CONTENTS
- Herpesviruses
- ⍺-herpesviruses
- β-herpesviruses
- Gamma-herpesviruses
- Enteroviruses
- Arboviruses
- JC virus and PML (progressive multifocal leukoencephalopathy)
- Podcast
- Questions & discussion
- Pitfalls
basics
- Herpes simplex virus encephalitis is caused mostly by HSV-1 (95% of cases), with 5% of cases due to HSV-2.(31378872)
epidemiology
- HSV encephalitis is the most common cause of sporadic encephalitis.
- HSV encephalitis commonly affects immunocompetent adults. The disease is usually not more frequent among immunosuppressed groups (although it may present in an atypical fashion).(28076019) Some exceptions exist, however (e.g., bone marrow transplantation and HIV may increase risk of infection).(30366551)
- Overall there is a bimodal age distribution of HSV encephalitis. Two peaks occur: patients <20 years old (likely related to primary acquisition) and patients >50 years old (likely related to waning immunity).(Mandell 2020)
clinical presentation
- HSV encephalitis usually presents in a subacute fashion, with symptoms evolving over several days.
- Fever occurs in ~80% of patients, with headache in ~70%.(Jankovic 2022)
- Altered consciousness is extremely common (usually lethargy or stupor, but mania is possible as well).
- Involvement of the limbic structures commonly leads to psychiatric or personality changes (e.g., delusions, agitation). Predilection for the temporal lobes also commonly causes seizures. Other focal neurologic abnormalities can occur as well (e.g., dysphasia/aphasia, visual field cuts, or even hemiparesis).
differential diagnosis
- See the section on limbic encephalitis. 📖
laboratory diagnosis of HSV
- Cellularity:
- There is usually a lymphocytic pleocytosis (~10-500 cells/mm3), although early on there may be a neutrophilic predominance.
- 96-100% of patients have a CSF pleocytosis (white count >5 cells/mm3).(Mandell 2020) Thus, pleocytosis may be absent, especially among immunocompromised patients. In rare cases, all CSF studies may be normal or nearly normal.
- Elevated erythrocytes and xanthochromia may be seen. However, this is a nonspecific and late finding. Erythrocytosis reflects temporal lobe necrosis, which is a late feature of the disease. Other viral encephalitides can behave similarly.
- Protein is modestly elevated in >80% of patients (~50-100 mg/dL).(34623096; 30366551)
- Glucose is generally normal, but may be slightly low.
- HSV PCR is highly sensitive (~98%), but it can be falsely negative within the first 72 hours after symptom onset, or due to blood in the specimen that interferes with the assay.(30366550, 32778604; Mandell 2020) If there is a suspicion for HSV encephalitis (e.g., based on MRI with frontal and/or temporal enhancement) and the HSV PCR is negative within <72 hours after symptom onset, then a lumbar puncture with HSV PCR should be repeated ≧4 days after symptom onset.(30921087) Following treatment with acyclovir for one week, PCR remains positive in 98% of patients.(Mandell 2020)
EEG
- EEG is frequently abnormal (especially in the temporal regions). Potential findings include:
- (1) Lateralized Periodic Discharges (LPDs) – usually seen in the first two weeks, may manifest before CT abnormalities occur.(34623096)
- Antiseizure medication may be considered for patients with LPDs, as discussed further here: 📖
- (2) Diffuse slowing, or focal slowing over the temporal lobes.
- (3) Spike and slow-wave activity.(31378872)
- (4) Seizures.
CT
- CT scan may be abnormal in roughly half of patients.(34623096)
- Early findings may be hypodensities in the temporal lobe and insular cortex, with mild mass effect.(31964490)
- In severe cases, hemorrhages may be visible.
MRI
- Overall performance of MRI for diagnosing HSV encephalitis:
- Qualitative findings:
- Patchy areas of diffusion restriction might be the most sensitive finding in the acute phase.(31485117, 30921087) This may be confused with an acute stroke.(Torbey, 2019)
- HSV encephalitis often causes edema that appears as hyperintensity on T2/FLAIR and hypointensity on T1 within the cortex and subcortical white matter, with an indistinct grey-white junction. Swelling with mass effect can occur.
- Contrast enhancement may be seen in the parenchyma (in a patchy or gyriform pattern) and/or in the leptomeninges .(26046515; 31378872)
- GRE/SWI sequences may reveal petechial hemorrhages that aren't visible on CT scan.(31964490) In more severe cases, hemorrhagic necrosis may cause hyperintensity on T1 and hypointensity on T2.(30921087)
- Anatomic distribution:
- HSV encephalitis commonly affects the bilateral limbic system in an asymmetric manner (anterior and medial temporal lobes, insular cortex, inferior frontal lobes, and cingulate gyri)(31485117) Alternatively, symmetric involvement of the limbic system may suggest an autoimmune limbic encephalitis.
- Unlike many other viral encephalitides, HSV typically spares the lentiform nuclei (the putamen and globus pallidus).(28076019)
- Immunocompromised patients may have abnormalities beyond the usual frontotemporal distribution, including brainstem involvement.(Jankovic 2022; 34623105)
- ⚠️ HSV cannot be excluded based on the location of involvement.
- ⚡️⚡️⚡️ FLAIR hyperintensity in the thalamus may reflect seizures, rather than direct viral involvement.(Wijdicks, 2019; 30921087)
treatment
- Acyclovir
- The typical dose of acyclovir is 10 mg/kg IV q8 hours. However, there are three nuances that should be considered:
- (#1) Dose adjust among patients with impaired renal function (even if the GFR is only <50 ml/min):
- GFR >50 ml/min: 10 mg/kg IV q8 hours.
- GFR 25-50 ml/min: 10 mg/kg IV q12 hours.
- GFR 10-25 ml/min: 10 mg/kg IV q24 hours.
- (#2) Dose based on ideal body weight among patients with obesity.
- (#3) Acyclovir can cause nephrotoxicity due to crystal formation in the urine. To minimize nephrotoxicity, patients may be provided with IV fluid plus diuretics as needed to maintain an even fluid balance. The goal is to maintain a brisk urine output that reduces crystal formation.
- Acyclovir is often initiated empirically among patients with suspected CNS infection (figure above). Patients with definite HSV encephalitis should receive a 14-21 day course.
- Acyclovir-resistant HSV:
- This may occur, especially among immunocompromised patients who are receiving long-term prophylactic acyclovir.(30366551)
- If patients are not responding adequately to IV acyclovir, repeat the lumbar puncture and consider the possibility of acyclovir resistance.
- Antiepileptic medications:
- Prophylactic antiepileptic therapy is not recommended.
- An EEG should be considered in patients with altered mental status if there is any concern regarding seizure.
- Antiepileptic therapy may be indicated to treat seizure or worrisome EEG findings (e.g., periodic epileptiform discharges).
- Steroid:
- There is no high-quality data supporting the role of steroid in HSV encephalitis. This is currently under investigation in the ongoing DexEnceph trial.
- In patients with severe vasogenic edema that threatens to cause herniation, steroid could be considered.(30366551)
follow-up
- Patients recovering from HSV encephalitis may develop a subsequent anti-NMDA receptor encephalitis. This occurs in ~25% of patients, within five weeks.(30921087)
- 💡 There should be a high index of suspicion for anti-NMDA receptor encephalitis in the months following HSV encephalitis. More on anti-NMDA receptor encephalitis: 📖
- Basics: HSV may cause a rapidly progressive lumbosacral myeloradiculitis (Elsberg syndrome). This results from HSV reactivation following dormancy in the sacral dorsal root ganglia. Myeloradiculitis is most often caused by HSV-2, but HSV-1 may behave similarly.
- Symptoms:
- Anogenital vesicular rash may occur initially.
- Pain, paresthesia.
- Progressive flaccid paraparesis.
- Urinary retention.
- Illness is usually monophasic, but recurrence may occur in 20% of patients.(Mandell 2022)
- Investigation:(33522738)
- CSF usually shows a lymphocytic pleocytosis. HSV-1/2 PCR is generally the crux of the diagnosis, but intrathecal HSV-specific immunoglobulins may be helpful in the diagnosis of recurrent cases.(Mandell 2020)
- MRI of the lumbosacral spinal cord shows T2 hyperintensities and enhancement of both the spinal cord and nerve roots.(34010967)
- Treatment:
- Acyclovir is generally utilized.
- Adjunctive steroid is frequently administered.(33522738)
pathophysiology
- VZV may cause a variety of presentations including vasculopathy, encephalitis, cerebellitis, cranial neuropathies, meningitis, and myelitis.(34623105) Multiple manifestations may occur simultaneously, affecting different parts of the neuraxis.
- Perhaps most notable is the ability of VZV to cause an infectious vasculitis that involves cranial arteries. VZV is the only virus known to replicate within arteries.(Louis 2021) Depending on the size and distribution of arteries involved, this may manifest with an ischemic stroke or with encephalitis (if several smaller arteries are involved).
presentation #1/3: Stroke due to large-vessel vasculitis
- Tends to occur in immunocompetent patients.
- Often occurs within months after an episode of herpes zoster, but this history may be absent in ~40% of patients.(31534609)
- This may present with acute, focal deficits due to occlusion of large arteries following the trigeminal distribution. The most common presentation is infarction of the carotid, middle cerebral artery (MCA), or anterior cerebral artery (ACA).(Jankovic 2022) This often occurs 2-10 weeks after herpes zoster involving the trigeminal nerve (ophthalmic zoster).(Torbey 2019)
- Recurrent stroke may occur.(31534609)
presentation #2/3: (Meningo)encephalitis due to small- to medium-vessel vasculitis
- Epidemiology:
- VZV encephalitis may be the second most common cause of sporadic (non-epidemic) encephalitis, following HSV.(Jankovic 2022)
- VZV encephalitis tends to occur in immunocompromised patients, for example:(Torbey, 2019)
- Clinical presentation:
- Encephalitis often follows an episode of herpes zoster. Disseminated herpes zoster in particular is a risk factor for VZV encephalitis (defined as >20 lesions outside the primarily affected dermatome).(26250729)
- Patients present subacutely with mental status changes, focal deficits, fever, headache, seizure, and CSF pleocytosis.
- Cranial neuropathies may occur, often multiple.(34950408)
- VZV encephalitis usually occurs simultaneously with VZV meningitis (with the latter being a relatively benign process).
- Going further: Case report of VZV encephalitis: 88-year-old man with mental status changes and vesicular lesions (Kim et al. PMID 26250729) 📄
presentation #3/3: Myelitis
- Myelitis tends to occur in immunocompromised patients, often simultaneously with involvement at other sites of the neuraxis. Myelitis may follow an episode of cutaneous herpes zoster.(34010967)
- Possible manifestations:(34623105)
- May cause paralysis, sensory loss, or bladder/bowel dysfunction.
- Myelitis may be longitudinally extensive, or have more of a transverse-myelitis pattern. MRI may show T2-hyperintense, contrast-enhancing inflammatory lesions. These may be diffuse, or ipsilateral to a dermatome affected by herpes zoster.(34798966) Autopsy evidence shows acute infection of the spinal cord, emphasizing the role of acyclovir.(30366551)
- Neuroimaging may also reveal enhancement of the spinal nerve roots and cauda equina.
- Differential diagnosis:
neuroimaging to diagnose VZV cerebral vasculitis
- (1) Patients presenting with a large-vessel occlusion:
- This usually affects the carotid, middle cerebral artery, or anterior cerebral artery territories (likely reflecting spread via trigeminal innervation of the vessels).(31534609)
- (2) Patients presenting with smaller-vessel involvement:
- Multiple infarctions may be present in the cortex and subcortical locations.
- The distribution can be ipsilateral to a prior herpes zoster rash.(Jankovic 2022)
- (3) Vascular imaging may help to suggest underlying vasculitis, with potential findings including:
- Segmental stenosis with poststenotic dilatation.(34623105)
- Vessel wall enhancement.(31534609)
- Diffuse irregularity or a beading appearance; stenosis in a distribution that is atypical for atherosclerosis.(31534609)
- Small and large vessels may be affected simultaneously.
- Large-vessel involvement with aneurysm formation or dissection.
lumbar puncture to diagnose VZV cerebral vasculitis
- CSF chemistries:
- CSF typically shows a mild lymphocytic pleocytosis, ranging from 7-260 white blood cells/mm3.(Torbey, 2019)
- CSF protein may be normal or slightly elevated (~50-80 mg/dL).
- Glucose should be normal.
- CSF PCR for VZV may have low sensitivity (~30%) for patients with vasculitis following herpes zoster, but may have higher sensitivity for infectious myelitis or meningitis.(31378872)
- Anti-VZV IgG in the CSF has improved sensitivity compared to PCR (>90%) for patients with vasculitis.(32332223) Specificity may be improved by utilizing the CSV VZV antibody index, with a value >1.5 suggesting IgG synthesis within the CSF (formula below).(30273243)
- Oligoclonal bands can be seen in a third of patients after >1 week.
management
- There is no high-quality evidence regarding the optimal therapy.
- (1) IV acyclovir is generally used, often for a 14-day course (although immunocompromised patients may require a longer course).(34950409)
- (2) Additional therapies for patients with vasculitis:
basics
- CNS involvement occurs in ~1% of patients with infectious mononucleosis.
- EBV may cause:
- Encephalitis, meningitis, meningoencephalitis.
- Cerebellitis, parkinsonism.
- Transverse myelitis.
- Optic neuritis.
- Cranial neuropathy, Guillain-Barre syndrome, and small fiber sensory or autonomic neuropathy.(Torbey, 2019)
- PTLD (posttransplant lymphoproliferative disorder), PCNSL (primary CNS lymphoma).
epidemiology
- Neurologic infections generally reflect reactivation of latent virus in the context of severe immunosuppression.(30273243)
- Risk factors include:
- Organ transplantation (either solid organ or hematopoietic stem cell transplantation).
- Antithymocyte globulin, azathioprine.(30273244)
clinical presentation
- EBV encephalitis may cause altered mental status, coma, seizures, and focal deficits.
- Encephalomyeloradiculitis may occur, which can include features such as fever, somnolence, and lower extremity numbness/weakness.
laboratory studies
- CSF PCR for EBV is difficult to interpret, as it may have a low positive predictive value for EBV-mediated CNS disease.(Louis 2021)
- (1) PCR may be positive in patients with other CNS infections. Incidental EBV positivity may reflect viral reactivation in the absence of EBV-associated disease.(Jankovic 2022)
- (2) Positive PCR may also reflect latent infection of peripheral blood mononuclear cells, with subsequent contamination of the CSF sample.(Louis 2021)
- (3) EBV positivity may be associated with PCNSL (primary CNS lymphoma).(34010967) Within the proper clinical context, a positive EBV PCR may be highly suggestive of PCNSL.
- Serum anti-EBV IgM supports an active EBV infection (but doesn't prove the presence of EBV within the brain).
imaging
- If there is encephalitis, MRI may show focal T2 hyperintense lesions in the cerebellum, cerebral white matter, thalami, striatum, cerebral peduncles, pons, and spinal cord.(28076019, 30273243)
- Contrasted MRI may show nerve root enhancement among patients with encephalomyeloradiculitis.
- Post-transplant lymphoproliferative disorder (PTLD) may resemble primary CNS lymphoma.
management
- EBV encephalitis is thought to be more benign than other herpesvirus encephalitides. It is generally self-limiting, without sequelae.(31378872)
- Use of acyclovir is controversial, with widely variable recommendations. Acyclovir has no effect on infectious mononucleosis, with its value in EBV encephalitis remaining unclear.(31378872) EBV encephalitis is generally considered a parainfectious or postinfectious encephalitis, so antivirals are often not administered.(34623096) However, antiviral therapy is probably indicated for patients with substantial immunosuppression.
basics
- CMV is a widespread opportunistic pathogen, which rarely causes encephalitis among immunocompetent patients. However, in the context of immunosuppression, viral reactivation may lead to encephalitis.
- Neurologically, CMV may cause encephalitis, myelitis, and/or radiculitis. These may occur in combination with CMV retinitis, CMV esophagitis, and/or CMV colitis.
epidemiology
- CMV doesn't generally affect immunocompetent patients. Risk factors include:
- (1) HIV with CD4 count <50-100/uL.
- (2) Transplant recipients, within months of transplantation.(34623105)
- (3) Treatment with alemtuzumab, antithymocyte globulin, rituximab.(30273244)
clinical manifestations
- Ventriculoencephalitis is the most common form. This may involve:
- Confusion that emerges over weeks.
- Cranial nerve palsies.
- Ataxia.
- Rhombencephalitis (brainstem involvement) occurs in about a quarter of patients. This may cause:
- Horizontal or vertical nystagmus.
- Internuclear ophthalmoplegia (INO).
- Cranial nerve neuropathies.
- Lumbosacral myeloradiculitis or cauda equina polyradiculitis.(30273244)
- A less common, acute form (microglial nodular encephalitis) presents with delirium.
laboratory evaluation
- CSF pleocytosis may be either neutrophilic or lymphocytic.
- CSF protein is typically elevated.
- Glucose may be normal or low.
- CSF PCR for CMV has a sensitivity and specificity of ~90%.(34623105)
- Serum PCR for CMV may be difficult to interpret, since it isn't uncommon for immunosuppressed patients to have low levels of CMV viremia.(31378872) Nonetheless, higher serum CMV PCR correlates with a greater likelihood of invasive infection.(31378872)
imaging
- CT
- May show ventricular dilation.
- May see regions of periventricular hypoattenuation.(28076019)
- MRI
- The classic finding is ventriculitis that is marked by periventricular FLAIR hyperintensities with corresponding diffusion restriction. (Torbey, 2019; 28076019) T1 sequences may show ependymal gadolinium enhancement. Ventriculitis may extend outwards to cause T2/FLAIR hyperintensity within the white matter.(figure above)
- Diffuse, nonspecific, nodular T2-hyperintense lesions may occur throughout the brainstem, basal ganglia, cerebellum, and hippocampus. Rim enhancement may occasionally occur.(34623105)
treatment
- Initial management usually involves ganciclovir 5 mg/kg IV q12 hours for 14-21 days, but this may cause bone marrow suppression.(Torbey, 2019) Foscarnet is an alternative. Some authors and guidelines recommend induction with dual therapy.(34623097, 28579869; Mandell 2020)
- Patients with HIV may require antiretroviral therapy. Alternatively, patients on therapeutic immunosuppression might benefit from reducing their level of immunosuppression.
basics
- HHV-6 is a ubiquitous herpesvirus which commonly causes exanthema subitum (roseola) in children, prior to establishing lifelong latent infection.
epidemiology
- HHV-6 is rare in adults, occurring almost exclusively in immunocompromised patients:
clinical presentation
- HHV-6 often presents with a limbic encephalitis, which has been called post-transplant acute limbic encephalitis (PALE).(34623105)
- Patients may have intercurrent myocarditis, hepatitis, thrombocytopenia, and hemophagocytic lymphohistiocytosis (HLH).(31378872)
diagnosis
- CSF typically is consistent with a viral infection (revealing lymphocytic pleocytosis, elevated protein, and normal glucose).(Mandell 2020)
- CSF PCR is very sensitive (>95%), but it's not specific. Asymptomatic reactivation may occur, so a positive PCR result doesn't necessarily indicate that HHV-6 is causing symptomatic disease. Additionally, ~1% of people have HHV-6 DNA integrated into their chromosomal DNA, causing their PCR results to always be positive! (31378872)
- Among patients without specific risk factors for HHV-6 (listed above), there is a low pretest probability of HHV-6. Any positive result in this context likely represents a false-positive.(31378872)
- ⚠️ Inclusion of HHV-6 in multiplex PCR assays (e.g., BioFire) may lead to diagnostic confusion in situations where HHV-6 is unlikely to occur.(Mandell 2022)
- Initial imaging may be normal in up to 30% of patients. Later on, nonenhancing T2 hyperintensities or diffusion restriction may develop in the mesial temporal and limbic areas, similar to HSV.(31378872; 31378872) Hippocampal atrophy may occur several weeks after the initial presentation.(34623105)
differential diagnosis
- See the section on limbic encephalitis. 📖
management
- Optimal treatment is unknown.
- HHV-6 is often resistant to acyclovir, but sensitive to ganciclovir and foscarnet.(Jankovic 2022) Infectious Disease Society of America (IDSA) guidelines recommend using one of these agents in immunocompromised patients.(Mandell 2020) Unfortunately, these agents have substantial toxicity, for example: (Toledano 2022)
- Foscarnet causes electrolyte depletion that requires daily monitoring and repletion.
- Ganciclovir causes bone marrow suppression.
- Immunosuppression should be reduced, if possible.
- There should be a low threshold for EEG monitoring, given a high risk of seizure.(34623105)
basics
- HHV-7 is similar overall to HHV-6, but it may be even less common.
- HHV-7 is a ubiquitous virus which commonly causes exanthema subitum in children. About 90% of children are infected, leading to lifelong latency with the possibility of subsequently reactivating.
epidemiology
- Uncommon, may affect patients status post hematopoietic stem cell transplantation.(30273244)
clinical features
- Acute HHV-7 in immunocompetent adults may rarely lead to neurological involvement (encephalitis, acute myeloradiculopathy, encephalo-radiculomyelitis, acute myelitis, or optic neuritis).(31378872)
diagnosis
- CSF PCR may reveal HHV-7, but this doesn't necessarily prove presence of acute infection (since HHV-7 may be found in normal brain tissue).(31378872)
- Rising antibody titers may support infection, but these take time to develop.
- MRI may show focal hyperintensity on T1 sequences, with gadolinium enhancement.
treatment
- No high-quality data exists regarding treatment.
- Treatment may include ganciclovir and possibly IV immunoglobulin.(31378872)
basics
- Enteroviruses are a group of protein-encapsulated viruses spread via a fecal-oral route. Since they are protein-coated, they are tougher than herpesviruses and better able to survive outside the human body. Enteroviruses include polioviruses, coxsackieviruses, and echoviruses.
epidemiology
- As a collective group, enteroviruses are a relatively common cause of encephalitis, accounting for ~10% of cases.
- Transmission usually occurs via a fecal-oral route. In temperate climates, enteroviruses tend to occur in late summer and early autumn.(28076019)
- Outbreaks of more virulent strains may cause spikes of neurological disease (e.g., enterovirus D68 or enterovirus 71).
- Enterovirus D68 is unique among enterovirus in that it is spread primarily via a respiratory route (rather than a fecal-oral route).
- (Enterovirus 71 is discussed in further detail below.)
- Enteroviruses are very common, but most people who are infected don't develop encephalitis. Encephalitis is more common among immunosuppressed patients, especially patients with hypogammaglobulinemia (e.g., patients previously treated with B-cell ablating therapies such as rituximab).
non-neurologic manifestations
- Some enteroviruses may produce signature syndromes outside of the neurologic system, which may help suggest the diagnosis. The following are some examples:
- Conjunctivitis.
- Pericarditis or pleurodynia.
- Herpangina (painful vesicles in the posterior oropharynx).
- Hand-foot-and-mouth disease.
encephalitis: clinical features & imaging
- Enteroviruses overall are generally less severe than other viral causes of encephalitis (e.g., coma is rare).
- EV71 (enterovirus 71) may be more severe:
- Affects younger adults, often manifesting with hand, foot, and mouth disease.
- May involve the brainstem and cerebellum (rhombencephalitis). Clinical features may include cranial nerve palsies, conjugate gaze abnormalities, nystagmus, ataxia, and coma.(28076019)
- Neurogenic pulmonary edema 📖 may occur, which carries a high mortality (possibly due to involvement of the vagus nerve dorsal nuclei and medial reticular formation in the posterior medulla).(28076019)
- Imaging:
- Encephalitis causes MRI abnormalities in only half of cases.
- Some patients have temporal lobe inflammation that mimics HSV encephalitis.
- Patients with rhombencephalitis may show T2 hyperintensity involving the medulla, pons, cerebellar dentate nuclei, and midbrain (sparing the corticospinal tracts).(28076019)
acute flaccid paralysis / acute flaccid myelitis: clinical features & imaging
- May be especially associated with enterovirus D68 or enterovirus 71.
- Often causes rapid onset (within 2-4 days) of asymmetric limb weakness, usually with hyporeflexia/areflexia.(34618764)
- Pain and sensory abnormalities are common, including paresthesias and numbness.
- Imaging: Myelitis may be associated with longitudinally extensive T2 hyperintensities of the gray matter (especially involving the cervical cord), sometimes with cranial nerve involvement.(34010967)
laboratory evaluation
- CSF usually shows a mild lymphocytic pleocytosis (with a median of 100 WBC/mm3)(Torbey 2019)
- CSF protein levels are often mildly elevated, with a normal glucose level.
- Viral PCR is very sensitive.
treatment
- There is no specific therapy.
- IVIG (intravenous immunoglobulin) may be used in patients with severe B-cell dysfunction (e.g., chronic agammaglobulinemia, or patients treated with B-cell ablating therapies such as rituximab).
basics
- West Nile virus is widely distributed throughout many parts of Africa, West Asia, Eastern Europe, Australia, and the Middle East. Recently it has emerged within the United States as the most important cause of arboviral meningitis, encephalitis, and anterior myelitis (causing acute flaccid paralysis).
epidemiology
- West Nile virus is an arbovirus, which is vectored by mosquitoes. Infection classically occurs between late spring and early fall.(34623097) However, due to global warming this season may extend later into the fall (if mosquitoes aren't killed off by frost in the early fall). In some warmer areas, West Nile virus can occur year-round.
- Incubation may range from 2-21 days.
- West Nile virus is the second most common cause of viral encephalitis in the United States after HSV, although rates vary depending on locale.(Mandell 2020)
- Only ~0.7% of infected people develop neuroinvasion. Risk factors for neuroinvasive disease include:
- Age >50 years old.
- Diabetes, chronic renal disease, or other chronic illness.
- Immunosuppression (including malignancy, chemotherapy, transplantation).
general clinical features
- Fever is extremely common.
- Maculopapular rash in about a third of patients.(28579869)
- Nausea/vomiting, anorexia.
- Back pain, myalgias.
- Headache, meningitis.
- Encephalitis, myelitis (more on these below).
clinical features of encephalitis
- Brainstem involvement may cause early loss of consciousness, cranial neuropathies (especially facial palsy), bulbar dysfunction, or respiratory failure.(34623096)
- Involvement of deep gray matter may cause extrapyramidal symptoms (e.g., coarse arm tremors, rigidity, bradykinesia, and/or myoclonus).(34623097) This may be a unique feature that helps suggest West Nile virus.(Jankovic 2022)
clinical features of myelitis
- Involvement of the anterior horn neurons leading to acute flaccid paralysis in the first 1-2 days of illness.(30245771) The basic attributes are as follows:
- Progressive weakness that is often initially asymmetric (e.g., beginning with monoparesis). In severe cases, this may progress to quadriplegia with acute neuromuscular respiratory failure.(34618763) The nadir weakness is usually reached within a week.(16295031)
- Reflexes are usually reduced or absent.(30245771)
- Sensory changes are usually absent.
- Bowel or bladder dysfunction may occur.(34010967)
- Patients presenting predominantly with myelitis often have simultaneous meningoencephalitis as well (e.g., tremor; see section above).
- ⚠️ The combination of meningoencephalitis plus acute flaccid paralysis may lead to confusion regarding lesion localization.
- West Nile virus myelitis may masquerade as Guillain-Barre syndrome. Features arguing against a diagnosis of Guillain-Barre syndrome include: (34618763)
laboratory diagnosis
- Basic CSF studies are similar for encephalitis and/or myelitis:
- Cell count is typically ~133-321/uL.(Mandell 2020)
- Early on there is often a neutrophilic predominance, but eventually this shifts towards a lymphocytic predominance.(34623097) If seen, the presence of a neutrophilic pleocytosis may suggest West Nile Virus, rather than various other arboviruses.(Wijdicks 2019)
- Protein is mildly elevated.
- Glucose is usually normal, but can be reduced.
- CSF PCR has moderate sensitivity (~60%), but it is specific.(Mandell 2020) Profoundly immunocompromised patients may fail to mount an antibody response, rendering PCR more sensitive.
- CSF testing for IgM and IgG antibodies against West Nile virus is generally more sensitive than PCR.
- IgM is indicative of neuroinvasive disease, because large IgM antibodies are poorly transported from the serum into the CSF.
- IgM takes time to develop, emerging within the CSF after one week in 95% of patients.(30245771) Repeat CSF evaluation may be needed to allow time for IgM to develop.
- IgM may persist for a year or longer, so this doesn't necessarily prove the presence of an acute infection.(Mandell 2020)
- Serum IgM antibodies against West Nile virus may support the diagnosis, but these may not appear within the first week. Specificity is limited, because IgM may remain in the serum for a year or more – so the presence of IgM doesn't necessarily establish an acute infection. Additionally, antibodies may cross-react with other flaviviruses (e.g., yellow fever, dengue virus, and Japanese encephalitis virus).(Jankovic 2022)
imaging
- Encephalitis:
- Imaging is normal in about half of patients.
- MRI may show diffusion restriction with or without hyperintensity on T2/FLAIR. Prognosis is more favorable if abnormalities are seen only on diffusion-weighted imaging.(28076019)
- Abnormalities are especially located in the bilateral lentiform nuclei (globus pallidus and putamen), caudate nuclei, and thalami. Other sites of involvement may include the brainstem and cerebellum. (Wijdicks, 2019)
- Leptomeningeal or periventricular enhancement is seen in about a third of patients.(28076019)
- In any case of encephalitis in which deep gray matter lesions are present, West Nile virus or other arboviruses are strong considerations.(34623096)
- Myelitis:
management
- Treatment is supportive; there is no specific therapy available.
going further
- Case report: 67-year-old man with fever, back pain, and lower extremity weakness (Reilkoff et al. PMID 16295031) 📄
basics
- Epizootic virus vectored by mosquitoes and birds in the eastern United States during the summertime.
- EEE is the most severe arbovirus encephalitis in the United States, with a mortality of about 50%.
symptoms
- Fever and headache occur initially, with rapid progression to delirium and coma.
- Meningeal irritation, seizures, focal neurologic deficits, and hypersalivation are common.(Jankovic 2022)
- Brainstem involvement is common, with associated gaze palsies, nystagmus, and pupillary abnormalities.(Mandell 2020)
laboratory evaluation
- CSF commonly reveals 500-3000 WBC/uL with a neutrophilic predominance, as well as elevated protein levels. Glucose levels are generally normal, but may be low. Red blood cells are common, reflecting the necrotic and hemorrhagic features of the encephalitis.(Mandell 2020)
- Diagnosis is based on PCR from the serum or blood, or isolation of IgM in the CSF or serum.
imaging
- Similar to West Nile virus, abnormalities are predominantly located in the basal ganglia, thalamus, and brainstem. EEE may be suggested by the “parentheses sign” – linear areas of T2/FLAIR hyperintensity in the internal and external capsules, with sparing of the lentiform nuclei.
- Diffuse cerebral edema may be seen.(Mandell 2020)
management
- No specific antiviral therapy is available.
- Supportive care may include monitoring of intracranial pressure and seizure management.
basics
- JC virus (John Cunningham virus) is an opportunistic pathogen that may cause PML (progressive multifocal leukoencephalopathy) – a gradually progressive demyelinating disorder.
- Most people acquire JC virus in childhood, with subsequent latent infection. Impairment of T-cell immunity later in life may cause viral reactivation.(33273175)
- JC virus usually infects oligodendrocytes (cells involved in myelination), so inflammation is limited to the white matter.
epidemiology: patients generally have a specific risk factor
- HIV (with CD4+ <200/mm3).
- Hematological malignancies (e.g., chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, Waldenstrom macroglobulinemia).(31483060)
- Transplantation.
- Immunomodulating & antineoplastic medications including adalimumab, alemtuzumab, brentuximab vedotin, cyclophosphamide, cyclosporine, dimethyl fumarate, efalizumab, fingolimod, methotrexate, mycophenolate mofetil, obinutuzumab, ofatumumab, rituximab.(34623105; 33273175) PML has been especially linked to natalizumab (a monoclonal antibody that blocks lymphocyte binding to alpha-4 integrin, which inhibits lymphocyte entry into the CNS).
- Chronic infectious or inflammatory disorders, such as tuberculosis and sarcoidosis.(Jankovik 2022)
clinical findings
- Progression usually occurs over weeks to months, with cognitive dysfunction often as a presenting feature. Other features may include personality changes, limb weakness, sensory abnormalities, cerebellar ataxia, dysarthria, and visual defects (cortical blindness).
- Headache, seizures, or extrapyramidal syndromes are rare.(Jankovic 2022)
laboratory evaluation
- CSF cell counts and protein level are usually normal or mildly abnormal (with mild elevation of white blood cell count or moderately elevated protein).(Jankovic 2022; 33273175)
- In HIV-associated PML, cell counts are usually <20 cells/uL.(Louis 2021)
- CSF PCR is ~80% sensitive and ~95% specific.(31378872) However, the performance may depend on context: (Mandell 2020)
- Patients with HIV may have higher viral loads, making PCR more sensitive.
- Patients with drug-induced progressive multifocal leukoencephalopathy (e.g., natalizumab) may have lower viral loads, making PCR less sensitive.
imaging
- General lesion properties:
- Imaging may show one or many confluent white matter lesions, which are often asymmetric.
- The supratentorial lobar white matter is most frequently affected (especially in the parieto-occipital lobes), with the cerebellar peduncles affected second most often.(31964490) Other sites of involvement may include the brainstem and spinal cord. U-fibers may be involved, giving the white matter abnormality a scalloped appearance.(28466277)
- Some mass effect may occur initially, but this is not a prominent feature. Over time, any mass effect is lost and this transitions to atrophy with volume loss.(31964490)
- CT findings:
- Lesions may appear hypodense and nonenhancing.
- MRI findings:
- Lesions are generally hyperintense on T2/FLAIR and hypointense on T1. FLAIR is useful to discern lesions abutting the ventricles.
- Patchy diffusion restriction may occur at the leading edge of newer lesions, but this is lost over time.
- Vasogenic edema or contrast enhancement isn't seen in HIV patients (with the exception of immune reconstitution inflammatory syndrome). Contrast enhancement may be seen in HIV-negative patients with progressive multifocal leukoencephalopathy.
- Sorting out PML vs. multiple sclerosis:
- PML causes larger, more diffuse, and less well-demarcated lesions compared to multiple sclerosis.(31378872)
- PML and multiple sclerosis have different distributions. PML tends to spare the periventricular region, which is commonly involved in multiple sclerosis.(31378872) Crescentic cerebellar lesions and/or deep gray matter lesions suggest PML, whereas involvement of the optic nerve, spinal cord, and/or brainstem favor multiple sclerosis.(31378872)
- Multiple sclerosis lesions show homogeneous or open-ring enhancement, whereas PML lesions enhance less often and in a sparse, peripheral pattern.(31378872)
management
- Immunosuppressive medications should be discontinued.
- HIV patients may be managed with antiretroviral therapy.
- Immune checkpoint inhibitors (e.g., PD-1 inhibitors pembrolizumab or nivolumab) might be useful to enhance immune responses to the JC virus. Some case series have reported favorable results.(33273175; 30969503)
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To keep this page small and fast, questions & discussion about this post can be found on another page here.
- Avoid assuming that a positive PCR result necessarily indicates active infection. For several viruses (especially human herpesvirus 6), a positive PCR result often doesn't reflect active disease.
- Post-HSV encephalitis often represents autoimmune anti-NMDA receptor encephalitis, rather than a recurrence of HSV. Both processes should be carefully considered, with a high index of suspicion for anti-NMDA receptor encephalitis.
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