Cranial nerve involvement in varicella zoster virus after renal transplantation

Abstract

This case describes a 60-year-old immunosuppressed man after renal transplant who presented to the emergency department with 1 week of generalized weakness, a 20-lb unintentional weight loss, sore throat, dysarthria, dysphagia, cough, and shortness of breath. Additionally, he developed tinnitus, headaches, photophobia, and neck stiffness. He underwent an extensive workup including a lumbar puncture with meningitis and encephalitis panel, which was positive for varicella zoster virus. He never developed a dermatomal vesicular rash but had persistent dysphagia and aspiration and was eventually diagnosed with Vernet syndrome. This case highlights theories for the increase in varicella zoster virus encephalitis cases causing neurologic symptoms and proposes that this trend is likely to continue.

Varicella zoster virus (VZV) is a very common infection that manifests in adulthood as shingles. Its primary infection, which causes chickenpox, lies latent in the dorsal root ganglia until reactivating during a time of stress or low immunity. The characteristic finding includes a painful rash of vesicles in a dermatomal distribution, commonly on the side of the trunk or face. ¹ VZV reactivation can cause several other complications, such as neuralgic pain without a rash (zoster sine herpete), encephalitis, meningitis, myelopathies, vasculitis, and Guillain-Barré syndrome. Additionally, involvement can occasionally extend to the brain and cranial nerves, which presents a challenging clinical diagnosis, especially due to the lack of the characteristic rash. ^{1 , 2} We present one such case.

CASE REPORT

A 60-year-old man with renal transplantation for autosomal dominant polycystic kidney disease, on immunosuppression with tacrolimus, mycophenolate, and prednisone, presented to the emergency department with 1 week of generalized weakness, fatigue, unintentional weight loss of 20 pounds, sore throat, dysarthria, dysphagia, cough, and dyspnea. He had previously been treated in the outpatient setting with azithromycin and subsequently a second time with levofloxacin for presumed bacterial pharyngitis, but failed to improve.

On the day of admission, he developed persistent bilateral tinnitus, frontal headache, photophobia, and neck stiffness. His admission hemoglobin was 12.0 g/dL, potassium 6.0 mEq/L, and total bilirubin 1.7 mg/dL. The chest radiograph and computed tomography of the head, chest, abdomen, and pelvis were not abnormal. Tests were negative for respiratory viruses, Legionella/Streptococcus urinary antigen, fluorescent treponemal antibody, Venereal Disease Research Laboratory test, Tropheryma whipplei, and Q fever, as well as serum antigens including cytomegalovirus, Cryptococcus, histoplasmosis, coccidioidomycosis, blastomycosis, tuberculosis, aspergillosis, West Nile virus, and Epstein-Barr virus. Workup for amyotrophic lateral sclerosis, Guillain-Barré syndrome (via cerebrospinal fluid evaluation), and multiple sclerosis (via oligoclonal bands) were all negative. Electromyography and neuromuscular junction testing were normal and did not explain his symptoms. Nevertheless, he was empirically started on intravenous immunoglobulin for possible Miller Fisher variant of Guillain-Barré syndrome without improvement.

The only test that did indicate a cause was a meningitis/encephalitis panel by polymerase chain reaction of cerebrospinal fluid, which was positive for VZV. Consequently, the patient was treated with intravenous acyclovir for 3 weeks. Throughout his hospitalization, he never developed a dermatomal vesicular rash; he had persistent dysphagia and aspiration when evaluated by speech pathology and was eventually diagnosed with Vernet syndrome involving cranial nerves IX, X, and XI, likely causing his persistent dysphagia. Consequently, a percutaneous gastrostomy tube was placed for enteral nutrition. He was followed up in 3 months with significant improvement of his dysphagia and dysarthria symptoms.

DISCUSSION

VZV reactivation (shingles) usually presents with a characteristic painful vesicular rash in a dermatomal distribution ² and usually occurs during immunosuppression or stress. ³ A small percentage of patients will have central nervous system involvement, presenting as encephalitis, meningitis, Guillain-Barré syndrome, myelitis, cranial nerve palsies, or strokes due to vasculitis. ^{1 , 2 , 4–7} In such cases, diagnosis is based on detection of VZV DNA in cerebrospinal fluid with amplification by polymerase chain reaction, anti-VZV IgG antibody in cerebrospinal fluid, or anti-VZV IgM antibody in cerebrospinal fluid or serum. ^{1 , 5}

VZV is known to effect cranial nerves, as in Ramsay Hunt syndrome (facial nerve palsy) and Vernet syndrome (paralysis of cranial nerves IX, X, XI). ^{1 , 4 , 5} Vernet syndrome is often due to a malignancy, traumatic injury, or vascular lesion, as these nerves traverse the jugular foramen, and consequently presents as hoarseness and dysphagia. Infections such as VZV have also been implicated in solid organ transplants due to the depletion of T and B lymphocytes with tacrolimus and mycophenolate to prevent organ rejection. ^{8 , 9}

To prevent infection by VZV, the varicella vaccine was licensed in 1995 in the United States for immunization of all healthy children. Approximately 90% of the country’s children have now been immunized. The incidence of the disease has also decreased by 90%, with a similar decrease in hospitalizations and mortality. This success led to development of the zoster vaccine, which was licensed in 2006, with the intent of similarly protecting the elderly from shingles. Immunization rates in this population are low, and the number of zoster cases is on the rise. ^{1 , 3}

Some have proposed that exposure to wild-type VZV in society is necessary to maintain a high level of immunity, resulting in concern that the varicella vaccine will subsequently result in a higher level of VZV reactivation. However, computer-based modeling studies have shown the slow increase in VZV cases is not as high it would have been expected if this theory were true, and therefore the increase cannot be solely attributed to the vaccine. Additionally, the gradual rise in zoster began many years before the varicella vaccine was administered and has been occurring in both vaccinated and nonvaccinated countries. Therefore, other factors such as the increased aging population, increased population of immunocompromised individuals, increased ability to diagnose the disease, and increased stress in today’s society have been considered more likely culprits. ^{1 , 3} Nevertheless, as medicine advances and more physicians are able to use polymerase chain reaction and serology to confirm cases of VZV, it can be expected that we may continue to see more severe cases of VZV reactivation with new types of neurologic presentations, especially in immunocompromised patients. ²