Varicella zoster virus (VZV) is an alpha herpes virus found exclusively in humans and producing the acute exanthematous, febrile illness known as chickenpox (varicealla), which usually occurs in childhood. Once the disease resolves, the virus remains dormant in the dorsal root ganglia of the cranial nerves, especially the trigeminal or spinal nerves. Under certain conditions, and particularly in patients who are elderly or immunocompromised, reduced virus-specific cell mediated immunity may cause the virus to reactivate and spread transaxonally via the peripheral sensory nerve to the skin, predominantly the epidermis. The virus then replicates in keratinocytes, producing radicular pain and the characteristic dermatomal vesicular rash known as shingles (herpes zoster). We report a patient with a prolonged rash and limb paresis, who was found to be positive for VSV.
Varicella zoster virus (VZV) causes the common childhood isease chickenpox (varicella), or upon reactivation, the dermatomal vesiculopustular eruption seen in shingles (herpes zoster). The clinical course of herpes zoster in immunocompromised patients is often recurrent, protracted and multidermatomal, and it can result in myelitis, meningoencephalitis, and cerebral or small-vessel vasculopathic or vasculitic changes. Commonly, the vesicular rash settles with aciclovir therapy and does not involve motor neuropathy. We report a 63-year-old man with a prolonged, multidermatomal, nonvesicular rash, and limb paresis secondary to brachioplexitis. PCR for VZV was positive, and the histological results were consistent with granulomatous vasculopathy. Prolonged treatment with valaciclovir was required to resolve the eruption and help improve the patient's motor function. We discuss the problems faced in clinical decision-making about immunosuppressive treatment of granulomatous vasculopathy and motor neuropathy, when any increase in immunosuppressive therapy may increase the likelihood of central nervous system complications.
A 63-year-old man was admitted to our hospital for elective amputation of his left toe secondary to diabetic neuropathy. In addition to insulin-dependent type 2 diabetes, the patient had hypertension, chronic renal impairment, cardiovascular and severe peripheral vascular disease. He had undergone an orthotopic liver transplant for alcoholic cirrhosis 10 years previously, and was receiving maintenance immunosuppression treatment with prednisolone 2.5 mg once daily and mycophenolate mofetil 500 mg twice daily. Three months before his admission, the patient had experienced sudden pain and subsequently a vesiculopapular, erythematous rash on his left arm, associated with reduced power in elbow flexion. The initial rash had resolved with two courses of oral aciclovir (400 mg five times a day for 5 days, 10 days apart) but 5 weeks after the second course, the patient developed a secondary papular, nonvesicular, erythematous and red-brown eruption in his left C4–6 dermatomes (Fig. 1a). The weakness in the patient's left arm progressed to involve all his shoulder muscles.
On physical examination, ipsilateral wasting and fasciculation of the supraspinatus, infraspinatus, deltoid, biceps, triceps and forearm flexor musles was seen (Fig. 2a), and the power and tone were markedly reduced in the corresponding muscle groups, with absence of reflexes. Sensory examination showed intact proprioception and vibration, but diminished sensation to light touch and pinprick. Allodynia was reported over the insertion of the left brachioradialis.
On histological examination of a 4-mm punch biopsy, a perivascular lymphohistiocytic infiltrate was seen, compatible with a granulomatous inflammatory vascular reaction (Fig 1b). No viral cytopathic effect was seen in the epidermis, and there were no signs of balloon degeneration, the histological hallmark of herpes virus. Stains for acid-fast bacilli and fungi were negative (Fig. 2b).
Laboratory investigations showed the patient had reduced haemoglobin (10.9 g/dL; 13.0–18.0 g/dL), and high readings for erythrocyte sedimentation rate (105 mm/h; normal range 0–20 mm/h), white cell count (8.4 × 109/L; 4–11 × 109/L), platelet count (684 × 109/L; 150–400 × 109/L), C-reactive protein (33 mg/L;< 10 mg/L), urea (10.5 mmol/L; 2.5–7.5 mmol/L) and creatinine (132 mmol/L; 60–110 mmol/L). Tests for anti-neutrophil cytoplasmic antibodies, rheumatoid factor, autoantibodies, anti-nuclear antibody/extractable nuclear antigen, and hepatitis B and C viruses were all negative. Skin swabs tested by PCR were positive for VZV.
Because of the significant motor weakness, nerve-conduction studies and electromyography were performed, which showed absence of sensory potentials and biceps denervation, suggesting a C5 pathology. In addition, T2-weighted magnetic resonance imaging (MRI) showed root enhancement of the left brachial plexus, supporting the diagnosis of a left brachial radiculoplexitis (Fig. 3). Based on the multidermatomal rash (C4–6), the history of pain and the positive VZV PCR results, a diagnosis of VZV-induced radiculobrachioplexitis was made. Our patient developed no other systemic features of vasculitis, and a lumbar puncture excluded the presence of VZV DNA.
Myelitis caused by VZV is well documented in patients with acquired immunodeficiency syndrome. It is is often insidious and progressive, and is sometimes fatal. Post-mortem findings in such cases include frank spinal-cord invasion by VZV, with more extensive necrosis and inflammation compared with that seen in immunocompetent people. A cerebral vasculitis, which classically does not respect arterial boundaries, can also occur and lead to infarction, often with a haemorrhagic component. Other central nervous system (CNS) features can include optic neuritis and acute inflammatory demyelinating polyradiculopathy, more commonly known as Guillain–Barré syndrome. We were concerned that increasing the immunosuppression to treat our patient cutaneous vasculitis might predispose to such CNS complications. However, his clinical history and examination did not support either a meningo-encephalitis or myelitis, and PCR of the cerebrospinal fluid was negative for VZV.
The striking feature in our case is the significant motor weakness. How virions from the sensory dorsal root ganglion affect motor nerves, in the absence of a spinal cord myelitis, is unknown. VZV infection has been proposed to spread from cell to cell via a cellular receptor called insulin-degrading enzyme. Myelin-associated glycoprotein and transfected oligodendrocytes have also been shown to complex with VZV glycoprotein B.
The clinical findings in this case were of a radiculoplexitis, with an MRI of the plexus showing root enhancement. This radiculoplexitis can be explained either by primary infection in multiple dorsal root ganglia or, via a single dorsal root ganglion with spread via contiguous and adjacent roots of the brachial plexus. The degree of immunosuppression in our patient given his diabetes, prednisolone and mycophenolate mofetil treatment and the persisting VZV replication in the skin after two 5-day courses of aciclovir, renders the latter hypothesis the more plausible. Underdosing may also have contributed to our patient developing complications, as the recommended dose of aciclovir for immunosuppressed patients is 800 mg five times a day for 7 days.
The neuropathological changes of herpes zoster include neuronal degeneration and neuronal phagocytosis by satellite cells resulting in fibrous scarring of the ganglia. Another possibility is that vasculitis in the nerve adjacent to the dorsal root ganglion results in myelin and axonal loss, with subsequent limb paresis. These mechanisms, together with the transaxonal spread from secondary to motor roots, may have accounted for the motor neuropraxia seen in our patient. A parallel might be drawn with Ramsay–Hunt syndrome in which, because of the close anatomical association of the facial and trigeminal nerves in the facial canal, herpes zoster reactivation in the sensory nucleus of the trigeminal nerve induces an ipsilateral motor neuropraxia in the facial nerve and a vesicular rash in the external auditory meatus (zoster oticus).
A non-necrotizing granulomatous vasculitis may occur in VZV reactivation, particularly in an immunocompromised host. It can occur without a vesicular component (zoster sine herpete), as a result of viral antigen hypersensitivity and/or direct VZV infection of dermal vessels from adjacent nerves. It has been suggested that poor immune defence, in combination with persistent viral proteins, predisposes to granulomatous and vasculopathic reactions. VZV glycoproteins may act as antigens, inducing a delayed hypersensitivity reaction, resulting in a spectrum of histological responses with non-necrotizing granulomatous change at one end and vasculitic change at the other. In most other reported cases of granulomatous vasculitis, there is no detectable viral DNA in lesional skin, supporting the theory that these viral glycoproteins provide the antigens that induce the granulomatous reaction, rather than the active replicating virus itself. In our case, however, PCR was positive for VZV DNA, which may indicate that active viral replication is important.
We treated our patient with oral valaciclovir 1 g three times daily. After 3 months of this treatment along with regular physiotherapy, the patient's motor neuropathy improved, with 5/5 power in elbow flexion and extension, but the reduced range of movement and weakness in shoulder abduction persisted. His papular red-brown eruption settled slowly 8 months after the initial presentation.
- In immunocompromised hosts, herpes zoster reactivation can produce diverse, prolonged and life-threatening CNS complications.
- Granulomatous vasculopathy might occur in any prolonged area of skin affected by herpes zoster; however, as biopsies are not obtained routinely from such patients, this possibility is difficult to confirm.
- Our patient had an unusual clinical finding of muscle wasting secondary to limb paresis from brachioplexitis.
- MRI is useful in investigating cases in which a prolonged, albeit atypical, eruption coincides with motor weakness and pain.
- Under-treatment of VZV in immunocompromised patients can increase the likelihood of complications. The recommended dose of aciclovir for shingles is 800 mg five times a day for 7 days. In immunosuppressed patients, this course can be extended to achieve clinical clearance or intravenous treatment may be considered.
- Prolonged oral treatment with valaciclovir improves aciclovir bioavailability, and might obviate the need for increasing immunosuppression when there are concerns about CNS complications, as in this case.
The recommended dose of aciclovir for shingles is:
- 400 mg five times a day for 10 days.
- 400 mg five times for 7 days.
- 800 mg five times for 5 days.
- 800 mg five times for 7 days.
- 800 mg five times for 10 days.
Which of the following statements is false?
- The Tzanck smear can differentiate between varicella zoster virus and other herpes viruses.
- Post-herpetic neuralgia is the most common complication of herpes zoster.
- Delirium, confusion or coma in immunosuppressed patients may be a presenting sign of varicella zoster meningoencephalitis.
- Zoster sine herpete describes dermatomal pain without visible cutaneous involvement.
- Haematogenous spread in the immunocompromised may result in the involvement of multiple dermatomes.
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