CNS Viruses—Diagnostic Approach




Diagnosis of CNS viral infections is challenging; yet, significant progress in laboratory diagnosis of CNS infections has come through applications of serology and polymerase chain reaction (PCR) to CSF and tissues. Advances in molecular and laboratory techniques, together with neuroimaging, epidemiologic, and surveillance efforts, are yielding greater success in CNS viral diagnosis and treatment.


Some viruses, such as herpes simplex and rabies, specifically target the brain; for hundreds of others, the central nervous system (CNS) is an unusual but potentially devastating site of involvement. The pathogens range from common to rare, acute to chronic, and mild to fatal ( Table 1 ). Signs of primary infection vary from subclinical infection, detected only by the presence of antibodies, to systemic febrile illnesses with nervous system symptoms (headache, lethargy, photophobia) or frank meningeal or parenchymal CNS disease.



Table 1

Viral causes of encephalitis












































































































































































































































































































































Family Genus Virus or vernacular name Abbreviation
Herpesviridae Human herpesvirus Herpes simplex virus-1 (or Human herpesvirus 1) HSV-1
Herpes simplex virus-2 (or Human herpesvirus 2) HSV-2
Varicella-zoster virus VZV
Epstein-Barr virus EBV
Cytomegalovirus CMV
Human herpesvirus 6 HHV-6
Human herpesvirus 8 HHV-8
Cercopithecine herpesvirus Simian B virus B virus
Picornaviridae Human enterovirus Poliovirus types 1–3 Polio
Coxsackievirus gp A, gp B Coxsackie A or B
Echovirus types 1–33 Echovirus
Enterovirus types 70,71 AHC
Flaviviridae Flavivirus West Nile virus WNV
Japanese encephalitis virus JE
St. Louis encephalitis SLE
Murray Valley encephalitis Murray Valley
Kunjin Kunjin
Tick-borne encephalitis (Central European encephalitis) TBE-W
Tick-borne encephalitis (Far Eastern encephalitis) TBE-FE
Powassan POW
Louping III virus Louping Ill
Kyasanur Forest virus Kyasanur Forest
Modoc virus Modoc virus
Rocio virus Rocio
Dengue type 1–4 Dengue
Hepacivirus Hepatitis C virus HCV
Togaviridae Alphavirus Eastern Equine Encephalitis virus EEE
Western Equine Encephalitis virus WEE
Venezuelan Equine Encephalitis VEE
Everglades EVE
Semliki Forest virus SF
Me Tri virus Me Tri
Rubivirus Rubella (German measles) Rubella
Bunyaviridae Bunyavirus California serogroup (includes California encephalitis, La Crosse, Jamestown Canyon, Snowshoe Hare in US and relatives: Tahyna, Batai, Inkoo in Europe) California serogroup
Phlebovirus Rift Valley Fever virus Rift Valley Fever
Toscana virus Toscana
Rhabdoviridae Lyssavirus Rabies Rabies
Australian bat lyssavirus
Vesiculovirus Chandipura virus Chandipura
Paramyxoviridae Morbillivirus Measles Measles
Unclassified Hendra Hendra
Nipah Nipah
Rubulavirius Mumps Mumps
Respirovirus Human Parainfluenza Parainfluenza
Orthomyxoviridae Influenza A virus Influenza A Flu A
Influenza B virus Influenza B Flu B
Retroviridae Lentivirus Human immunodeficiency virus 1 HIV-1
Human Immunodeficiency virus 2 HIV-2
Deltaretrovirus Human T-lymphotropic virus 1 HTLV-1
Human T-lymphotropic virus 2 HTLV-2
Polyomaviridae Human polyomavirus (formerly papavovirus) JC virus (agent of PML) JCV
BK virus BKV
Arenaviridae Arenavirus Lymphocytic choriomeningitis LCMV
Lassa Fever virus Lassa Fever
Junin virus Argentine Hem. Fever
Machupo virus Bolivian Hem. Fever
Parvoviridae Parvovirus Parvovirus B19 Fifth disease
Poxviridae Orthopoxvirus Variola virus Smallpox
Vaccinia virus
Monkeypox virus Monkeypox
Reoviridae Coltivirus Colorado Tick Fever virus CTFV
Eyach virus Eyach
Seadornavirus Banna virus BAV
Rotavirus Rotavirus Rotavirus
Adenoviridae Adenovirus Adenovirus (serotypes 7, 12, 32) Adenovirus


Viral meningitis, an inflammatory response to viral infection of leptomeningeal cells and subarachnoid space, is characterized by fever, headache, photophobia, stiff neck, mild lethargy, or drowsiness. The presence of more severe alterations in consciousness, such as confusion, behavior disorders, stupor, or coma, leads to consideration of other diagnoses. Viral encephalitis, the manifestation of brain parenchymal viral infection, may be diffuse or focal. In diffuse encephalitis, altered mental status and seizures are early signs of disease. Focal findings, such as aphasia, visual disturbances, hemiparesis, movement disorders, or ataxia, if present, reflect predilection of some viruses for specific brain regions or cell types. Many patients with encephalitis also have associated meningitis (meningoencephalitis) and, in some cases, involvement of spinal cord or nerve roots (encephalomyelitis, encephalomyeloradiculitis). On the other hand, some viruses (rabies, simian B virus) produce encephalitis without meningeal involvement.


Diagnosis of CNS viral infections is challenging for several reasons. The physical findings may be nonspecific, ie, the basic clinical features of most types of viral meningitis or encephalitis are similar. Host factors can influence the clinical phenotype, with the same organism causing meningitis in a normal host also causing encephalitis or complex syndromes in immunocompromised patients. Rapid diagnostic tests are available for some but not all viruses. The sensitivity and specificity of polymerase chain reaction (PCR) is equivalent to serology for some viruses (West Nile virus [WNV]). Serology may show cross reactivity with related viruses. Culture diagnosis can be difficult, time-consuming, or unavailable. Time is critical because it is the brain.


Diagnostic decision making begins with a detailed history, with attention to recent travel, insect or animal bites, immunizations, occupational or other potential exposures, or immunosuppression. Then, physical examination findings, neurologic findings, laboratory tests, and imaging studies produce further guidance and support. The physician uses clinical, imaging, and laboratory studies to narrow the field, paying particular attention to diagnoses for which agent-specific treatment is available.


Physical examination aids to diagnosis


Specific physical examination features provide clues to the diagnosis of individual viruses. Viral exanthems are helpful when they occur. Vesicular eruptions occur at sites of inoculation of herpes simplex viruses and in dermatomal distribution when latent varicella zoster virus reactivates. “Hand, foot, and mouth disease” with vesicles on palms, soles, and buttocks, signifies enterovirus infection. Maculopapular rashes occur with EBV after ampicillin treatment; as “roseola” with human herpes virus-6 (HHV-6); and in Colorado Tick fever (CTF). A maculopapular rash beginning on the face/chest and extending downward is measles. Confluent erythema over the cheeks or distal purpura is seen with parvovirus .


Respiratory, ocular, cardiovascular, or systemic signs and symptoms point to additional diagnoses. Pharyngitis occurs with adenovirus or enterovirus (as “herpangina” or vesicles on the soft palate). Conjunctivitis is seen with adenovirus, enterovirus, or St. Louis encephalitis (SLE); and retinitis with cytomegalovirus (CMV), WNV, measles, rubella. Parotitis is associated with mumps or lymphocytic choriomeningitis virus (LCMV); orchitis with mumps, LCMV, or EBV; and lymphadenopathy with mumps or LCMV. Pneumonia is caused by influenza and parainfluenza; and myocarditis/pericarditis by enteroviruses, and gastroenteritis with rotavirus. Arthritis is associated with LCMV or parvovirus infections; myalgias with arboviruses; mononucleosis syndromes with Epstein-Barr virus (EBV) or CMV . High viremias typical of arboviruses cause “fever-arthralgia-rash” syndrome of WNV, CTF, Toscana (TOS), and Venezuelan equine encephalitis virus (VEE).




Neurologic aids to diagnosis


Besides the fever and signs of meningeal involvement characteristic of meningitis, patients with encephalitis will have evidence of either diffuse or focal brain involvement. Patients with encephalitis commonly have confusion, behavioral changes, or altered level of consciousness. Furthermore, every possible type of focal neurologic disturbance has been described in viral encephalitis. Specific signs and symptoms reflect sites of infection, inflammation, and injury.


Focal findings commonly encountered include aphasia, hemiparesis, ataxia, hyperkinetic or parkinsonian movement disorders, and cranial nerve deficits. Focal examination findings in a patient with encephalitis raises the possibility of herpes simplex virus type-1 (HSV-1) encephalitis ( Fig. 1 ) and necessitates neuroimaging studies to exclude brain abscess, subdural empyema, cranial extradural abscess, septic venous thrombosis, or infectious vasculitis with ischemic or hemorrhagic stroke and establish the safety of proceeding with the lumbar puncture. In cases with apparent involvement of spinal cord and/or nerve roots (encephalomyelitis, encephalomyeloradiculitis), spine MRI is performed to exclude compressive lesions.




Fig. 1


HSV-1 encephalitis. Axial T2-weighted images from a patient with HSV-1 encephalitis. Image at the level of the sylvian fissure ( left ) shows significant abnormalities of the right insular cortex and right medial thalamus. A more caudal section at the midbrain shows confluent right temporal polar and medial temporal signal abnormalities incorporating limbic structures ( center ). The most caudal section at the level of the pons shows the process extending to inferior portions of the right temporal lobe ( right ). Note relative sparing of brainstem and other noncontiguous areas.


HSV-1, accounting for 10% to 20% of viral infections of the CNS in the United States , is a common etiologic agent of focal viral encephalitis in North America. Japanese encephalitis (JE) virus is the most common cause of focal viral encephalitis in Asia ( Fig. 2 ) where there are 30,000 to 50,000 cases and 10,000 deaths from Japanese encephalitis each year . Other viruses causing focal encephalitis are WNV, St. Louis encephalitis virus ( Fig. 3 ), varicella zoster virus (VZV) ( Fig. 4 ), HHV-6, EBV, enteroviruses, Powassan’s virus, La Crosse virus, the equine encephalitis viruses, measles, Nipah virus, tick-borne encephalitis (TBE) viruses, and Influenza A .




Fig. 2


Japanese encephalitis. In a 6-year-old patient, axial T2-weighted sequences through the brainstem show remarkable signal abnormalities with involvement of tegmentum, sparing red nuclei and corticospinal tracts. There is tectal involvement, pontine sparing, and signal abnormalities surrounding the fourth ventricle. The pattern in the mesencephalon ( left ) simulates the face of a giant panda (occasionally referred to as “giant panda sign”).



Fig. 3


St. Louis encephalitis. Axial T2-weighted sequences. At the level of the lateral ventricles, the image shows bilateral near symmetric signal abnormalities involving opercular structures bilaterally ( upper left ). At the level of the sylvian fissures, the image shows symmetric involvement of insular cortex bilaterally and pulvinar nuclei of thalamus ( upper right ). A caudal section at level of midbrain shows involvement of substantia nigra, greater on the right side, and involvement of the remainder of mesencephalon, including red nuclei ( lower left ) (which is distinct from JE). The most caudal section at the level of the fourth ventricle shows circumventricular involvement of rhombencephalic areas ( lower right ).



Fig. 4


Varicella encephalitis. Axial T2-weighted ( upper left ) and sagittal T1 weighted ( lower left ) scans on admission show bilateral signal abnormalities of inferior cerebellar hemispheres with mass effect compressing the fourth ventricle and displacing the tonsils downward. Axial ( upper right ) and coronal ( lower right ) T2-weighted scans 5 weeks later show bilateral prominence of cerebellar fissures due to volume loss. The fourth ventricle has expanded beyond normal limits ( upper right ) and there is considerable loss of cerebellar gray matter ( lower right ).


Despite a large number of candidate viruses, a more limited group of viruses is responsible for most cases in which a specific cause is identified. In the United States, the most common causes of acute aseptic (viral) meningitis in both adults and children are enteroviruses and the most common causes of viral encephalitis are herpes simplex virus and arboviruses . Seasonal and geographic predilections for arboviruses and enteroviruses can be useful in their diagnoses. Arbovirus and enterovirus infections occur predominantly in summer, sometimes as classical seasonal epidemics. CMV, EBV, human immunodeficiency virus (HIV), VZV, and measles are less common, and other causes are rare. The less frequent pathogens may be associated with immunodeficiency, and testing for additional viruses is justified in these patients. Animal exposure or occupational data raise the possibility of other rare causes of meningitis and encephalitis: herpes (simian) B virus, LCMV, or rabies. Worldwide, there are tens of thousands of deaths from rabies each year . The more common causes of myelitis or motor neuronitis in the United States are WNV, the nonpolio enteroviruses, and HSV-2. Lumbosacral radiculitis without myelitis also occurs with HSV-2 and WNV ( Fig. 5 ).




Fig. 5


West Nile virus lumbosacral radiculitis. Sagittal ( left ) and axial ( right ) postcontrast fat-saturated images show diffuse enhancement of cauda equina nerve roots ( arrow ) beginning at the distal end of the spinal cord and extending caudally to the distal thecal sac. Lack of spinal cord involvement is consistent with lumbosacral radiculitis without myelitis.


Another form of encephalitis not due to direct viral infection of brain parenchyma but instead due to an alteration of normal immune function following recent viral infection or vaccination is acute disseminated encephalomyelitis (ADEM) ( Fig. 6 ). It is a monophasic demyelinating syndrome characterized by rapid development of focal or multifocal neurologic dysfunction and may follow vaccination or acute viral illness by 1 to 3 weeks. Postinfectious encephalomyelitis followed an estimated 1 in 1000 cases of measles, usually within 2 weeks of the rash . Before introduction of non-neural human diploid cell vaccine against rabies, postvaccination encephalomyelitis was estimated at 1 per 3,000 to 35,000 recipients for vaccinations prepared in rabbit brain or 1 per 25,000 recipients of duck embryo rabies vaccine . After primary smallpox vaccination, ADEM rates were reported as 1 in 4000 to 1 in 80,000 and after revaccination, from 1 in 50,000 to 1 in 450,000 . The clinical signs and symptoms—sudden fever, seizures, loss of consciousness, or focal deficits—can be identical to acute viral encephalitis. The onset of postinfectious or postvaccination disease is usually more abrupt and the ADEM patient need not be febrile.




Fig. 6


Acute disseminated encephalomyelitis (ADEM). Composite cervical-thoracic T2-weighted images from a patient with spastic quadriparesis 2 weeks after a respiratory illness showing near continuous signal abnormality from level C3 to distal T cord. Viral and MS studies were negative. The clinical and radiologic findings were consistent with ADEM and the patient made a full recovery after solumedrol treatment.




Neurologic aids to diagnosis


Besides the fever and signs of meningeal involvement characteristic of meningitis, patients with encephalitis will have evidence of either diffuse or focal brain involvement. Patients with encephalitis commonly have confusion, behavioral changes, or altered level of consciousness. Furthermore, every possible type of focal neurologic disturbance has been described in viral encephalitis. Specific signs and symptoms reflect sites of infection, inflammation, and injury.


Focal findings commonly encountered include aphasia, hemiparesis, ataxia, hyperkinetic or parkinsonian movement disorders, and cranial nerve deficits. Focal examination findings in a patient with encephalitis raises the possibility of herpes simplex virus type-1 (HSV-1) encephalitis ( Fig. 1 ) and necessitates neuroimaging studies to exclude brain abscess, subdural empyema, cranial extradural abscess, septic venous thrombosis, or infectious vasculitis with ischemic or hemorrhagic stroke and establish the safety of proceeding with the lumbar puncture. In cases with apparent involvement of spinal cord and/or nerve roots (encephalomyelitis, encephalomyeloradiculitis), spine MRI is performed to exclude compressive lesions.




Fig. 1


HSV-1 encephalitis. Axial T2-weighted images from a patient with HSV-1 encephalitis. Image at the level of the sylvian fissure ( left ) shows significant abnormalities of the right insular cortex and right medial thalamus. A more caudal section at the midbrain shows confluent right temporal polar and medial temporal signal abnormalities incorporating limbic structures ( center ). The most caudal section at the level of the pons shows the process extending to inferior portions of the right temporal lobe ( right ). Note relative sparing of brainstem and other noncontiguous areas.


HSV-1, accounting for 10% to 20% of viral infections of the CNS in the United States , is a common etiologic agent of focal viral encephalitis in North America. Japanese encephalitis (JE) virus is the most common cause of focal viral encephalitis in Asia ( Fig. 2 ) where there are 30,000 to 50,000 cases and 10,000 deaths from Japanese encephalitis each year . Other viruses causing focal encephalitis are WNV, St. Louis encephalitis virus ( Fig. 3 ), varicella zoster virus (VZV) ( Fig. 4 ), HHV-6, EBV, enteroviruses, Powassan’s virus, La Crosse virus, the equine encephalitis viruses, measles, Nipah virus, tick-borne encephalitis (TBE) viruses, and Influenza A .




Fig. 2


Japanese encephalitis. In a 6-year-old patient, axial T2-weighted sequences through the brainstem show remarkable signal abnormalities with involvement of tegmentum, sparing red nuclei and corticospinal tracts. There is tectal involvement, pontine sparing, and signal abnormalities surrounding the fourth ventricle. The pattern in the mesencephalon ( left ) simulates the face of a giant panda (occasionally referred to as “giant panda sign”).



Fig. 3


St. Louis encephalitis. Axial T2-weighted sequences. At the level of the lateral ventricles, the image shows bilateral near symmetric signal abnormalities involving opercular structures bilaterally ( upper left ). At the level of the sylvian fissures, the image shows symmetric involvement of insular cortex bilaterally and pulvinar nuclei of thalamus ( upper right ). A caudal section at level of midbrain shows involvement of substantia nigra, greater on the right side, and involvement of the remainder of mesencephalon, including red nuclei ( lower left ) (which is distinct from JE). The most caudal section at the level of the fourth ventricle shows circumventricular involvement of rhombencephalic areas ( lower right ).



Fig. 4


Varicella encephalitis. Axial T2-weighted ( upper left ) and sagittal T1 weighted ( lower left ) scans on admission show bilateral signal abnormalities of inferior cerebellar hemispheres with mass effect compressing the fourth ventricle and displacing the tonsils downward. Axial ( upper right ) and coronal ( lower right ) T2-weighted scans 5 weeks later show bilateral prominence of cerebellar fissures due to volume loss. The fourth ventricle has expanded beyond normal limits ( upper right ) and there is considerable loss of cerebellar gray matter ( lower right ).


Despite a large number of candidate viruses, a more limited group of viruses is responsible for most cases in which a specific cause is identified. In the United States, the most common causes of acute aseptic (viral) meningitis in both adults and children are enteroviruses and the most common causes of viral encephalitis are herpes simplex virus and arboviruses . Seasonal and geographic predilections for arboviruses and enteroviruses can be useful in their diagnoses. Arbovirus and enterovirus infections occur predominantly in summer, sometimes as classical seasonal epidemics. CMV, EBV, human immunodeficiency virus (HIV), VZV, and measles are less common, and other causes are rare. The less frequent pathogens may be associated with immunodeficiency, and testing for additional viruses is justified in these patients. Animal exposure or occupational data raise the possibility of other rare causes of meningitis and encephalitis: herpes (simian) B virus, LCMV, or rabies. Worldwide, there are tens of thousands of deaths from rabies each year . The more common causes of myelitis or motor neuronitis in the United States are WNV, the nonpolio enteroviruses, and HSV-2. Lumbosacral radiculitis without myelitis also occurs with HSV-2 and WNV ( Fig. 5 ).




Fig. 5


West Nile virus lumbosacral radiculitis. Sagittal ( left ) and axial ( right ) postcontrast fat-saturated images show diffuse enhancement of cauda equina nerve roots ( arrow ) beginning at the distal end of the spinal cord and extending caudally to the distal thecal sac. Lack of spinal cord involvement is consistent with lumbosacral radiculitis without myelitis.

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Mar 28, 2017 | Posted by in NEUROLOGICAL IMAGING | Comments Off on CNS Viruses—Diagnostic Approach
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