibodies from the periphery into the CNS). Using a higher cutoff (e.g., 1:320) improves the specificity for neurosyphilis.(34623102)
CSF analysis
- Neurosyphilis usually causes a relatively mild pleocytosis (e.g., 10-400 cells/uL for patients with syphilitic meningitis). This pleocytosis tends to diminish over time. About half of patients with late syphilis causing general paresis may lack pleocytosis.(34623102)
- Pleocytosis is nonspecific. For example, patients with untreated HIV may have chronic pleocytosis due to HIV itself (e.g. up to ~20 cells/uL). 📖
- Protein may be mildly elevated (ranging ~50-250 mg/dL).(31533185)
- Glucose may be normal or decreased.(Louis 2021)
management
front line therapy is penicillin 💉
- Start IV penicillin G 3-4 million units IV q4 hrs for 10-14 days.
- Alternatively, 2.4 million units of penicillin G procaine may be given intramuscularly once daily, in combination with 500 mg probenecid PO q6hrs.
- If the patient is allergic to penicillin, consider desensitization while the patient is admitted to ICU.
ceftriaxone 💉
- Ceftriaxone may be a reasonable alternative therapy.(34623102)
- The dose is 2 grams ceftriaxone IV/IM daily.(31533185)
followup
- Consult with infectious disease specialists regarding ongoing therapy and followup.
- Syphilis is a reportable disease. Sexual contacts may need to be notified.
- Treatment success is suggested by a four-fold reduction in serum nontreponemal titer.
going further
- Case report: 62-year-old man with back pain and lower extremity weakness (Yost et al. PMID 28351506) 📖
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- Developing the appropriate level of suspicion for tuberculosis is challenging, especially in areas where this is rare.
- Listeria may be a challenging diagnosis, since no single diagnostic test is highly sensitive for its detection.
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References
- 22886060 Sauchelli D, De Pascale G, Scoppettuolo G, Frisullo G, Bernardo D, Cuccagna C, Tumbarello M, Antonelli M, Servidei S. Neurological involvement during legionellosis, look beyond the lung. J Neurol. 2012 Oct;259(10):2243-5. doi: 10.1007/s00415-012-6552-0 [PubMed]
- 26065933 Shih RY, Koeller KK. Bacterial, Fungal, and Parasitic Infections of the Central Nervous System: Radiologic-Pathologic Correlation and Historical Perspectives. Radiographics. 2015 Jul-Aug;35(4):1141-69. doi: 10.1148/rg.2015140317 [PubMed]
- 26631897 Tomizawa Y, Hoshino Y, Sasaki F, Kurita N, Kawajiri S, Noda K, Hattori N, Amemura-Maekawa J, Kura F, Okuma Y. Diagnostic Utility of Splenial Lesions in a Case of Legionnaires' Disease due to Legionella pneumophila Serogroup 2. Intern Med. 2015;54(23):3079-82. doi: 10.2169/internalmedicine.54.4872 [PubMed]
- 27321918 Tyner HL, Baddour LM. 26-Year-Old Man With Nausea, Delirium, and Fever. Mayo Clin Proc. 2016 Oct;91(10):e137-e141. doi: 10.1016/j.mayocp.2016.03.023 [PubMed]
- 27979685 Halperin JJ. Nervous System Abnormalities and Legionnaire's Disease. Infect Dis Clin North Am. 2017 Mar;31(1):55-68. doi: 10.1016/j.idc.2016.10.005 [PubMed]
- 28351506 Yost MD, Greenlund LS. 62-Year-Old Man With Back Pain and Lower Extremity Weakness. Mayo Clin Proc. 2017 May;92(5):805-809. doi: 10.1016/j.mayocp.2016.06.034 [PubMed]
- 30273244 Pruitt AA. Central Nervous System Infections Complicating Immunosuppression and Transplantation. Continuum (Minneap Minn). 2018 Oct;24(5, Neuroinfectious Disease):1370-1396. doi: 10.1212/CON.0000000000000653 [PubMed]
- 30782478 Grün D, Unger MM, Kauffmann J, Zimmer V, Fassbender K, Fousse M. Legionnaire's-disease-associated meningoencephalitis: A case report. Pulmonology. 2019 Mar-Apr;25(2):128-130. doi: 10.1016/j.pulmoe.2018.12.006 [PubMed]
- 30921086 Halperin JJ. Lyme neuroborreliosis. Curr Opin Infect Dis. 2019 Jun;32(3):259-264. doi: 10.1097/QCO.0000000000000545 [PubMed]
- Torbey, M. T. (2019). Neurocritical Care (2nd ed.). Cambridge University Press.
- 31533184 Halperin JJ. A Neurologist's View of Lyme Disease and Other Tick-Borne Infections. Semin Neurol. 2019 Aug;39(4):440-447. doi: 10.1055/s-0039-1692143 [PubMed]
- 31533185 Gonzalez H, Koralnik IJ, Marra CM. Neurosyphilis. Semin Neurol. 2019 Aug;39(4):448-455. doi: 10.1055/s-0039-1688942 [PubMed]
- 31577877 Ropper AH. Neurosyphilis. N Engl J Med. 2019 Oct 3;381(14):1358-1363. doi: 10.1056/NEJMra1906228 [PubMed]
- 31964490 Nguyen I, Urbanczyk K, Mtui E, Li S. Intracranial CNS Infections: A Literature Review and Radiology Case Studies. Semin Ultrasound CT MR. 2020 Feb;41(1):106-120. doi: 10.1053/j.sult.2019.09.003 [PubMed]
- 33522738 Toledano M. Infectious Myelopathies. Continuum (Minneap Minn). 2021 Feb 1;27(1):93-120. doi: 10.1212/CON.0000000000000930 [PubMed]
- 33549266 Carter LE, Patel PP, Chirila RM. 44-Year-Old Man With Headache and Neurological Symptoms. Mayo Clin Proc. 2021 Feb;96(2):483-487. doi: 10.1016/j.mayocp.2020.06.065 [PubMed]
- 33896533 McEntire CRS, Anand P, Cervantes-Arslanian AM. Neuroinfectious Disease Emergencies. Neurol Clin. 2021 May;39(2):565-588. doi: 10.1016/j.ncl.2021.02.003 [PubMed]
- 34623095 Aksamit AJ Jr, Berkowitz AL. Meningitis. Continuum (Minneap Minn). 2021 Aug 1;27(4):836-854. doi: 10.1212/CON.0000000000001016 [PubMed]
- 34623096 Venkatesan A. Encephalitis and Brain Abscess. Continuum (Minneap Minn). 2021 Aug 1;27(4):855-886. doi: 10.1212/CON.0000000000001006 [PubMed]
- 34623097 Bhattacharyya S, Bradshaw MJ. Infections of the Spine and Spinal Cord. Continuum (Minneap Minn). 2021 Aug 1;27(4):887-920. doi: 10.1212/CON.0000000000001031 [PubMed]
- 34623099 Garcia HH. Parasitic Infections of the Nervous System. Continuum (Minneap Minn). 2021 Aug 1;27(4):943-962. doi: 10.1212/CON.0000000000000986 [PubMed]
- 34623100 Grill MF. Neurologic Complications of Human Immunodeficiency Virus. Continuum (Minneap Minn). 2021 Aug 1;27(4):963-991. doi: 10.1212/CON.0000000000001035 [PubMed]
- 34623101 Saylor D. Neurologic Complications of Tuberculosis. Continuum (Minneap Minn). 2021 Aug 1;27(4):992-1017. doi: 10.1212/CON.0000000000001005 [PubMed]
- 34623102 Chow F. Neurosyphilis. Continuum (Minneap Minn). 2021 Aug 1;27(4):1018-1039. doi: 10.1212/CON.0000000000000982 [PubMed]
- 34623103 Roos KL. Neurologic Complications of Lyme Disease. Continuum (Minneap Minn). 2021 Aug 1;27(4):1040-1050. doi: 10.1212/CON.0000000000001015 [PubMed]
- 34623105 Anand P. Neurologic Infections in Patients on Immunomodulatory and Immunosuppressive Therapies. Continuum (Minneap Minn). 2021 Aug 1;27(4):1066-1104. doi: 10.1212/CON.0000000000000985 [PubMed]
- Louis ED, Mayer SA, Noble JM. (2021). Merritt’s Neurology (Fourteenth). LWW.
- Ramachandran PS, Grill FM, Toledano M (2022): Diagnosed a patient with a neuroinfectious disease – Now what? Presentation at the American Academy of Neurology Conference, Seattle 2022.