Postherpetic neuralgia, the most common complication of herpes zoster, is defined as pain in a dermatomal distribution that is sustained for at least 90 days after the rash. It occurs in approximately 20% of patients with herpes zoster, 27,28. And 80% of cases occur in patients 50 years or older. Zoster sine herpete - Shingles without a rash. Familiar to anyone? All symptoms come with a typical viral prodrome of mild fever, tachycardia, lethargy etc. These patterns had been getting progressively more frequent and severe in the past 6 months, so I decided to self-treat with Acyclovir 400mg twice daily.
Reactivation of varicella zoster virus (VZV) from latently infected human ganglia usually produces herpes zoster (shingles), characterized by dermatomal distribution pain and rash. Zoster is often followed by chronic pain (postherpetic neuralgia or PHN) as well as meningitis or meningoencephalitis, cerebellitts, isolated cranial nerve palsies that produce ophthalmoplegia or the Ramsay Hunt syndrome, multiple cranial nerve palsies (polyneuritis cranialis), vasculopathy. Myelopathy, and various inflammatory disorders of the eye. Importantly, VZV reactivation can produce chronic radicular pain without rash (zoster sine herpete), as well as all the neurological disorders listed above without rash. The protean neurological and ocular disorders produced by VZV in the absence of rash are a challenge to the practicing clinician. The presentation of these conditions vanes from acute to subacute to chronic.
Virological confirmation requires the demonstration of amplifiable VZV DNA in cerebrospinal fluid (CSF) or in blood mononuclear cells, or the presence of anti-VZV IgG antibody in CSF or of anti-VZV IgM antibody in CSF or serum. 1 IntroductionVaricella zoster virus (VZV) is an exclusively human neurotropic alphaherpesvirus Primary infection causes varicella (chickenpox), after which virus becomes latent in cranial nerve ganglia, dorsal root ganglia, and autonomic ganglia along the entire neuraxis. Years later, as cell-mediated immunity to VZV declines with age or immunosuppression, as in patients with cancer or AIDS or organ transplant recipients, VZV reactivates to cause zoster (shingles), a syndrome characterized by pain and a vesicular rash on an erythematous base in 1–3 dermatomes. Because VZV becomes latent in any and all ganglia, zoster can develop anywhere on the body. In most patients, the disappearance of skin lesions is accompanied by decreased pain and complete resolution of pain in 4–6 weeks.
Nevertheless, zoster is often followed by chronic pain (postherpetic neuralgia) as well as meningitis or meningoencephalitis, cerebellitis, isolated cranial nerve palsies that produce ophthalmoplegia or the Ramsay Hunt syndrome (RHS), multiple cranial nerve palsies (polyneuritis cranialis), vasculopathy, myelopathy and various inflammatory disorders of the eye, the most common of which is progressive outer retinal necrosis (PORN). Importantly, VZV reactivation can produce chronic radicular pain without rash (zoster sine herpete), as well as all the neurological disorders listed above without rash – the subject of this chapter. 2 Zoster Sine HerpeteThe concept of zoster without rash in not new and was initially suggested as a nosological entity by, who described a 38-year-old man with thoracic distribution pain, hyperesthesia, a dilated left pupil, a mononuclear pleocytosis in the cerebrospinal fluid (CSF), and a negative Wasserman test for syphilis.
Serologic studies for VZV were not performed. Later described two patients with segmental pain and weakness who ultimately developed facial and truncal zoster. In the largest series of zoster sine herpete, 120 patients were described as experiencing “zoster-type” pain without rash in a dermatome distribution distant from a dermatome with rash.
CSF examination revealed the modest mononuclear pleocytosis often encountered in patients with zoster, but serologic studies were not done.The first serologic confirmation of zoster sine herpete was reported by a physician who developed acute trigeminal distribution pain that lasted 16 days and was associated with a rise in complement-fixing antibody to VZV from 1:8 on day 15 to 1:128 on day 32 and no rise in antibody to herpes simplex virus (HSV). Later reported four patients, who years after trigeminal distribution zoster, developed pain without rash in the same distribution of the trigeminal nerve; unfortunately, none were studied virologically. Virologic confirmation of zoster sine herpete did not come until the analysis of two men, ages 62 and 66 years, with thoracic-distribution radicular pain that had lasted for months to years without zoster rash. An extensive search for systemic disease and malignancy was negative. VZV DNA, but not HSV DNA, was found in the CSF of the first patient 5 months after the onset of pain, and in the second patient, 8 months after pain onset.
After diagnosis, both men were treated successfully with intravenous acyclovir. A third virologically confirmed case of thoracic-distribution zoster sine herpete that persisted for years included the demonstration of frequent fibrillation potentials restricted to chronically painful thoracic root segments. In that case, the patient did not improve after treatment with intravenous acyclovir and oral famciclovir.Although the nosologic entity of zoster sine herpete as a clinical variant has now been established, its prevalence will not be known until a greater number of patients with prolonged radicular pain have been studied virologically. Analysis should include both PCR to amplify VZV DNA in CSF and in blood mononuclear cells (MNCs), as well as a search for antibody to VZV in CSF. The latter, even in the absence of amplifiable VZV DNA, has been useful to support the diagnosis of vasculopathy and myelopathy produced by VZV without rash Analysis of serum anti-VZV antibody is of no diagnostic value in patients with prolonged pain, because such antibodies persist in nearly all adults throughout life, and the presence of serum antibodies to different VZV glycoproteins and non-glycosylated proteins is variable. Zoster sine herpete is essentially a disorder of the peripheral nervous system (ganglioradiculopathy) produced by VZV without rash. VZV also produces disease of the CNS without rash (described below).
At the University of Colorado, School of Medicine, we have encountered more cases of VZV infection without rash in the CNS than in the peripheral nervous system. 3 Preherpetic NeuralgiaThe existence of ganglionitis without rash is supported by radicular pain preceding zoster, so-called preherpetic neuralgia. We studied six patients whose pain preceded rash by 7–100 days and was located in dermatomes different from as well as in the area of eventual rash. Two patients ultimately developed disseminated zoster with neurologic complications of zoster paresis and fatal zoster encephalitis; both had been taking long-term low-dose steroids. A third case of preherpetic neuralgia developed in a patient with prior metastatic carcinoma and a fourth was in a patient with an earlier episode of brachial neuritis.
Two subjects had no underlying disease. Further documentation of preherpetic neuralgia will determine whether its apparent association with steroid therapy and serious complications is statistically significant. 4 Meningitis/MeningoencephalitisMeningitis is characterized by headache, fever, and stiff neck.
Additional impairment of higher cognitive function, alterations in state of consciousness, or seizures indicate underlying parenchymal involvement (encephalitis). VZV involvement of the CNS without rash was verified by the intrathecal synthesis of antibodies to VZV in two patients with aseptic meningitis and later in four additional patients with aseptic meningitis , and in one patient with acute meningoencephalitis. Reported a patient with meningoencephalitis without rash whose CSF contained VZV DNA, and described a patient with encephalomyelitis without rash, in whom anti-VZV antibody was detected in the CSF. Most recently VZV meningitis with hypoglycorrhachia in the absence of rash developed in an immunocompetent woman. 5 Ramsay Hunt SyndromeThe strict definition of the RHS is peripheral facial nerve palsy accompanied by an erythematous vesicular rash on the ear (zoster oticus) or in the mouth. VZV causes the RHS.
Some patients develop peripheral facial paralysis without ear or mouth rash associated with either a fourfold rise in antibody to VZV or the presence of VZV DNA in auricular skin, blood MNCs, middle ear fluid, or saliva. In a study of 32 patients with isolated peripheral facial palsy, identified RHS zoster sine herpete in six (19%) of the patients based on a fourfold rise in serum antibody titer to VZV; four of these six patients were positive for VZV DNA by PCR when geniculate zone skin scrapings were studied.
Further, found that 9.3% of Bell's palsy patients seroconverted to VZV, and found that blood MNCs from 4 of 17 Bell's palsy patients were positive for VZV DNA by PCR. Thus, a small proportion of “Bell's palsy patients” (idiopathic peripheral facial palsy) have RHS zoster sine herpete. 6 Polyneuritis CranialisThere have been multiple instances of polyneuritis cranialis produced by VZV. The first report was of a 70-year-old man who seroconverted to VZV during acute disease. Another report described a 43-year-old man with acute polyneuritis cranialis who developed antibody in CSF to VZV but not to other human herpesviruses or to multiple ubiquitous paramyxoviruses or togaviruses.
Both men were immunocompetent. VZV-induced polyneuritis cranialis without rash has also been described in a patient with involvement of cranial nerves IX, X, and XI as well as upper cervical nerve roots without rash, and with anti-VZV antibody in the CSF. 7 CerebellitisWhile acute cerebellar ataxia (unsteadiness with or without tremor) is well-recognized as a potential complicating factor in childhood varicella , there is one report of a child who became ataxic 5 days before chickenpox developed. A virologically documented case of VZV cerebellitis without rash was in a 66-year-old man whose CSF at the time of presentation revealed mild lymphocytic pleocytosis and VZV DNA; 3 weeks later, anti-VZV IgG antibodies were detected in his CSF and additional analysis revealed intrathecal synthesis of anti-VZV IgG. A second case of acute cerebellitis caused by VZV in the absence of rash occurred in a middle-aged, immunocompetent woman; virological analysis of her CSF revealed VZV DNA and anti-VZV IgG antibody. The primary clue that led to the request for virological tests for VZV in the CSF of this patient was the patient's early age of chickenpox.
Interestingly, many individuals who develop zoster before age 60 had chickenpox before age 4 years (; ). The reason that early chickenpox predisposes to early zoster remains unknown, but is reminiscent of the observation that many patients with subacute sclerosing panencephalitis, a chronic fatal encephalitis caused by measles virus, had measles before the age of 2 years. 8 VasculopathyTransient ischemic attacks and focal deficit are not uncommon after VZV reactivation. A prototype fatal case of chronic progressive vasculopathy of 314 days' duration in an immunocompetent 73-year-old-man ( was virologically verified to be caused by VZV. Reported another case of VZV vasculopathy without rash with virological confirmation. Described an HIV-positive patient with fatal encephalomyelitis and necrotizing vasculitis without rash, pathologically verified to be caused by VZV. In the past two decades, there have been numerous reports of VZV vasculopathy without rash.
In fact, the largest study of virologically confirmed cases of VZV vasculopathy revealed that more than one-third of patients did not have rash. Even in a virologically confirmed case of spinal cord infarction caused by VZV, rash did not occur until 3 days after the onset of myelopathy. 9 MyelopathyAcute VZV myelopathy is usually characterized by paralysis in the legs, with bladder and bowel incontinence, and occurs in the absence of rash. Initially described a 31-year-old immunocompetent man who developed transverse myelitis with partial recovery.
Disease was attributed to VZV based on the development of antibody in CSF. Later, we encountered two patients with VZV myelopathy in the absence of rash. The first patient developed zoster followed by myelopathy 5 months later, when PCR-amplifiable VZV DNA was detected in CSF. The second equally fascinating patient developed myelopathy at the time of acute zoster.
The myelopathy resolved, but recurred 6 months later. Five months after the recurrence of myelopathy, the patient's CSF contained both amplifiable VZV DNA as well as antibody to VZV. Another case of recurrent VZV myelopathy revealed anti-VZV IgG in CSF with reduced serum/CSF ratios of anti-VZV IgG at the time of recurrence in the absence of rash Overall, the spectrum of VZV myelopathy is broad, ranging from acute to chronic and rarely recurrent. 10 Ocular DisordersAn emerging body of literature describes multiple ocular inflammatory disorders produced by VZV in the absence of rash. VZV is the most common cause of PORN.
Multiple cases of PORN caused by VZV in the absence of rash have been described (; ). A case of severe unremitting eye pain without rash was proven to be caused by VZV based on the detection of VZV DNA in nasal and conjunctival samples. Other cases include third cranial nerve palsies , retinal periphlebitis , uveitis (; ), iridocyclitis , and disciform keratitis , all without rash and all confirmed virologically to be caused by VZV. 11 Remarkable Cases of VZV Infection Without RashTwo remarkable cases of VZV infection without rash deserve mention. The first and most extreme example of VZV infection of the nervous system that we encountered was a 77-year-old man with T cell lymphoma and no history of zoster rash who developed meningoradiculitis of the cranial nerve roots and cauda equina; he died 3 weeks after the onset of neurologic disease, confirmed pathologically and virologically to have been caused by VZV. Autopsy revealed hemorrhagic inflammatory lesions with Cowdry A inclusions in the meninges and nerve roots, extending from cranial nerve roots to the cauda equina.
The same lesions were present in the brain, although to a lesser extent. VZV antigen and nucleic acid, but not herpes zoster virus (HSV) or cytomegalovirus antigen or nucleic acid, were found in the infected tissue at all levels of the neuraxis. Thus, VZV should be included in the differential diagnosis of acute encephalomyelor-adiculopathy, particularly since antiviral treatment is available.The second case was an immunocompetent 45-year-old woman with a 13-month history of right facial numbness and “lightning bolt-like” pain in the maxillary distribution of the right trigeminal nerve.
Initially, numbness was present over the right side of the nose adjacent to the zygoma, and a light touch over this area or the right forehead produced pain (allodynia) over the entire face. Neurological examination revealed loss of pinprick sensation in the maxillary distribution of the right trigeminal nerve. Fifth nerve motor function and the corneal reflex were intact. The CSF was acellular. Brain scanning by both computerized tomography (CT) and MRI was normal. She was treated with neurontin, 900 mg three times daily, but her pain increased. One year later, both CT and MRI scans revealed a 0.9 × 0.9 × 2.0-cm homogeneously enhancing mass at the base of the right brain at the site of the trigeminal ganglion.
There was never any history of zoster rash. The tumor was removed surgically. Pathological and virological analysis of the trigeminal ganglionic mass confirmed chronic active VZV-induced ganglionitis.
12 Systemic Disease Produced by VZV Reactivation Without Rashreported a case of fatal hepatic necrosis caused by VZV in a 64-year-old woman. She had undergone splenectomy 14 months before the fatal hepatitis. The postmortem diagnosis was based on characteristic pathological changes in the liver, the detection of herpesvirus virions in liver by electron microscopy, and serologic evidence of recent VZV infection. A report of fulminant fatal disseminated VZV infection without rash occurred in an 8-year girl undergoing chemotherapy for leukemia; virus was present in blood, lungs, liver, kidneys, and bone marrow. Although the nervous system was spared in both patients, these cases confirm the existence of disseminated VZV infection of multiple organs in the absence of rash.
13 Subclinical VZV ReactivationAll of the above reports support the notion that VZV can reactivate to produce neurological and systemic disease without a characteristic zosteriform rash. VZV also reactivates subclinically. Demonstrated subclinical reactivation in 19 of 73 (26%) bone marrow transplant recipients, as determined by a fivefold increase in VZV-specific antibody titers or a reappearance of a specific lymphoproliferative response to VZV antigen.
Only 2 of the 19 patients with VZV reactivation had signs: one experienced transient fever, and the other developed hepatitis simultaneously with increasing VZV titers. Serologic analysis has also indicated VZV as the cause of unexplained fever in three of nine metastatic breast cancer patients. In addition, VZV reactivates subclinically (without pain or rash) in astronauts , including shedding of infectious virus , most likely reflecting transient stress-induced depression of cell-mediated immunity to VZV. Importantly, asymptomatic shedding of human neurotropic alphaherpses-viruses is not restricted to VZV, since HSV-1 and HSV-2 also show subclinical reactivation. Finally, VZV DNA has been detected in saliva of patients with zoster in multiple dermatomes , suggesting the simultaneous reactivation of VZV not only from geniculate ganglia but also from ganglia corresponding to the dermatome where zoster occurred. Detection of VZV DNA in saliva of such zoster patients provides a virological explanation for the classic clinical observations of who described dermatomal distribution radicular pain in areas distinct from pain with rash.
Such clinical and virological phenomena are not surprising, since VZV becomes latent in cranial nerve ganglia, dorsal root ganglia, and autonomic ganglia along the entire neuraxis. 14 Diagnostic TestingWhile zoster is usually diagnosed based on observation alone, all neurological complications of VZV reactivation without rash require virological confirmation. Evidence of active VZV infection is supported by any or all of the following positive tests: the presence of anti-VZV IgM antibody in serum or CSF or anti-VZV IgG antibody in CSF, or the detection of VZV DNA in blood MNCs or CSF. Because nearly all adult serum contains anti-VZV IgG antibody, serological testing for anti-VZV IgG antibody alone without other virological testing is of no value In our experience, the most valuable tests are those that detect VZV DNA or anti-VZV IgG antibody in CSF. Much less frequently, anti-VZV IgM is found in serum or CSF, and even less often, VZV DNA is found in blood MNCs during acute neurological disease. Some, but not all, clinical hospital laboratories either perform tests for anti-VZV lgG antibody or send the specimen to an outside laboratory. If the hospital cannot conduct a test for anti-VZV IgG or IgM antibody, the referring hospital cannot conduct a test for anti-VZV IgG or IgM antibody, the referring physician should contact Dr.
Don Gilden who will arrange to have the specimen tested at no cost to the patient. Because VZV DNA was found in the saliva of every zoster patient in the study by, it is possible that saliva may be a useful source to detect VZV in patients with neurological disease in the absence of rash. To date, definitive virological confirmation has required blood and CSF examination for VZV DNA and anti-VZV IgM and/or lgG antibody. The continuing challenge for the clinician is in establishing a diagnosis at a time when treatment will still benefit the patient.
A 63-yr-old white man presented to the chronic pain clinic for evaluation of left-sided midabdominal and flank pain. The pain had begun approximately 2 months prior, and the patient had noticed a small “soft tissue mass” in his midabdominal area that had been gradually increasing in size. He complained of burning pain and hyperesthesia in the distribution of the bulge. A surgeon had been consulted for evaluation of what was initially thought to be a lipoma. The surgeon noted that the area had the appearance of a surgically denervated muscle, but the patient had never had surgery in this region. The patient was referred to the chronic pain clinic for further evaluation. Abdominal computed tomography performed previously did not show any pathologic processes, including hematoma, lipoma, or other tumor masses.
Further workup included thoracic spine magnetic resonance imaging, which revealed no evidence of nerve root impingement that might explain the thoracic nerve root symptoms. Serologic studies showed that the patient had positive anti-varicella-zoster virus (VZV) immunoglobulin G titers but was negative for anti-VZV immunoglobulin M. Electromyelography to evaluate the external abdominal oblique, internal abdominal oblique, rectus abdominus, and thoracic paravertebrals revealed membrane irritability in the form of positive waves and fibrillations in all of the muscle groups on the left, most prominently in the T10 distribution. Motor unit action potentials were present but were decreased in number, although the configuration and amplitude appeared essentially normal. Varicella-zoster virus is responsible for chickenpox, during the primary infection, and shingles, during reactivation episodes later in life.
Following primary infection, the virus remains latent in the dorsal root ganglia of the nervous system. Its reactivation gives rise to shingles (herpes zoster), which is usually characterized by unilateral neuralgia followed by a vesiculobullous eruption in a dermatomal distribution. The incidence of shingles is known to be higher in the elderly ( 55 yr old), in the immunocompromised, and in those originally infected prior to 1 yr of age. Virologic evidence of herpes zoster is difficult to obtain due to a lack of specificity, and because most cases are diagnosed based on clinical features.
Positive anti-VZV immunoglobulin G antibodies represent previous exposure. Positive anti-VZV immunoglobulin M antibodies are suggestive, but not specific, for herpes zoster. Sundqvist showed that increases in anti-VZV immunoglobulin M, due to zoster, are transient.
In a study of 25 patients, 21 were positive for VZV immunoglobulin M; however, only one patient was still positive 46 days after the illness. Therefore, it is not surprising that the immunoglobulin M serologic results were negative in this patient, since the delay in diagnosis resulted in the serologic results not being obtained until approximately 70 days after the onset of his illness. Reported that the specificity of clinical diagnosis of zoster (with a rash) is 95% and, therefore, laboratory confirmation is not always required.
The specificity of clinical diagnosis in zoster sine herpete is unclear. Herpes zoster usually affects sensory nerves; however, it can also damage motor neurons. The incidence of motor involvement with VZV reactivation has been estimated to be 0.5 to 5%. The electromyelographic findings seen with thoracic motor paralysis are identical to those observed in our patient, with positive waves and fibrillations seen in the affected muscle groups. Documented cases most commonly have involved cranial nerves; however, there are also reports of abdominal, diaphragmatic, and lower extremity paralysis. Yaszay et al. Describe unilateral left C5–C6 segmental paresis associated with a zoster rash in an otherwise healthy individual.
The true incidence of thoracic motor paralysis with herpes zoster is unknown. Thomas and Howard reviewed 1,210 patients with herpes zoster, 61 of whom were found to have zoster-induced segmental muscle weakness. The thoracic dermatome was involved in only two of these cases. Although the thoracic dermatome seems to be the most frequently affected in herpes zoster, it appears to have the lowest incidence of motor paralysis. This apparent low incidence may be misleading due to the fact that segmental weakness of intercostal and abdominal muscles is likely to pass unnoticed.
The differential diagnoses entertained in this case included soft tissue tumor mass (including lipoma or cyst), herniation of abdominal musculature, abdominal muscle hematoma, and lower motor neuron lesion. Tumor mass, hematoma, and muscle herniation were excluded by physical examination and abdominal computed tomography scan.
Causes of lower motor neuron injury could include surgical injury, trauma, cutaneous nerve entrapment, or thoracic nerve root injury due to neural foraminal stenosis, compression fracture, or herniated nucleus pulposus. The patient had no history of surgery or trauma to the area, and magnetic resonance imaging revealed no evidence of thoracic nerve root injury.
Cutaneous nerve entrapment is most commonly found in patients who have had previous surgery. Entrapment of these cutaneous nerves is typically noted as intermittent pain in the lateral rectus abdominis musculature with a single painful trigger point on palpation. A literature search revealed no descriptions of cutaneous nerve entrapment in the external or internal oblique musculature. As stated previously, electromyelographic evaluation of our patient revealed involvement of the internal and external oblique, rectus abdominus, and thoracic paravertebral musculature, making cutaneous nerve entrapment an unlikely diagnosis. As discussed, diagnoses of zoster sine herpete are most often made clinically given the difficulty of obtaining serologic evidence. Clinical evidence suggests that our patient had both zoster sine herpete and thoracic motor paralysis secondary to herpes zoster.
A literature search revealed that no similar cases have been reported. In this case, serologic evidence is consistent with, but not diagnostic of, herpes zoster. The clinical symptoms of pain and thoracic motor involvement, as documented by electromyelography, further strengthen the validity of the diagnosis.
The patient's rapid recovery over 5 months is also consistent with the natural course of zoster motor paralysis. We believe that thoracic motor paralysis secondary to zoster sine herpete is a rare diagnosis. However, as mentioned previously, this diagnosis may be more common than is apparent due to the difficulty in diagnosing each occurrence. The authors thank John C. Hendricks, M.D. (Associate Professor, Department of Surgery, Scott & White Memorial Hospital, Texas A&M University, Temple, Texas), for referral; John A.
Schuchmann, M.D. (Associate Professor and Chairman, Department of Physical Medicine and Rehabilitation, Scott & White Memorial Hospital, Texas A&M University, Temple, Texas), for electromyelographic evaluation; and Jolene D.
Bean-Lijewski, M.D. (Associate Professor, Department of Anesthesiology, Scott & White Memorial Hospital, Texas A&M University, Temple, Texas), and Jeff R. (Assistant Professor, Department of Anesthesiology, Scott & White Memorial Hospital, Texas A&M University, Temple, Texas), for valuable comments in the preparation of this manuscript.