CONTENTS
- Neurocysticercosis
- Toxoplasmosis
- Creutzfeldt-Jakob disease (CJD)
- Podcast
- Questions & discussion
- Pitfalls
basics
- Neurocysticercosis results from neurological invasion by the pork tapeworm (Taenia solium).
- Cysticercosis refers to any disease due to Taenia solium.
- Neurocysticercosis is a subset of patients with cysticercosis, in whom parasites invade the central nervous system.
- Cysticerci (the larval form of the parasite) in the brain parenchyma may quietly live as viable 0.5-1.5 cm cysts for years or decades, before being recognized by the immune system. An immune response subsequently destroys the cyst, often leaving behind a calcified granulomatous scar.(30366559) Symptoms are largely due to immune-mediated inflammation.
- Cysts within the ventricles may obstruct the flow of CSF, causing obstructive hydrocephalus. Cysts within the subarachnoid space can grow as large cystic masses.
epidemiology
- Neurocysticercosis may affect ~15% of people in endemic regions (e.g., Central America, South America, sub-Saharan Africa, parts of South and East Asia). Worldwide, cysticercosis is the most common parasitic infection of the central nervous system.(33522738)
- Travel and migration lead to >1,000 cases/year in the United States.(30366559)
presentations
- Seizures and epilepsy:
- Seizures are the most common presenting symptom (~80%).(31378868) These may be caused by cysts in any stage of their life (ranging from viable cysts to old calcified lesions).
- Hydrocephalus:
- Elevated intracranial pressure may be caused by CSF obstruction due to intraventricular or subarachnoid cysts, by external compression of CSF pathways by intraparenchymal cysts, or by residual chronic scarring of the subarachnoid membranes (aka, chronic arachnoiditis).
- Mass effect and focal deficits:
- Large cysts with surrounding edema may cause headache and focal deficits.
- Spinal cord cysts are less common, but may cause myelopathy (e.g., due to external compression of the cord, or intramedullary lesions).(34623099)
neuroimaging
- Stages:
- (#1) Vesicular stage: Uninflamed, viable cysts have liquid contents with signal similar to CSF, without surrounding inflammation (image A, above). The tapeworm head is often seen as an eccentric nodule within the cyst.(34623099)
- (#2) Colloidal stage: Immune recognition causes pericystic edema and contrast enhancement (images B-C, above). The density of fluid within the cyst may increase.
- (#3) Granular-Nodular stage: The cyst collapses into an inflammatory granulomatous nodule, with surrounding gliosis.
- (#4) Nodular calcified stage: A calcified nodular scar is left behind, without surrounding inflammation (image D, above).
- Cysts in the subarachnoid space may grow and occupy large spaces, especially in the Sylvian fissures and basal cisterns (images G-H, above).(30366559)
laboratory studies
- ELISA for antibodies against lentil-lectin purified antigens have high sensitivity (~98%) among people with >1 viable brain cyst, but sensitivity is lower among patients with a solitary lesion. The main limitation of this test is that most people who are exposed to cysticercosis don't develop neurologic manifestations, so a positive result may simply reflect prior exposure.
- Lumbar puncture may not be safe in the context of noncommunicating hydrocephalus. If CSF is obtained, it is nonspecific (potentially showing a moderate lymphocytic pleocytosis, increased protein, and occasionally low glucose in severe cases).(34623099)
management
- (1) Destroying the parasite is not an immediate priority (infection is a chronic process, with cysts lacking the ability to proliferate within the brain). In some situations, antiparasitic therapy may exacerbate inflammation and thereby worsen matters (e.g., cysticercal encephalitis).
- ⚠️ Don't start antiparasitic therapy immediately. This should be done in consultation with an infectious disease specialist, often after stabilizing the patient.
- (2) Seizures should be managed in the usual fashion (e.g., levetiracetam).
- (3) Elevated intracranial pressure should be managed:
- Obstructive hydrocephalus may require neurosurgical interventions (e.g., external drain placement, shunt placement, or rarely excision of a large cystic lesion).
- (4) Steroid may be utilized:
- Indications include treatment of perilesional edema (if this is contributing to clinical deterioration), or prevention of disease exacerbation when initiating antiparasitic therapy.
- Frequently used doses are ~0.1-0.2 mg/kg/day dexamethasone.(30366559)
- Consider screening or empiric treatment for Strongyloides if steroid is utilized (since steroid may exacerbate an asymptomatic, chronic Strongyloides infection).
basics
- Toxoplasmosis is an opportunistic disease, which infects about half of the world's population – usually with minimal symptoms.
epidemiology
- The disease may be acquired from cat litter, contaminated soil, or raw meat. Following initial infection, latent infection occurs, which may lead to subsequent reactivation in the context of immunosuppression.
- Encephalitis may occur in immunosuppressed patients:
- HIV is the major risk factor (with greatest risk when CD4 count is <100/mm3).(34623099) Toxoplasmosis is the most common opportunistic CNS infection in AIDS patients.(Tang 2015)
- Transplantation.
- Steroid or cytotoxic medications (especially methotrexate, rituximab, ruxolitinib).(30273244)
- Malignancy.
clinical manifestations of encephalitis due to toxoplasmosis
- Presentation is usually subacute, with variable symptoms depending on the location and number of lesions.
- Headache and fever may occur.
- Focal symptoms may include:
- Movement disorder is common, given a predilection for abscesses to involve the basal ganglia.
- Subacutely progressive confusional state.
- Hemiparesis.
- Seizure.
- Ataxia.
- Spinal cord involvement is rare. When present, this generally occurs simultaneously with brain involvement. Symptoms of spinal cord involvement may include weakness (91%), sensory loss (70%), and sphincter dysfunction (50%).(34623097)
- Visual impairment may result from retinal toxoplasmosis.
pulmonary involvement
- Respiratory involvement is rare, usually occurring within the context of multisystem involvement. Pneumonia or ARDS can occur especially among immunocompromised patients, for example:
- HIV patients with CD4 <50/uL.
- Recipients of stem cell or solid organ transplantation.
- Hematologic malignancy.
- (Rarely, pulmonary toxoplasmosis can occur in immunocompetent patients, usually resembling an atypical pneumonia.)(33664833)
- Clinically, toxoplasmosis may be suggested by the presence of a mononucleosis-like syndrome in combination with pulmonary findings.(33664833)
- Radiographic findings: Most often, a bilateral interstitial pneumonia pattern is seen (which may be confused with pneumocystis). However, discrete opacities or cavitation have also been reported. (Murray 2023)
- Diagnostic studies:
- Bronchoscopy with bronchoalveolar lavage may allow for detection via Giemsa staining, PCR, and/or culture.
- Nearly all patients are seropositive, so negative serologic tests suggest an alternative diagnosis.(Murray 2022)
laboratory evaluation
- Toxoplasma IgM has high sensitivity and specificity for acute infection. However, most cases of toxoplasmosis encephalitis are due to reactivation, rather than primary infection.
- Toxoplasma IgG is positive in ~97% of HIV patients with toxoplasmosis encephalitis.
- Presence of IgG doesn't establish an active infection (as this may reflect remote infection).
- Absence of IgG should cast doubt upon the diagnosis of toxoplasmosis encephalitis (but doesn't absolutely exclude toxoplasmosis).
CT scan
- Toxoplasmosis usually causes multifocal abscesses involving the basal ganglia, thalamus, subcortical white matter, and posterior fossa.(31378868) However, up to a quarter of patients may have only a single lesion.(34623105)
- May see multiple irregular, hypodense lesions (reflecting central necrosis), with peripheral edema.
- Ring enhancement is typical, but this may be absent in profoundly immunosuppressed patients (e.g., AIDS patients with CD4 count <50/uL).
MRI
- Basic properties of the lesion are similar to a bacterial abscess:
- (i) A central necrotic portion is hypointense on T1 and hyperintense on T2.
- (ii) This is surrounded by a rim that is hyperintense on T1 and hypointense on T2.
- (iii) Surrounding the lesion there is marked edema with associated mass effect (e.g., with hyperintensity on T2/FLAIR sequences).
- (iv) Contrast administration usually produces a ring or nodular pattern.
- Contrast may show an “eccentric target sign” in about a third of patients. This is formed by the combination of ring enhancement plus a small eccentric mural nodule (figure above). If encountered, this suggests toxoplasmosis.(28466277)
- Some diffusion restriction may occur in the periphery of the lesion.(28466277) However, unlike a bacterial abscess, diffusion restriction of the lesion core is not seen.(34623100)
- Punctate hemorrhage can occur (causing hyperintensity on T1 and more notable blooming artefact on SWI/GRE sequences).
- In patients with more severe immunosuppression (e.g., very low CD4 count or status post bone marrow transplantation), disseminated lesions in the basal ganglia and subcortical grey matter may occur with minimal edema or enhancement.(28466277; 33741796)
radiological differentiation of toxoplasmosis vs. PCNSL (primary CNS lymphoma)
- Toxoplasmosis and primary CNS lymphoma may appear similar, with both processes often affecting immunocompromised patients. Several features may help differentiate the two pathologies:(26065933)
- (1) Size and number of lesions:
- Toxoplasmosis is often numerous and smaller.
- PCNSL is often solitary and larger.
- (2) Location:
- Toxoplasmosis lesions are usually predominantly located in the basal ganglia and gray-white matter junction. (Alternatively, there is typically an absence of corpus callosal or leptomeningeal involvement.)
- PCNSL lesions are often located in the subependymal/periventricular area, sometimes with subependymal spread.
- (3) Contrast enhancement:
- Toxoplasmosis causes ring enhancement, sometimes with an eccentric target sign.
- PCNSL typically causes homogeneous enhancement.
- (4) Diffusion restriction:
- Toxoplasmosis may cause some peripheral diffusion restriction.
- PCNSL commonly causes diffusion restriction.
- (5) Degree of surrounding edema:
- Toxoplasmosis may cause marked surrounding edema.
- PCNSL only causes mild surrounding edema.
- (6) Laboratory studies:
- Toxoplasmosis usually is associated with positive toxoplasmosis serologies.
- PCNSL is usually associated with Epstein-Barr virus in the CSF.
- More sophisticated perfusion imaging (e.g., PET scan or MR perfusion) may help differentiate PCNSL from toxoplasmosis (PCNSL lesions are hypermetabolic, whereas those of toxoplasmosis are hypometabolic).
- More on primary CNS lymphoma: 📖
differential diagnosis of toxoplasmosis may include
- Malignancy:
- Primary CNS lymphoma might be the most similar entity (discussion of the imaging differential of toxoplasmosis vs. lymphoma above).
- Primary brain tumor (e.g., glioblastoma).
- Infection:
- Tuberculoma.
- Bacterial abscess(es), including those due to septic embolization.
- Fungal mass lesions (e.g., cryptococcoma).
- Nocardia.
management
- Empiric treatment is indicated if clinical and radiologic features are consistent with toxoplasmosis.
- Front-line therapy may involve either trimethoprim-sulfamethoxazole or sulfadiazine plus pyrimethamine and leucovorin (folinic acid).(34623105)
- In HIV patients with typical features of toxoplasmosis, empiric therapy may be appropriate without necessarily obtaining a biopsy. Close follow-up with serial imaging is required to ensure resolution.
- Steroid may be considered if lesions have mass effect or if substantial cerebral edema is seen.(34623099)
- Seizures should be treated in the usual fashion if they occur. Seizure prophylaxis may be considered, depending on the location of lesion(s) with respect to more epileptogenic parts of the brain. 📖 (Jallo 2021)
- Clinical and radiographic improvement expected in ~85% of patients within two weeks.(Cervantes-Arslanian 2022) Failure to improve after two weeks should raise concern for alternative diagnoses, such as PCNSL (primary CNS lymphoma), and possible need for a brain biopsy.
basics
- Sporadic CJD (Creutzfeldt-Jakob disease) accounts for >90% of sporadic prion disease. Less common forms of prion disease include iatrogenic Creutzfeldt-Jakob disease, genetic Creutzfeldt-Jakob disease, and variant Creutzfeldt-Jakob disease (aka, “mad cow disease”).
- This section refers primarily to sporadic Creutzfeldt-Jakob disease.
epidemiology
- Incidence of ~1 person per million per year.
- Peak age of onset is during the patient's sixties, but there is a broad potential age range.
symptoms
- The disease may typically progress through three stages:(Wijdicks, 2019)
- Stage 1: One third of patients experience a prodrome including nonspecific symptoms (e.g., fatigue, dizziness, headache, altered sleeping and eating patterns, weight loss).
- Stage 2: Rapid cognitive decline and visual disturbances (e.g., blurred or double vision, cortical blindness). (Louis 2021)
- Stage 3: Severe dementia and “startle myoclonus.” Eventually patients may progress to akinetic mutism.
- The range of potential symptoms is broad, including:
- Cortical deficits (e.g., aphasia, apraxia, frontal lobe dysfunction). Behavioral symptoms may include irritability, anxiety, depression, or occasionally psychosis. (Louis 2012)
- Cerebellar ataxia.
- Extrapyramidal symptoms: bradykinesia, hypokinesia, rigidity, dystonia, tremor.
- Corticospinal tract dysfunction may occur later in the disease course (e.g., spasticity, hyperreflexia).
MRI findings
- Overall performance of MRI may have sensitivity and specificity >90%, although numbers vary depending on disease severity.(Wijdicks, 2019; LaRoche 2018) Performance would be expected to be high among patients with sufficient disease severity to merit ICU admission.
- MRI abnormalities involve diffusion restriction and hyperintensity on T2/FLAIR, without contrast enhancement.
- Diffusion-weighted images (DWI) may show abnormalities most clearly, since this sequence integrates together signals from both vasogenic and cytotoxic edema.(28076019) This reflects true diffusion restriction, with ADC hypointensity. (Louis 2021)
- Lack of contrast enhancement may help differentiate this from other types of acute encephalitis.
- Anatomic areas which may be involved in sporadic Creutzfeldt-Jakob disease:
- (1) Symmetric involvement of the caudate nuclei and putamina.
- (2) Diffuse cortical abnormality (“cortical ribboning“), although the perirolandic cortex is often spared. The differential diagnosis of cortical ribboning on MRI also includes hypoxic-ischemic encephalopathy, SITMA (seizure-induced transient MRI abnormalities), PCNSL (primary CNS lymphoma), PRES (posterior reversible encephalopathy syndrome), and acute hepatic encephalopathy.
- The pattern of abnormalities varies between patients:(28076019)
- ~70% have abnormalities involving the caudate nuclei, putamina, and cortex.
- ~25% have abnormalities involving only the cortex.
- ~5% have abnormalities involving only the caudate nuclei and putamina.
EEG findings (LaRoche 2018)
- The hallmark finding is GPDs (generalized periodic discharges) with biphasic or triphasic morphology occurring at 0.5-2 Hz. These are unrelated to myoclonic jerks.
- GPDs occur in ~65% of sporadic or iatrogenic CJD.
- Early in the disease course, periodic discharges may be lateralized (LPDs).
- Similar EEG findings may also be seen in a variety of diseases that can present similarly to CJD, including: Alzheimer disease, Lewy body disease, vascular dementia, hypoxic encephalopathies, PML (progressive multifocal leukoencephalopathy), Hashimoto encephalopathy, and autoimmune encephalitis (especially antibodies against voltage-gated potassium channels). (Louis 2021)
- Other EEG findings may include frontally predominant rhythmic delta activity and background slowing.
lumbar puncture
- ⚠️ If a lumbar puncture is performed, this must be done with special measures to avoid disease transmission.
- Routine CSF chemistries are generally unremarkable, although protein may be elevated.
- Lumbar puncture may show elevated levels of 14-3-3 protein, but its performance is controversial – with limited sensitivity and specificity.(Wijdicks, 2019)
- ⚠️ Avoid making any management decisions based on 14-3-3 protein.
- RT-QuIC (real-time quaking-induced conversion) is a functional bioassay to evaluate the ability of CSF to induce conformational transformation of a recombinant prion protein (figure below). Sensitivity appears to be >90%, with a specificity of ~99%.
- Perhaps the most important role of lumbar puncture is to help exclude alternative diagnoses (e.g., autoimmune or paraneoplastic encephalitides).
- The National Prion Disease Pathology Surveillance Center may be consulted to help confirm the diagnosis and determine if there is an underlying genetic mutation.
management
- There is no specific treatment.
- Palliative care is indicated for patients with substantial impairment, given the progressive nature of the disease.
prognosis
- Mean survival is about six months.
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- Beware of excessive focus on 14-3-3 protein levels when evaluating for Creutzfeldt-Jakob disease. This test is not entirely specific. Even if the result is positive, the patient could still have an alternative, treatable disease (e.g., autoimmune encephalitis).
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