Neuro-Oncology
NF2-related schwannomatosis
Dec. 13, 2024
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Support: service@medlink.com
Editor: editor@medlink.com
ISSN: 2831-9125
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Varicella-zoster virus causes chickenpox (varicella) during primary infection, often in childhood. The virus becomes latent in dorsal root ganglia and can reactivate years later to produce shingles (zoster, zona) in adults, as well as postherpetic neuralgia and vasculopathies, which may involve brain, spinal cord, cranial nerves, or peripheral nerves or plexus. Diagnosis of varicella-zoster virus infection of the central and peripheral nervous system is critical as antiviral therapy can suppress productive infection with clinical benefit.
• Varicella-zoster virus central nervous system infection can have various presentations, including encephalitis, meningitis, cranial neuropathies, vasculopathy, and myelitis. | |
• Varicella-zoster virus has been identified as accounting for 15% to 23% of viral encephalitis in the United States (79). | |
• The absence of a rash or history of shingles does not exclude the possibility of varicella-zoster virus meningoencephalitis, myelopathy, or vasculopathy (29; 72). | |
• Identifying varicella-zoster virus as the etiology of CNS involvement can be challenging especially in the setting of no preceding rash. However, a rapid and accurate diagnosis is paramount as early initiation of antivirals is likely to improve patient outcomes. |
Varicella-zoster virus causes chickenpox (varicella) as a primary infection in childhood or, more rarely, in adults. The virus then becomes latent in neurons of dorsal root ganglia, cranial nerve ganglia, and autonomic ganglia. Varicella-zoster virus can reactivate years later to produce shingles (zoster) in adults. Chickenpox is a generalized exanthem, whereas shingles is usually limited to one or more adjacent sensory dermatomes. However, in immunocompromised individuals, systemic involvement can be seen in the setting of reactivation. Herpes zoster was described in medieval literature, and it was recognized as caused by varicella-zoster virus by the end of the 19th century (89). The relationship between varicella and zoster was not recognized until the end of the 19th century partially because varicella was not differentiated from variola (smallpox) (69). In 1888 Von Bokay suggested that chickenpox and shingles were related after observing that susceptible children could acquire chickenpox after exposure to adults with shingles (85). Varicella was shown to be infectious in 1875 by Steiner, and shingles in 1925 by Kundratitz (81; 48). The characteristic intranuclear inclusion bodies seen in varicella-zoster virus infections were described in chickenpox lesions by Tyzzer in 1906 and in shingles lesions by Lipschultz in 1921 (84; 54). In 1943 Garland suggested that shingles was due to the reactivation of latent varicella-zoster virus (25). The tissue culture and serologic studies of Weller and colleagues firmly established that chickenpox and shingles were due to a single etiologic agent (89; 90).
Developments include the use of polymerase chain reaction and in situ hybridization techniques to demonstrate that varicella-zoster virus DNA is latently present in trigeminal and thoracic ganglia (56). Specific prophylactic and therapeutic agents have also become available. Intravenous acyclovir is the mainstay of treatment for varicella-zoster virus dissemination and neurologic complications. Although not indicated for neurologic involvement, varicella-zoster virus immune globulin can prevent varicella infection in exposed seronegative pregnant women and immunocompromised children and newborns (05). A report of two neonates with severe varicella, despite intravenous immunoglobulin, suggests that infected infants should also receive acyclovir (75). In 1995 the U.S. Food and Drug Administration approved a live attenuated varicella-zoster virus vaccine (Varivax-Merck); this vaccine has been recommended for people 12 months of age or older, who are in good health and without a history of prior varicella-zoster virus infection (05).
The clinical manifestations of varicella-zoster virus infections can be divided into primary varicella zoster infection (chickenpox) and reactivated varicella-zoster virus infection (dermatomal shingles or disseminated herpes zoster). Varicella-zoster virus is a neurotropic human herpesvirus, and the cause of neurologic complications has been postulated as either direct viral invasion through retrograde infection of neurons or immune-mediated mechanisms (71; 59). In the setting of virus reactivation, varicella-zoster virus vasculopathy can occur as an uncommon but life-threatening neurologic complication for which clinical presentations will be discussed in more detail. Studies with Gilden and colleagues have identified the presence of varicella-zoster virus antigen in the adventitia of vessels walls, thus, supporting the mechanism of varicella-zoster virus spreading transaxonally from ganglionic afferent fibers to the artery (64). Pathologically, three main patterns have been described including large and small vessel vasculopathies and, rarely, ventriculitis (64). Clinically, patients can present with various manifestations, including encephalopathy, stroke, seizures, myelitis, cranial neuropathies, and even temporal arteritis.
In this section, both primary varicella-zoster virus and complications of virus reactivation will be discussed in detail as well as potential neurologic complications.
Acute primary varicella infection (chickenpox). Chickenpox is an exanthematous illness that occurs with primary varicella-zoster virus infection. The rash typically starts on the scalp and then spreads to the trunk. The distal extremities are usually involved to a lesser extent. Lesions of different ages are seen. Early lesions are rose-colored macules with clear vesicles in the center. Within hours, the vesicles become purulent and, later, dry and crusted. A prodromal syndrome of 1 to 2 days of fever and malaise is more likely to be seen in adults. During the exanthem, fever usually lasts for 2 to 3 days. Non-neurologic complications, such as varicella-zoster virus pneumonitis and secondary bacterial infections (58) can be seen; however, these complications are more common in adults compared to children. In some patients, the infection can be slight, with only rare skin lesions. Reye syndrome (nausea, vomiting, headache, and encephalopathy with progression to coma) historically has been seen in the setting of primary varicella infection; however, since the discontinuation of salicylate use in children, this complication is almost nonexistent (71).
Zoster or varicella-zoster virus reactivation. Herpes zoster can occur anywhere in the neuraxis, but it is most common in the thoracic region. The second most common involved area is the ophthalmic division of the trigeminal nerve; this can lead to ocular involvement and blindness. Herpes zoster is not only more common in immunocompromised patients, but it is also more likely in these patients to become generalized, with diffuse cutaneous lesions and internal organ involvement. In a study of 282 patients with varicella-zoster virus reactivation who were hospitalized in the department of neurology, the most common clinical manifestations were trigeminal nerve ganglionitis with rash, dorsal root ganglionitis with rash (most commonly in thoracic region), CNS infection (eg, encephalitis, meningitis, or myelitis), facial nerve palsy, and less commonly dorsal root ganglionitis with radiculitis (80). The age distribution in this cohort showed a sharp rise in incidence after the age of 50 years and peaking in the eighth decade of life (80).
Postherpetic neuralgia. Postherpetic neuralgia is persistence of the pain of herpes zoster for more than 4 to 6 weeks after the rash disappears and can persist for months to years (57). It is estimated that 5% to 20% of patients with zoster will develop postherpetic neuralgia (47); the risk increases in patients over the age of 60 years and cases with ophthalmic involvement (24).
Neurologic complications of varicella-zoster virus. Varicella-zoster virus is known to cause neurologic involvement; however, complications following primary infections are rare. The main neurologic syndromes related to primary acute varicella infections are acute cerebellar ataxia, meningitis, encephalitis, and myelitis; however, varicella-zoster virus can involve every level of the neurologic system, and prognosis appears to differ between different levels of involvement. In a retrospective review of 72 patients with confirmed varicella-zoster virus positivity by PCR in the cerebrospinal fluid, aseptic meningitis had a good prognosis, whereas the presence of encephalitis, myelitis, and stroke have a higher risk of mortality, peripheral involvement, and a long-term sequelae (49). Neurologic complications occur in approximately 1 in 2000 cases of varicella among children (74).
Acute cerebellar ataxia. Acute cerebellar ataxia is the most common extracutaneous complication of chickenpox in healthy children. It can precede the exanthema or, in rare cases, occur in the absence of an exanthema, but usually occurs 5 to 10 days after the rash (77; 19). Although most commonly seen as a neurologic complication of varicella-zoster virus infection in healthy children, it can be a rare manifestation of viral reactivation in adults (19). It usually presents with truncal ataxia and tremor. MRI findings can include bilateral and symmetric T2 hyperintense changes in the cerebellar cortex with or without associated contrast enhancement (93). Cerebrospinal fluid studies typically demonstrate a pleocytosis.
This illness is typically self-limiting, and generally there is complete recovery. Treatment remains unclear, but experts typically recommend IV acyclovir, which likely hastens recovery and reduces morbidity. That said, varicella-zoster virus cerebellitis is often self-limited, and patients typically recover within weeks without long-term sequalae (19). The pathophysiologic mechanism of cerebellar ataxia from varicella-zoster virus remains elusive with hypothesis including direct infection versus postinfectious, autoimmune mechanisms.
Meningitis or encephalitis. Both viral meningitis and encephalitis can be seen with primary varicella-zoster virus infection; furthermore, encephalitis is often severe, and most cases occur within weeks following the exanthema. In fact, varicella-zoster virus is likely the second most common pathogen causing severe sporadic viral encephalitis after herpes simplex infection (79). Many patients will present primarily with confusion and seizures. MRI is almost always abnormal, and findings can include ischemic or hemorrhagic changes. Cerebrospinal fluid studies typically demonstrate a pleocytosis and elevated protein.
Pathological studies have shown that many cases of encephalitis are due to either large or small vessel vasculopathy as a result of the viral infection of the vascular endothelium (22) rather than direct invasion of the brain parenchyma. Kleinschmidt-DeMasters and colleagues also mention involvement of oligodendrocytes to cause demyelination (45). In fact, the small vessel vasculopathy that leads to leukoencephalopathy was first described by Horten and colleagues and later confirmed by Morgello and colleagues (40; 62). Both demyelination and necrosis can be seen in the small vessel disease of varicella-zoster virus encephalitis (40; 62; 37; 04). This also supports that zoster reactivation can present as a post-infectious, immune-mediated demyelinating process typically seen in acute disseminated encephalomyelitis. Acute disseminated encephalomyelitis typically presents as encephalitis with progressive altered mental status, confusion, headache, and fever. MRI classically demonstrates multiple deep and subcortical white matter abnormalities, typically with gadolinium enhancement consistent with demyelination.
Myelitis. Varicella-zoster virus myelitis is less common than encephalitis. In the study of 282 patients with varicella-zoster virus reactivation admitted to the neurology service, 34 patients had CNS infection, in which eight patients (53%) had encephalitis, 15 (44%) had meningitis, and one patient (3%) had myelitis (80). Most cases of myelitis have a radiographical appearance and clinical presentation of typical transverse myelitis. The myelopathy characteristically presents with upper motor neuron signs, including weakness, hyperreflexia, and positive Babinski sign. Myelitis can be a complication of primary varicella-zoster virus infection or reactivation and can occur with or without the classical zoster rash. Although myelitis has typically been described in immunocompromised patients, it has also occurred in immunocompetent patients (31). MRI will typically show a longitudinally extensive lesion, likely with enhancement. The pathogenesis is likely similar to that of encephalitis with small vessel vasculopathy with or without demyelination and necrosis. Additionally, varicella-zoster virus vasculopathy has been reported in spinal cord infarction (31). If myelopathy is from infarction, diffusion-restriction abnormalities may be seen in the cord.
Cranial neuropathies. Varicella-zoster virus is latent in cranial nerve ganglia; therefore, multiple cranial nerve palsies can develop typically days to weeks after zoster (29). Involvement of these nerves can result in debilitating weakness and pain. Several classic syndromes have been described. Herpes zoster ophthalmicus refers to reactivation in the V1 trigeminal nerve dermatome and can lead to multiple complications, including cranial neuropathies, retinal necrosis, uveitis and scleritis, and even contralateral ischemic or hemorrhagic strokes (60). Ophthalmoplegia is a well-documented complication with involvement of cranial nerve 3, 4, or 6 or any combination of these. Optic neuritis has been reported in the immunocompromised as well as the immunocompetent and, even more rarely, after varicella-zoster virus vaccination (07; 39). Ramsay Hunt syndrome type 2 is caused by varicella-zoster virus of the geniculate ganglion and includes the combination of peripheral facial palsy and ipsilateral external auditory canal (zoster oticus) involvement. Patients commonly present with tinnitus, severe ear pain, hearing loss, vertigo, or nystagmus. Importantly, varicella-zoster virus associated polyradiculoneuritis (18) and polyneuritis cranialis (63; 30) have been reported in the absence of rash.
Arteritis. Varicella-zoster virus vasculopathy can manifest as a stroke, aneurysm, dissection, or other vascular abnormalities. Presentations can be acute and monophasic or chronic and progressive. Given varicella-zoster virus’ tropism for vessels, it can cause isolated ischemic and hemorrhagic infarcts (03) and the development of multiple cerebral aneurysms (53), and more recent evidence has suggested infection may lead to temporal arteritis or giant cell arteritis (68). Giant cell arteritis is typically seen in individuals over the age of 50 years, and diagnosis is made by clinical features including headaches, acute onset visual changes, jaw claudication, accompanying symptoms of polymyalgia rheumatic, and suggestive laboratory values including a high erythrocyte sedimentation rate (ESR). Diagnosis is confirmed with temporal artery biopsy. Studies have found varicella-zoster virus in the temporal arteries of some patients with signs and symptoms of giant cell arteritis, including patients found to be giant cell arteritis biopsy-positive as well as -negative (27). The mainstay treatment for giant cell arteritis is prolonged corticosteroids, but given these studies, the use of antiviral in addition to steroids has been suggested (30).
Rare cases of dissection resulting from varicella-zoster virus vasculopathy have been described (68). Two pediatric cases had a rash followed by carotid dissections in the setting of vigorous activity 2 to 4 weeks later (17).
A study of 20 varicella-zoster virus vasculopathy cases demonstrated 63% had rash, 67% had a CSF pleocytosis, 97% had braining imaging abnormalities, and 70% had angiographic abnormalities (67).
Acute inflammatory demyelinating polyradiculoneuropathy or Guillain-Barre syndrome. Acute inflammatory demyelinating polyradiculoneuropathy or Guillain-Barre syndrome has been identified as a rare complication of herpes zoster. A study done with data from a Taiwan health registry found that although GBS was a rare complication, the risk of GBS 2 months after herpes zoster was significantly higher compared to age- and sex-matched controls (44). Clinical features of GBS included progressive, symmetric muscle weakness and loss of deep-tendon reflexes over days to a week after symptom onset. Presentation severity can vary leading to weakness of respiratory, facial, and bulbar muscles.
Autonomic and gastrointestinal involvement. Varicella-zoster virus can infect and become latent in sensory, enteric, and other autonomic neurons. Reactivation in enteric neurons can cause a painful gastrointestinal disorder (“enteric zoster”) without cutaneous manifestation (26). Varicella-zoster virus has been identified to establish latency in autonomic ganglia as well (33).
Dementia (chronic sequelae). Studies have suggested that herpes simplex virus and/or varicella zoster infection are associated with an increased risk of dementia (78). A study conducted in Taiwan based on the National Health Insurance Research Database claimed that varicella-zoster virus was associated with an increased risk of dementia (HR = 1.11) (15), and a cohort study conducted in South Korea revealed that patients with varicella-zoster virus had a higher risk of dementia (adjusted HR = 1.12) (08). However, other studies report contradictory results with no association of varicella and dementia seen in the United Kingdom (87) or with the national Danish data (42). At this point data remain conflicting, and the link between varicella zoster virus and dementia remains unclear. From a pathological standpoint, some data have suggested that varicella infection may increase the toxic amyloid burden, thus contributing to amyloid-associated disease progression as a possible link (12).
Childhood chickenpox tends to be a benign, self-limited disease, and overall prognosis is good in immunocompetent children. However, in adolescent, adult, and immunocompromised individuals, the disease can be much more severe. Prior to the introduction to the varicella vaccine, acute complications were more prevalent; those primarily include secondary bacterial infections of skin and soft tissue, pneumonia, and hepatitis. The major complications of varicella-zoster virus infection are the generalized and reactivated infection, which are typically more severe in immunocompromised individuals. Postherpetic neuralgia can last for years or even decades and can be a significant source of morbidity. The prognosis for arteritis often depends on the extent of the neurologic involvement and underlying immunocompromising illness.
This is a case of a 32-year-old Brazilian male who moved to the United States about 8 years prior to presentation. He was diagnosed with HIV 6 years before he presented to the emergency department with fever, chills, headache, and right-sided face, eye, and jaw pain. He endorsed severe neck pain over the past week and dysphagia for 4 days. In terms of his HIV, he was anti-retroviral naïve, and his most recent CD4 count was 208 cells/mm3. When he arrived at the emergency department, he was febrile with a temperature of 102 degrees Fahrenheit. His physical examination was remarkable for multiple, small vesicular lesions on his face, neck, and chest. Due to poor mental status and respiratory distress, he was intubated shortly after his arrival. Off sedation he would open his eyes to voice and followed simple commands. Both pupils were reactive to light with asymmetry; left pupil was 6 to 4 mm, and his right pupil was 8 to 6 mm. His face was symmetric, and he moved all four extremities spontaneously and symmetrically. His reflexes were brisk throughout, and he had bilateral positive Babinski sign.
He had a non-contrast head CT that showed no evidence of hemorrhage, herniation, or mass effect, so a lumbar puncture was obtained. His CSF analysis demonstrated 1850 white blood cells (9% neutrophils, 68% lymphocytes, 19% monocytes), 805 red blood cells, total protein 337, and glucose 132 (with a serum glucose of 180). Negative infectious studies on the CSF included a Gram stain and culture with acid fast bacillus (AFB) stain and culture, herpes simplex virus (HSV) polymerase chain reaction (PCR), enterovirus PCR, cytomegalovirus (CMV) PCR, human herpes virus 6 (HHV-6) PCR, Epstein-Barr virus (EBV) PCR, West Nile IgG/IgM, and cryptococcal antigen. His varicella-zoster virus PCR was positive in the CSF. Varicella-zoster virus IgM and IgG were not tested in the CSF.
This patient was diagnosed with varicella-zoster virus meningoencephalitis and disseminated varicella-zoster virus infection in the setting of an immunocompromised state with HIV. He was started on intravenous acyclovir as well as meningitic dosing of vancomycin, ceftriaxone, and ampicillin until his CSF culture were negative for bacterial infection for 48 hours. Acyclovir was continued with dosing of 10 mg/kg every 8 hours for a total of 14 days. He was also started on antiretroviral therapy.
This case highlights the severity of varicella-zoster virus meningoencephalitis in an immunocompromised patient as his course was complicated by disseminated disease and vesicular eruption involving his face, neck, and chest. The classical appearance of the rash facilitated a rapid diagnosis in this case. He presented with typical findings of meningoencephalitis, including fever, nuchal rigidity, headache, and confusion. CSF studies were consistent with an infectious etiology and confirmed the diagnosis with varicella-zoster virus PCR positivity. Varicella-zoster virus antibodies in the CSF were not tested in this case; however, these would have been imperative to check in the setting of a negative PCR. Varicella-zoster virus PCR in the CSF have a sensitivity of 80% and specificity of 98% in patients with HIV, whereas varicella-zoster virus antibodies have a higher sensitivity (22). MRI findings show classical findings of varicella-zoster virus encephalitis, including ischemic changes and brainstem and cerebellar involvement.
Chickenpox and herpes zoster are due, respectively, to primary and reactivated infection by varicella-zoster virus, a human herpes virus.
In the animal model of varicella, varicella-zoster virus invades through the mucosa of the upper respiratory tract and oropharynx and possibly the conjunctiva. Initially, replication occurs at these primary inoculation sites in the head and neck. After an interval of 4 to 5 days, primary viremia occurs and disseminates the virus throughout the body. A week later, after replication in secondary sites (reticuloendothelial system cells), a second viremia leads to the exanthem. The total incubation period is usually 14 to 15 days, with a range of 10 to 20 days (91).
After primary varicella-zoster virus infection, the virus becomes latent in the sensory root ganglia. As immunity, particularly cellular immunity, wanes with age or disease, the virus reactivates, replicates in the dorsal root ganglia, and may travel down the sensory nerve to infect the skin in the dermatome innervated by the nerve, resulting in herpes zoster (64). In acute zoster, a hemorrhagic inflammation involving the dorsal root ganglia and nerve can be seen. In patients with postherpetic neuralgia, fibrosis and cell loss in the dorsal root ganglion with loss of myelin occur (88). Occasionally, the immune response is able to abort the cutaneous lesions but not the dorsal root ganglia virus replication with subsequent inflammation, necrosis, and fibrosis of the ganglia. In this setting, the patient may present with radicular pain without the skin lesions (zoster sine herpete) (35). Varicella-zoster virus DNA has also been detected in human nodose and celiac ganglion of the autonomic nervous system (33).
Varicella-zoster virus has been detected in the involved blood vessels, specifically in the setting of vasculopathy, this develops after the virus reactivates from ganglia and spreads transaxonally to arterial adventitia resulting in persistent inflammation (43).
Reactivation of varicella-zoster virus can also result in generalized infection, particularly in immunocompromised patients, presumably through a hematogenous route. This can result in granulomatous arteritis, which may lead to stroke, myelitis, meningitis, and encephalitis (29; 03).
Chickenpox is a highly contagious disease of childhood with a peak incidence in the Spring in temperate climates. Prior to the availability of the chicken pox vaccine in 1995, approximately 4 million cases occurred yearly in the United States. Since then, the incidence has fallen by over 80% per the Centers for Disease Control and Monitoring.
Herpes zoster is primarily a disease of the elderly and immunocompromised. The incidence in the United States is approximately four cases per 1000 persons annually and about 10 cases per 1000 persons over the age of 60 years, with almost 1 million cases per year occurring in the United States (92; 14). Risk increases with age. Unlike primary varicella, which is more common in the Spring, herpes zoster is not seasonal. Postherpetic neuralgia occurs primarily in patients older than 60 years of age and in about 5% to 20% of those with zoster (57). An increase in the incidence of herpes zoster has been noted in the United States population. Of note, studies have shown that the incidence of herpes zoster had begun to increase even before the implementation of the childhood varicella vaccine program (51; 38).
There are now vaccines for varicella (Varivax®, Merck) and zoster (Zostavax®, Merck; and SHINGRIX, GlaxoSmithKlein). The World Health Organization currently recommends that varicella vaccination be implemented in all countries where varicella is an important public health concern but only if resources allow for sustained vaccination rates of more than 80% as lower rates may be associated with increased morbidity and mortality among vulnerable populations (06).
A 2-dose immunization schedule for varicella vaccine has decreased the incidence of breakthrough varicella and is now recommended (02). Children should receive the first dose at 12 to 15 months and the second dose at 4 to 6 years old.
Varicella vaccine given to children within 3 days of varicella-zoster virus exposure may reduce the rate and severity of infection (55).
The lifetime risk of varicella-zoster virus reactivation is around 30% (86). Therefore, safe and effective vaccination has the potential to reduce the burden of varicella-zoster virus disease. Vaccination against varicella-zoster virus (Zostavax, a live vaccination) given to adults 60 years old and older resulted in decreased morbidity from herpes zoster and postherpetic neuralgia (70). In October 2017, a recombinant, adjuvanted zoster vaccine (Shingrix) was approved for the prevention of herpes zoster in adults over 50 years of age with recommended use in immunocompetent adults (23). The Shingrix vaccine has been shown to reduce varicella-zoster virus reactivation by more than 95% and, thus, has largely supplanted the live attenuated vaccine in the U.S. due to improved efficacy and safety (13). As of 2021, Shringrix has also received full FDA approval in the U.S. for administration for immunocompromised patients over the age of 18 years old (it was previously only approved for those over 50 years old).
As Shingrix is a non-live vaccine, it is considered safe in the immunocompromised population. There are two studies demonstrating the prevention of herpes zoster in autologous hematopoietic stem cell transplant recipients and those with hematological malignancies (20; 21).
For immunocompromised patients at risk for primary infection after varicella-zoster virus exposure, varicella-zoster virus immune globulin is recommended. Varicella-zoster virus immune globulin administration is also recommended for susceptible pregnant women but does not protect the fetus from sequelae (05). Varicella vaccine is not recommended for pregnant women (02). Herpes zoster, meningitis, and encephalitis due to the varicella-zoster virus strain in the varicella vaccine have been reported (52; 41; 16). CNS vasculopathy due to vaccine varicella-zoster virus strain has been reported in patients with DOCK8 deficiency (76).
Although chickenpox has a distinctive rash, the differential diagnosis includes other childhood viral exanthems.
Herpes zoster also has a unique presentation; however, when rash is not present (eg, zoster sine herpete), it can be difficult to distinguish from other radiculopathies (35). Varicella-zoster virus-associated arteritis is usually distinguished from other types of arteritis by its association with chickenpox or zoster, particularly herpes zoster ophthalmicus. Varicella-zoster virus encephalitis is often, but not always, associated with the zoster rash. Varicella-zoster virus encephalitis presents with the typical findings of encephalitis, including altered mental status, seizures, fever, or focal neurologic deficits. There can be clues on brain MRI with ischemic or hemorrhagic infarcts. Therefore, other encephalitides that present with a complication of ischemic or hemorrhagic infarcts must be considered in the differential diagnosis, such as herpes zoster virus encephalitis, infectious endocarditis, syphilis, tuberculosis, fungal meningitis, certain arboviruses such as West Nile Virus, and the autoimmune vasculitides (73).
The diagnosis of chickenpox and herpes zoster is primarily clinical. Tzanck smears of the skin lesions may demonstrate intranuclear inclusions. Virus from vesicles can be isolated in cell culture. PCR testing of skin vesicle fluid in chickenpox and herpes zoster may identify varicella-zoster virus. Diagnosis of vaccine-modified varicella is challenging, and PCR testing of the macular or popular lesions often seen can confirm diagnosis (50). Antibody titers rise after primary varicella-zoster virus infection and can be used to confirm diagnosis retrospectively. Patients with zoster or immune deficiency may not demonstrate a rise in antibodies.
In varicella-zoster virus encephalitis, brain imaging may show large and small ischemic or hemorrhagic infarcts, often both. Deep-seated ischemic or demyelinating white matter lesions often predominate (04). The EEG shows nonspecific slowing. Varicella-zoster virus is almost never isolated from CSF by culture, but CSF can be examined by PCR for detection of varicella-zoster virus DNA (46). CSF antibodies to the varicella-zoster virus may also be found in varicella-zoster virus infections of the nervous system and in the setting of vasculopathy, particularly more chronic presentations, are more sensitive than PCR in varicella-zoster virus vasculopathy (66). For more acute, encephalitic clinical pictures, DNA PCR testing is often sufficient. However, if CNS disease is suspected, CSF should be examined for both varicella-zoster virus DNA by PCR and varicella-zoster virus–specific antibody. There are newer meningitis Biofire FilmArrays© available that allow for broad infectious testing with a multiplex PCR, thus, allowing the ability to simultaneously test for several infectious agents. These methodologies appear to have acceptable-to-high sensitivities for identifying bacteria and some viruses, however not all of them. For varicella-zoster virus specifically, sensitivities for PCR were between 75.5% and 93.8%, and, importantly, antibody testing is not included (82). When there is clinical suspicion for varicella-zoster virus, it is best to still relay on the standard CSF varicella-zoster virus DNA by PCR and varicella-zoster virus–specific antibody. Pathologic specimens may show classic Cowdry A inclusion bodies and can be tested for varicella-zoster virus by in situ hybridization and PCR.
Childhood chickenpox tends to be a benign, self-limited disease. Primary or secondary varicella-zoster virus infection in immunocompromised individuals can be treated with acyclovir. Resistance can be a problem in individual patients, and foscarnet has been used to treat acyclovir-resistant varicella-zoster virus infections (36).
Varicella-zoster virus encephalitis, myelitis, and vasculopathy are treated with intravenous acyclovir. Gilden and colleagues suggest that patients with varicella-zoster virus vasculopathy be treated with 10 to 15 mg/kg of intravenous acyclovir every 8 hours for 7 to 10 days. Steroid therapy (prednisone 60 to 80 mg/day for 3 to 5 days) should be considered as well, in conjunction with acyclovir. Concomitant or delayed administration of corticosteroids may help mitigate the strong inflammatory cascade and immune response seen with the varicella-zoster virus infection; however, there are no randomized clinical trials available, and expert opinion is largely based on case reports and case series (65; 28). Immunocompromised patients may require longer treatment. Repeat CSF should be negative for varicella-zoster virus by PCR prior to discontinuing antiviral treatment (32). As varicella-zoster virus antigen is frequently found in temporal artery biopsies of patients with giant cell arteritis, consideration of the addition of antiviral therapy to corticosteroids for treatment of temporal arteritis has been suggested (34).
Famciclovir, used in the acute phase of herpes zoster, has been shown to reduce the duration of postherpetic neuralgia in patients older than 50 years of age who have a severe rash (83). Valacyclovir has also been shown to shorten the duration of postherpetic neuralgia in patients older than 50 years of age (10). Either valacyclovir or famciclovir is the preferred drug of choice over acyclovir for zoster due to less frequent dosing. As prompt antiviral therapy may not only shorten the acute phase of herpes zoster but also lessen the duration and severity of postherpetic neuralgia, prompt diagnosis and treatment are critical. Optimal duration of treatment is not clear.
The treatment of established postherpetic pain is often difficult. Recommended first-line therapies include tricyclic antidepressants (amitriptyline, nortriptyline, or desipramine), gabapentin and pregabalin, or topical lidocaine patches and second-line therapies with oral opioid therapy and topical capsaicin cream (57). Despite these therapies, postherpetic neuralgia pain can be intractable.
Primary varicella-zoster virus infection during pregnancy can result in severe pneumonia in the mother and premature labor and delivery (09). Varicella-zoster virus can cross the placenta and cause congenital varicella syndrome, resulting in limb anomalies, cutaneous scarring, chorioretinitis, and microcephaly (11). In a systematic review of 130 reported cases from 1947–2013, the estimated incidence of congenital varicella syndrome was 0.59% for women infected with varicella-zoster virus during the entire pregnancy and 0.84% for those infected during the first 20 weeks of pregnancy (01). Pregnant women who have not had chickenpox but are exposed to varicella-zoster virus should be treated with varicella-zoster virus immunoglobulin (05). If maternal varicella occurs during the week prior to delivery and the infant acquires the infection in utero or within days of delivery, the virus is usually disseminated, and the disease is usually severe because of a lack of maternal antibody to provide protection. Infants born to women infected with varicella-zoster virus during pregnancy without clinical features of varicella-zoster virus syndrome do not have an increased risk of neurologic sequelae (61).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Amanda L Piquet MD
Dr. Piquet of the University of Colorado received consulting fees from Alexion/AstraZeneca, EMD Serono, Genentech/Roche, and UCB.
See ProfileJohn E Greenlee MD
Dr. Greenlee of the University of Utah School of Medicine has no relevant financial relationships to disclose.
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