The challenging patient with varicella-zoster virus disease – Europe PMC Article

The challenging patient with varicella-zoster virus disease - Europe PMC Article

For about five years now I have suffered off and on from what everyone believes to be Zoster Sine Herpete (Shingles without the rash)  It is textbook, it’s like everything I’ve read in medical articles and journals and forums online. An extensive search for systemic disease and malignancy was negative. Thanks to such a lesion, real time-polymerase chain reaction (PCR) analysis on vesicle fluid swab was possible, thus revealing a significant number of VZV genome copies. We thus determined whether detecting VZV DNA in saliva facilitates identification of enteric zoster. “I was having exams at college and I got a rash in a band around one side of my waist. While it IS RARE that this occurs, nonetheless, it does. In case of multiple cranial nerve palsies of unknown etiology with mononuclear pleocytosis in CSF tumors of the skull base, meningitis tuberculosis, and meningeosis have to be excluded, and antiviral therapy should be discussed.

Primary infection usually causes varicella (chickenpox), after which virus become latent in ganglionic neurons along the entire neuraxis. I’ve tried to reason this out so many times in 5 years, is is menstrually related? Zoster is characterized by dermatomal distribution pain and rash (figure 1) and is frequently complicated by chronic pain (postherpetic neuralgia [PHN]) as well as meningoencephalitis, myelopathy, retinal necrosis, and vasculopathy, including multifocal VZV vasculopathy with temporal artery infection (figure 2). A major diagnostic challenge to the practicing neurologist is that all of these disorders can occur without rash, as well as months after rash, and frequently in the absence of a CSF pleocytosis or amplifiable VZV DNA in CSF. After recovery, VZV DNA and proteins were not detected in gastric biopsies or saliva. While young people do develop shingles, the disease most often strikes after age 40. Here’s hoping they will come up with some something to make daily activities more attainable.

PHN is operationally defined as dermatomal-distribution pain that persists for more than 3 months after zoster. Age is the most important risk factor. More than 30% of zoster patients >60 years of age develop PHN. PHN is also slightly more frequent in women and after trigeminal-distribution zoster.2 PHN may be due to a chronic ganglionitis from persistent viral infection. Chronic inflammatory cells were found in ganglia from patients with PHN of 2.5 months3 and 2 years4 duration; furthermore, VZV DNA and proteins were found in blood mononuclear cells of many patients with PHN.5,6 Although treatment of acute zoster with corticosteroids does not prevent PHN, some patients improved with intense antiviral treatment.7 Currently, treatment of PHN with IV acyclovir is not Food and Drug Administration (FDA)–approved. A noninvasive method is clearly needed to diagnose or suggest enteric zoster when a rash is absent. Like VZV, other herpesviruses can hide in the nervous system after an initial infection and then travel down nerve cell fibers to cause a renewed infection.

Shingles without rash is called “zoster sine herpete”. Combination therapy such as gabapentin and nortriptyline, morphine and gabapentin, or pregabalin with a lidocaine 5% patch may provide greater analgesic effects. Lower starting doses and slower titrations to therapeutic dose in elderly patients must be used. A newer potentially promising treatment is percutaneous peripheral nerve field stimulation. Under monitored anesthesia care, stimulating electrodes are placed subcutaneously over the area of maximal pain. Leads are connected to an external pulse generator for 2–14 days. The second group of patients with a characteristic rash clinically diagnosed as varicella or zoster served as a positive control; polymerase chain reaction (PCR) detected VZV DNA in cutaneous lesions.

The sensory ganglia, which are adjacent to the spinal cord and brain, relay information to the brain about what the body is sensing – heat, cold, touch, pain. If this works, they inject phenol to essentially “cut” the nerve to prevent it from sending the pain signal to your brain – repeat every 3-4 months and can lower your oral meds. Productive VZV infection of cerebral arteries causes ischemic and hemorrhagic stroke (VZV vasculopathy). VZV vasculopathy is not uncommon, given that herpes zoster affects >50% of individuals by 80 years of age and increases the risk of stroke by 30% within the following year and by 4.5-fold if zoster is in the ophthalmic distribution of the trigeminal nerve.9 Recognition, diagnosis, and treatment of VZV vasculopathy pose a significant challenge. Finally, immunocompetent patients with VZV vasculopathy should be treated with a full 14-day course of IV acyclovir, 10–15 mg/kg given 3 times daily. Immunocompromised patients or those with recurrent VZV vasculopathy may need a longer course. Since virus-infected arteries typically contain inflammatory cells, we give oral prednisone, 1 mg/kg daily for 5 days without taper.

Saliva was collected with OriGene-Discover kits (Ottawa, Canada) or on swabs placed in the mouth for approximately 3 minutes. Most people who get shingles re-boost their immunity to VZV and will not get the disease for another few decades. VZV should only come out once to cause shingles or other neurological disease. Recently, we encountered 2 elderly patients with clinical and laboratory features of GCA in whom temporal artery (TA) biopsy was negative for GCA. The first patient was an 80-year-old man with left ophthalmic-distribution zoster who developed painless ipsilateral loss of vision with elevated ESR and CRP, was diagnosed clinically with possible GCA, and treated with steroids without improvement of vision. TA biopsy was GCA-negative, but analysis revealed inflammation and VZV antigen in the adventitia, after which he was treated with IV acyclovir and vision improved.11 A second even more remarkable patient was a 75-year-old woman without a history of zoster, who developed left periorbital pain and loss of vision with elevated ESR and normal CRP; she was treated with steroids for presumed GCA and vision worsened. TA biopsy revealed inflammation and VZV antigen in the adventitia, and CSF analysis revealed the presence of anti-VZV IgG antibody with reduced serum/CSF ratios of anti-VZV IgG antibody compared to ratios for albumin and total IgG, indicative of intrathecal synthesis of anti-VZV IgG antibody; vision improved after antiviral treatment.12 Overall, we have learned that in some patients who manifest clinically as GCA but whose TAs are GCA-negative, VZV infected their extracranial temporal arteries and produced temporal arteritis.
The challenging patient with varicella-zoster virus disease - Europe PMC Article

In both patients (with and without zoster), treatment with steroids for presumed GCA resulted in no improvement or actual worsening of vision, VZV antigen was present in TA biopsies, and antiviral treatment improved vision. Digestion of WT strains, which contain 2 SmaI restriction sites, produces 153-, 79-, and 36-bp fragment sets, whereas vOka, which contains 3 SmaI restriction sites, produces 112-, 79-, 41-, and 36-bp fragment sets. Shingles pain can be mild or intense. Treatments often fail because the dose is not high enough or the doc went up too fast on the meds and the patient doesn’t have time to get used to side effects. Patients present with paraparesis with or without sensory features and often without rash. MRI of the spinal cord reveals longitudinal, serpiginous enhancing lesions in myelitis (figure 3B) and diffusion-weighted abnormalities after spinal cord infarction. CSF contains antibodies to VZV indicative of intrathecal synthesis, and treatment is with IV acyclovir.

Zoster sine herpete is defined as chronic radicular pain without rash caused by VZV. It was initially described in patients with dermatomal distribution radicular pain in areas distinct from pain with zoster rash.13 Virologic verification of zoster sine herpete was first provided by detection of VZV DNA in CSF14 or in blood mononuclear cells, as well as by detection of anti-VZV IgG antibody in CSF and a favorable response to antiviral therapy in patients with chronic radicular pain. Primary antibodies were omitted as a control. For most healthy people, shingles rashes heal within a few weeks, the pain and itch that accompany the lesions subside, and the blisters leave no scars. The Neurologist I was seen by told me that there were NO NERVES going to the area where I was experiencing the pain, it was my entire rib cage, even in between the ribs themselves. VZV infection produces acute retinal necrosis (ARN) or progressive outer retinal necrosis. ARN presents with periorbital pain and floaters with hazy vision and loss of peripheral vision.

Progressive outer retinal necrosis presents with painless loss of vision, floaters, and constricted visual fields with resultant retinal detachment. Multifocal, discrete opacified lesions begin in the outer retinal layers peripherally or posterior pole; only late in disease are inner retinal layers involved. Diffuse retinal hemorrhages and whitening with macular involvement bilaterally are characteristic findings. The presence of salivary VZV DNA was thus limited to the symptomatic phase of varicella or zoster. Other treatments to consider are anti-inflammatory corticosteroids such as prednisone. After the trial period if the doctor and myself agree that the stimulation is going to work for me they then implant the device permanently. Intravitreal injections of foscarnet and oral acyclovir have also been effective.

The best treatment for progressive outer retinal necrosis in patients with AIDS may be prevention with highly active antiretroviral therapy. In 2006, a VZV vaccine (Zostavax, Merck) that boosts cell-mediated immunity to VZV was approved by the FDA for immunocompetent individuals over age 60 years with no recent history of zoster. Zoster vaccine is safe and effective. When administered to people in this age group, Zostavax boosted VZV-specific T-cell–mediated immunity (CD4 and CD8 cells, CD4 and CD8 effector memory T cells, and CD8 early-effector T cells), with a half-life of the boost of at least 5 years.16 Clinically, the 3-year Shingles Prevention Study showed that Zostavax significantly reduced burden of disease due to zoster and PHN.17 Zostavax is given once after age 60. Five had gastroesophageal reflux, 2 had idiopathic gastroparesis, and 1 had chronic intestinal pseudo-obstruction. People who have been vaccinated against chickenpox are less likely to get shingles because the weak, “attenuated” strain of virus used in the chickenpox vaccine is less likely to survive in the body over decades. As a matter of fact, this was when they began doing every test known to man on each of my internal organs and zip, nada, nothing came up, after all the tests completed they began telling me it was “Atypical”, meaning ‘a unknown cause’ so they began telling me it was all in my head and I only wanted the narcotics.

Perhaps most importantly, vaccine supply has been repeatedly disrupted, which has reduced provider and patient interest as well as promotional efforts. Merck vaccine is now widely available, and the “shingles vaccine” is being widely advertised. Disparities in uptake based on race and ethnicity have also been noted. Unlike type 1 herpes simplex virus (HSV), which reactivates from latency in cranial nerve ganglia to produce mucosal lesions around the mouth and nose, and unlike type 2 HSV, which is latent in sacral ganglia and reactivates to produce genital herpes, VZV is latent in cranial nerve ganglia, dorsal root ganglia, and autonomic ganglia along the entire neuraxis; thus, zoster can occur anywhere on the body. VZV is latent in more than 90% of people. C, The difference in frequency between the detection of salivary VZV DNA in the group of patients with unexplained abdominal pain is significantly greater than that in the negative control population. And in people who still got the disease despite immunization, the severity and complications of shingles were dramatically reduced.

I broke out last September with the rash and that’s when I discovered that it was shingles. During latency, at least 12 VZV gene transcripts have been detected,18,19 although the latest state-of-the-art technology of multiplex reverse transcriptase PCR revealed no VZV transcripts at a postmortem interval of 9 hours or less.20 Considerable VZV research continues to focus on understanding the configuration of viral DNA and extent of viral gene expression in latently infected human ganglia with an eye toward preventing viral reactivation. VZV reactivation leads to herpes zoster, which is frequently complicated by PHN as well as meningoencephalitis, myelopathy, retinal necrosis, and vasculopathy, including VZV temporal arteritis. Thus, patients who present with these conditions should be queried for a history of zoster within the past year, since many of the neurologic conditions develop months after zoster. Furthermore, even without rash, VZV should be considered as a possible etiologic agent. For diagnosis of VZV-induced CNS disease, the CSF should be examined for both VZV DNA and anti-VZV antibody; in VZV vasculopathy and myelopathy, which are often protracted, detection of anti-VZV antibody is often more sensitive than PCR for VZV DNA. Immunoglobulin levels and numbers of circulating CD4, CD8, and natural killer cells were also normal.

The vaccine also reduced the number of cases of postherpetic neuralgia by two-thirds compared with the placebo.

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