Case Report of a Malignant Melanoma Patient with Longitudinally Extensive Transverse Myelitis: Immune-Related Adverse Event or Human Herpesvirus-7 Infection?

Immune checkpoint inhibitors (ICIs) are used in patients with metastatic malignant melanoma. Programmed cell death-1 (PD-1) and cytotoxic lymphocyte–associated protein 4 (CTLA-4) are found on the surface of T cells and are used as targets for the formation of an immune response against the tumor. Anti-CTLA-4 antibody ipilimumab and anti-PD-1 antibodies nivolumab and pembrolizumab are used as treatment options in patients with advanced melanoma. However, immune-related adverse events (irAEs) occur in approximately 40% of patients. Neurological side effects are rare. Ipilimumab and nivolumab combination therapy was applied in a 60-year-old male patient due to malignant melanoma after detection of metastasis after pembrolizumab, another immune checkpoint inhibitor. After the last course of treatment, numbness in the legs, loss of strength, and inability to walk developed. Neurological examination revealed 5-/5 muscle strength of all upper extremity muscle groups, 1/5 muscle strength in the lower extremities, and loss of sensation in the lower extremities that did not give a clear level. In spinal cord imaging, the longitudinal, diffuse, edematous image extending from the upper cervical to the lower thoracic levels was evaluated as transverse myelitis. Human herpesvirus-7 (HHV-7) DNA detected in cerebrospinal fluid (CSF) which could not be demonstrated in serum. A second CSF examination could not be performed regarding the role of HHV-7 in the etiology. Patients given immune checkpoint inhibitors should be followed up for signs and symptoms of irAEs. Prompt diagnosis and treatment will increase the likelihood of complete recovery from neurological complications.


Introduction
Immune checkpoint inhibitors (ICIs) are used to treat several types of cancer, including melanoma of the skin, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancers, and Hodgkin lymphoma [1]. In physiological conditions, immune checkpoints have a crucial role in preventing the development of autoimmunity and sustain immunological tolerance in healthy individuals [2]. Programmed cell death-1 (PD-1) and cytotoxic lymphocyte-associated protein 4 (CTLA-4) are expressed in T cells and are used as a target for immune system response against the tumor. Anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibodies nivolumab and pembrolizumab are treatment options in advanced-stage melanoma [3]. However, when the immune system destroys tumor cells, it can cause abnormal immune responses in normal organs and tissues in the body. Immune-related adverse events (irAEs) most commonly include dermatologic, endocrine, gastrointestinal, and hepatic adverse events. Neurological adverse events related to ICIs are rarely observed [4,5]. With the use of ICIs, 7.67% of any neurological irAEs were reported, as well as 2.8% of severe neurologic irAEs with combination of PD-1 and CTLA-4 blockage [6,7].
Primary infection with human herpesvirus-7 (HHV-7) usually occurs during childhood. The virus then remains latent in CD4 + T lymphocytes and epithelial cells of salivary glands. Infection with HHV-7 may also occur in immunocompromised patients [8].

Topical Collection on Medicine
Herein, we describe a case of irAEs associated longitudinally extensive transverse myelitis in a HHV-7 + malignant melanoma patient.

Case Report
A 60-year-old man with nodular type melanoma had an initial diagnosis at age 58 and was treated with resection of pigmented nevus located on the anterior surface of the left thigh in September 2016. In September 2017, he was found with metastatic lesions in lymph nodes located in the abdomen and left inguinal region and diagnosed with stage IIIb melanoma according to AJCC Stage. Immediately after the detection of progression, he was then treated with pembrolizumab completing 4 cycles until January 2018. In February 2018, radiological follow-up with FDG-PET/CT scan showed metabolically active metastases on the left thigh and newly detected lymph nodes located in the abdominal region. He was then treated with ipilimumab and nivolumab (1 mg/kg IV) every 3 weeks, owing to the progression of the disease, in February 2018. After receiving the 2 nd dose of ipilimumab and nivolumab in March 2018, he developed numbness and tingling in the lower extremities. One week later, his symptoms had become stable, and he began having difficulty walking and weakness in the lower extremities.
The patient's vital signs were normal; he demonstrated no signs of autonomic signs or fever. Neurological examination showed decreased strength in the proximal and distal muscles of the upper (5-/5) and lower (1/5) extremities, affecting hip flexion, knee flexion/extension, and dorsiflexion/plantarflexion. The patient also showed decreased sensation on the lower extremities but did not have a defined sensory level. Deep tendon reflexes were normoactive (2 +) in the biceps, triceps, and brachioradialis bilaterally, hypoactive (1 +) in the lower extremities. The Babinski sign was absent bilaterally. The patient was unable to walk.
Magnetic resonance imaging (MRI) showed hyperintensities on T2 sequences within the entire spinal cord, from the upper segments of the cervical cord to the lower thoracic spine with extensive cord edema without gadolinium enhancement (Fig. 1).
A lumbar puncture was performed, which revealed 79 mg/ dL protein, 62 mg/dL glucose, and 130 cell/dL white blood cells with predominantly lymphocytoid cells. Cerebrospinal fluid was negative for malignant cells. No oligoclonal bands or Aquaporin-4 was observed in cerebrospinal fluid (CSF). CSF analyses were negative for Escherichia coli K1, Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis,  Transverse myelitis induced by irAEs was suspected and ipilimumab and nivolumab were withheld. A course of highdose intravenous methylprednisolone (1000 mg/day for 7 days) was given. Despite the treatment, the patient progressively deteriorated consistent with septic shock and referred to intensive care unit (ICU) of another hospital. That's why, HHV-7 DNA for blood sample analysis and verification of CSF sample positivity could not be performed. Plasmapheresis treatment was planned but cannot be implemented. Unfortunately, the patient died few days after hospitalization. A written informed consent was obtained from the patient's family for this report.

Discussion
This case highlights that the etiologic role of immune checkpoint inhibitors as the cause of acute extensive myelitis, while most cases of irAEs present with dermatologic, endocrine, gastrointestinal, and hepatic adverse events [9]. Older patients receiving immune checkpoint inhibitors are shown to be at greater risk to develop irAEs with the cumulative risk of 48.6% within 6 months after the treatment initiation [9]. With the use of immune checkpoint inhibitors, 7.67% of any neurological irAEs were reported, as well as 2.8% of severe neurologic irAEs with combination of PD-1 and CTLA-4 blockage [6,7]. These include myopathy, polyneuropathies, aseptic meningitis, myasthenia gravis, Guillain-Barre syndrome, and posterior reversible encephalopathy syndrome, encephalitis, and transverse myelitis [5].
Previously reported results showed that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma [10]. However, in general, there is a higher incidence of treatment-related adverse events with nivolumab plus ipilimumab vs ipilimumab alone [11,12]. Our patient was treated with pembrolizumab completing 4 cycles, then treated with ipilimumab and nivolumab (1 mg/ kg IV) every 3 weeks that may have facilitated the formation of longitudinally extensive transverse myelitis (LETM). The occurrence of LETM after 4 weeks of the ipilimumab and nivolumab treatment is also appropriate with the clinical characteristics of irAEs as Wilson et al. reported previously [13]. Similar to our patient's clinical features, Wilson et al. and Liao et al. reported patients presenting with lower extremity weakness and paresthesia, as well as urogenital signs 2-4 weeks after ICI treatment whose MRI also indicated continuous longitudinal edematous lesions of the spinal cord [13,14]. Both of those patients were negative for Aquaporin-4 antibody, meanwhile, another patient was reported to suffer from longitudinal extensive transverse myelitis 2 months after nivolumab treatment with similar clinical findings and who was positive for Aquaporin-4 antibody [15].
In our patient, we excluded the differential diagnosis including neuromyelitis optica, sarcoidosis, spinal cord infarction, systemic lupus erythematous, and B12 deficiency. The detection of HHV-7 DNA in patient's CSF cannot be verified with HHV-7 DNA for blood sample analysis. On the other hand, HHV-7 is a virus that is highly prevalent and has been detected in normal brain tissue [16]. Therefore, CSF PCR has a low positive predictive value. HHV-7 is mainly reported to cause neurological diseases in children including febrile seizure, meningoencephalitis, and occasionally meningoradiculopathy [17,18]. An adult bone marrow transplant recipient who presented with spastic paraparesis was reported with HHV-7 positivity in CSF and no abnormal signaling in the spinal cord. The hypothesis was that HHV-7 reactivated in the central nervous system [19]. In addition, an HIV-positive adult patient with myelitis was reported to have a positive CSF HHV-7 [20]. Meanwhile, the same study reported that HHV-7 DNA was detected in CSF of 1 in 36 patients with confirmed CNS infection and 7 in 172 patients with other noninfectious neurological diseases and emphasized that HHV-7 could be the responsible microbial agent in suspected CNS infections with unknown etiology if the diagnosis is supported by sustained amplification of HHV-7 DNA in 2 different CSF studies [20].
In some cases, lumbar puncture may be useful and as in our case, increased white blood cell counts including high lymphocyte proportion can point to immune-mediated origin. However, definite differential diagnosis and exclusion of the other possible causes for the neurological consequences must be performed. Clinical features of our patient and compliance of the clinical picture with other reported irAEs suggest the etiology as immunerelated adverse event due to combination of ICIs and not HHV-7. The main weakness of this report is the inability to perform two separate CSF sample analyses to rule out the etiologic role of HHV-7 as a cause of acute myelitis due to transfer of the patient to the ICU short after hospitalization in our neurology inpatient clinic.
Cessation of immune checkpoint inhibitor therapy is the initial action while facing a neurological irAE. After characterization of AE, rapid start of high-dose steroid, 1-2 mg/kg prednisolone or i.v. equivalent dose may reverse the neurological deficits. Additionally, plasmapheresis may be required if non-steroid responsive [21]. Previous reports indicated beneficial effects of immune checkpoint inhibitor withdrawal and high doses of methylprednisolone [13,14]. We argue that our patient could not benefit from these treatments, as a result of septicemia added to the clinical picture.
In summary, immune checkpoint inhibitor treatment-associated longitudinal extensive transverse myelitis is quite a rare condition. Corticosteroids and plasmapheresis are effective in the treatment of longitudinal myelitis in irAEs. As the number of indications for these agents increases, the rapid diagnosis and treatment of neurological complications is essential to have a complete recovery.