Myelopathy after zoster virus infection in immunocompetent patients: A case series

Abstract

Context

After primary infection, varicella zoster virus (VZV) becomes latent in ganglionic neurons. If immunity declines, VZV is reactivated and can spread to the dermatome depending from this ganglion and in some cases to the spinal cord. Myelopathy is rare and may develop in the absence of skin rash making the diagnosis very difficult.

Findings

From 1994 to 2014, we collected five observations of clinically and laboratory confirmed zoster myelopathy. The age of our patients ranged from 14 to 78. They did not have any significant past medical history. Four patients had a history of radicular rash. After 3 weeks (4–45 days), patients presented paraparesis, sensory loss, and sphincter dysfunction. Cerebrospinal fluid (CSF) analysis revealed an elevated protein level (5/5cases) and pleocytosis (2/5 cases). Spinal cord magnetic resonance imaging (MRI) demonstrated T2 hyper intense lesions with swelling and contrast enhancement. The diagnosis was supported by laboratory evidence, including the detection of VZV antibodies in the CSF. All patients received intravenous acyclovir and two patients received IV methylprednisolone. A marked improvement was observed in most of the patients within 2 months.

Conclusion /Clinical Relevance

Based on our patients and on previous reports, we highlight the possibility of the occurrence of VZV myelopathy in immunocompetent subjects. The diagnosis must be evoked even in the absence of typical skin lesions. In this case, spinal cord MRI and virological tests are useful tools for the diagnosis. We also emphasize on the importance of accurate diagnosis to enable the specific treatment and ameliorate the outcome.

Introduction

Varicella-zoster virus is an exclusively human neurotropic herpes virus. It can cause a wide spectrum of disorders, including varicella and zoster which are the most common.¹ Although the majority of cases are uncomplicated, neurological symptoms may develop and are estimated at approximately 0.01–0.3%.² The occurrence of transverse myelitis and cerebral or spinal cord angitis during or after zoster is uncommon.^3,4 This has been noticed particularly in immunocompromised patients, and it is rather rarer in immunocompetent patients.⁵ In the majority of cases, the vesicular lesions precede neurological symptoms. However, myelopathy may occur in the absence of typical skin lesions.⁶ In such cases, the diagnosis can be challenging. The principal goal when managing a patient with VZV myelopathy is to preserve walking autonomy. Since a motor function can be severely threatened, it is crucial to better understand the clinical spectrum, the neuro-imaging and the laboratory features, and evaluate the prognostic factors of this complication. In this study, we report a series of patients with VZV myelopathy. Our main goals are to determine the clinical presentation, the laboratory and the neuro-imaging findings, the treatment to administer and the outcome of our cohort. We will also discuss the underlying mechanisms of the myelopathy.

Methods

All patients with VZV myelopathy diagnosed between 1994 and 2014 were included. In this retrospective study, we reviewed the medical records of these patients as well as the corresponding literature. We prepared a case report form to collect epidemiological data (sex and age); medical history; clinical data (dermatologic signs, the interval between rash and myelopathy, neurologic manifestations and examination findings). All patients underwent spinal cord MRI using 1.5 Tesla Prisma scanner (Siemens), with the standardized protocol including the following sequences: sagittal T1-, sagittal T2- and axial T2-weighted sequences. The second acquisition of sagittal T1 sequence was performed after a single dose of gadolinium (0.1 mg/kg). Diffusion-weighted image was performed when ischemic myelopathy is suspected. We explored the whole spinal cord: cervical, thoracic, and lumbar spine. We recorded the number of lesions, their extent in height (sagittal sections) and in large (axial sections). All the MRI scans were reviewed by an experimented neuro-radiologist with the neurologist in a multidisciplinary staff. In all cases, MRI showed spinal cord lesions extending over three or more vertebral segments: the so-called longitudinal extensive transverse myelopathy.⁷ Brain imaging was not indicated in our cases. All patients underwent routine blood tests, including autoimmune antibody (anti-nuclear, anti-DNA, antibodies against aquaporin-4), as well as CSF analysis, including cell count, protein content, oligoclonal banding and virological analyses (serology of herpes simplex virus, Borrelia burgdorferi, human immunodeficiency virus (HIV), cytomegalovirus, hepatitis A, B and C, adenovirus, VZV, Epstein–Barr virus, human herpesvirus 6, mycoplasma, enterovirus and chlamydia). In our series, the diagnosis of VZV-myelopathy was confirmed by the detection of specific IgG antibody in CSF by Screening tests by enzyme-linked immunosorbent assay (ELISA).

Results

Five persons with clinical and laboratory confirmation of zoster myelopathy from 1994 to 2014 were included in our study. The patients’ past medical history was not significant (no history of HIV infection or AIDS, solid organ transplantation, cancer, stem cell transplantation, asplenia, chronic inflammatory conditions, congenital immune deficiencies, diabetes … .) and their ages range between 10 and 78 years. Four patients presented radicular zoster. After a mean interval of 3 weeks (range: 4–54 days), these 4 patients presented paraplegia, superficial hypoesthesia of the lower part of the body with a clear-cut upper limit and sphincter dysfunction. In our last case, the neurological deficit had a sudden onset; the interval from onset of symptoms to nadir was 30–45 min, suggesting a vascular mechanism. In other cases, VZV myelopathy was developed progressively within 2–5 weeks (Table 1).

Table 1. Clinical, laboratory, imaging and pathological features in our five patients with varicella zoster virus myelopathy.

Patients	1	2	3	4	5
Age (years)	10	78	70	17	69
Sex	F	F	M	M	M
Dermatologic signs	Vesicular rash (dermatomes D1–D2)	Vesicular rash (dermatomes C4–C6)	Hemi-thoracic vesicular rash	-	Vesicular rash (dermatomes C5–C6)
Interval from skin rash to myelopathy	4 days	54 days	15 days	-	19 days
Neurologic manifestations	Lower limbs weakness urinary retention	Lower limbs weakness Urinary retention	Lower limbs weakness Urinary incontinence	Lower limbs weakness Urinary retention	Lower limbs weakness Urinary retention
Mode of onset of symptoms	Progressive (16 days)	Progressive (20 days)	Progressive (34 days)	Progressive (29 days)	Abrupt (30–45 min)
Physical examination	Paraparesis Superficial sensory loss with upper limit at D1 Meningeal syndrome	Paraparesis Superficial sensory loss with upper limit at D6 Loss of vibratory sensation	Paraparesis Superficial sensory loss with upper limit at D4 Loss of vibratory sensation	Paraparesis	Paraparesis Superficial sensory loss with upper limit at C5
CSF analysis	200 WBC/mm3 Protein level: 0.55 g/l Anti-VZV antibodies: (+)	3 WBC/mm3 Protein level: 0.5 g/l Anti-VZV antibodies: (+)	6 WBC/mm3 Protein level: 0.65 g/l Anti-VZV antibodies: (+)	20 WBC/mm3 Protein level: 0.39 g/l Anti-VZV antibodies: (+)	2 WBC/mm3 Protein level: 0.6 g/l Anti-VZV antibodies: (+)
MRI findings	T2 Hyperintense dorsal spinal cord lesion with meningeal enhancement	High T2 signal extending from D3 to conus medullaris with gadolinium enhancement on T1 sequence.	High T2signal extending from D4 to D7 with spinal cord swelling and contrast enhancement (Figure 1)	T2 hyperintense lesion of conus medullaris with contrast enhancement	High T2 signal and diffusion-weighted images (C3–C7) causing obvious spinal cord swelling without contrast enhancement. (Figure 2)
Physiopathology	infectious	Post-infectious	Post-infectious	Post-infectious	vascular
Treatment	Acyclovir (10 mg/kg/8H) X 21 days	Acyclovir (10 mg/kg/8H) × 21 days Methylprednisolone (1 g/days X 3 days)	Acyclovir (10 mg/kg/8H) × 21 days	Acyclovir (10 mg/kg/8H) × 21 days	Acyclovir (10 mg/kg/8H) × 21 days Methylprednisolone (1 g/days × 3 days)

Note: CSF, cerebrospinal fluid; F, female; M, male; WBC, white blood cells; VZV, varicella zoster virus.

The spinal cord MRI demonstrated large T2 hyper intense lesions (more than three vertebrae) with swelling and contrast enhancement in certain cases (Figure 1, Table 1). The diffusion-weighted MRI showed a hyper intense lesion in our last patient (Figure 2, Table 1). CSF analysis revealed raised protein level in all patients and pleocytosis in two cases. HIV screening was negative and no other causes of immunological impairment were detected.

Figure 1.

Sagittal spinal cord MRI showing high T2 signal extending from D4 to D7 causing an obvious segmental swelling of the cord (a). T1-weighted sequence after gadolinium infusion shows enhancement of the lesion (b) (patient 3).

Figure 2.

Sagittal spinal cord MRI showing high T2 signal extending from C3 to C7 with obvious swelling of the cervical spinal cord (a). This lesion is hypo-intense on T1-weighted sequence (b) and hyper intense on diffusion-weighted images (c) (patient 5).

The diagnosis of VZV myelopathy in all cases was supported by the presence of specific antibodies to VZV in CSF. All patients received a 3-week course of intravenous (IV) acyclovir, and two patients received IV methylprednisolone. All patients improved; a complete recovery was obtained in two patients within 2 months. The remaining three cases became ambulant, they walked with crutch assistance (spastic paraparesis) and kept sphincter dysfunction with urinary retention (intermittent catheterization) (Table 1).

Discussion

In our study, as well as in the literature, symptoms of VZV myelopathy are similar to any myelopathy.⁸ Four patients had a history of radicular rash. The interval between the vesicle eruption and the appearance of the symptoms of myelopathy varied from 1 day to several months (3 weeks in our series). However, VZV-myelopathy can occur in the absence of typical skin lesions, as it is the case of our fourth patient.⁹

There are three pathologic mechanisms of VZV myelopathy: a post-infectious process, a direct invasion of the spinal cord and a vasculitis.⁹

The post-infectious myelitis usually occurs in immunocompetent patients, after acute VZV infections, while the patient is recovering. This is the result of a pathological immune response to the infection rather than a direct effect of the virus.⁶ CSF analysis usually shows a mild pleocytosis, with normal or slightly elevated protein level. This was observed in three of our five patients (Table 1: patients 2, 3 and 4). Search for the virus in CSF or nervous tissue is always negative (viral culture, polymerase chain reaction …); the virus does not cross the blood-brain barrier and the infection does not reach the nervous parenchyma or meninges.¹⁰ The diagnosis was confirmed in all our cases, as well as in the literature, by the presence of anti-VZV IgG in CSF.¹¹ Steroids are used to treat myelitis, although certain patients improve spontaneously.

A direct invasion of the spinal cord has also been suggested as an etiology of VZV-myelitis. This mechanism is observed sometimes in immunocompromised and rarely in immunocompetent patients. VZV spread from the affected dorsal root ganglia to the contiguous area and infects meninges and the spinal cord.^12,13 The invasion of the cord is accompanied with an extensive cord inflammation, necrosis, and hemorrhage.⁹ In such a case, antiviral treatment (acyclovir) must be administered urgently, even if the biological confirmation of the diagnosis is not yet available. Early acyclovir treatment limits virus proliferation, reduces spinal cord damage and increases the chance to obtain better neurological recovery.¹⁴ A direct viral infection is the most likely mechanism for our first patient, considering the short interval between the skin rash and myelitis (4 days), the spatial concordance between the level of the myelopathy and the territory of the vesicular eruption, the lymphocytic meningitis (200 white blood cells /mm³) and the good response to acyclovir treatment.

VZV can also produce spinal cord infarction; this was suspected in our last case regarding the sudden onset of neurological symptoms. Hyper-intensity observed on the diffusion-weighted sequence is highly suggestive of ischemic lesion of the spinal cord.⁴ The absence of contrast enhancement is another argument against inflammatory process and favors ischemia. This complication is explained by the likelihood that virus spread trans-axonally along ganglionic afferent fibers to cause occlusion of small and large arteries.^3,15 In our last case, the clinical presentation of zoster skin eruptions in the dermatomes C5–C6, and anti-VZV IgG in the CSF were strongly suggestive of VZV involvement in vasculitis and spinal cord infarction.

The best argument to confirm the diagnosis of VZV myelopathy is the presence of intrathecal synthesis of anti-VZV antibodies.^9,16 The detection of IgG against VZV in CSF with a reduced serum/CSF ratio confirms the intrathecal synthesis of these antibodies and leads to the diagnosis. However, even though this diagnostic test is specific, it lacks sensitivity. In fact, VZV antibody may be negative in certain cases.¹⁷ In our series, the serum/CSF ratio was not evaluated.

With a diagnosis of VZV myelopathy, our patients received IV acyclovir. This antiviral treatment contributes to viral elimination and limits the cord tissue damage.⁹ Researchers suggested the combination therapy of acyclovir and corticosteroids particularly if there is spinal cord swelling at MRI. Methylprednisolone was prescribed in two cases of our series.

Finally, our study demonstrates once again that early diagnosis and urgent specific treatment of VZV myelopathy are the most important prognostic factors.¹⁸

Conclusion

There are several forms of VZV myelopathy, including a post-infectious process, a viral invasion of the cord or a VZV vasculopathy. Based on our patients and on previous reports, we emphasize the fact that VZV myelopathy may occur in immunocompetent subjects and this has been described even in the absence of typical skin lesions. In such cases, spinal cord MRI and virological tests are very useful tools for the diagnosis. Early treatment, associating steroids and anti-viral, is effective, limits the spinal cord damage, accelerates recovery and ameliorates the outcome.

Disclaimer statements

Contributors None.

Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflicts of interest The authors report no conflicts of interest.