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Peculiar Cytological Cerebrospinal Fluid Pattern in a Case of Encephalomyelitis During Anti-Tumor Necrosis Factor-α Therapy

Introduction Tumor necrosis factor-α (TNF-α) blocking agents may be associated with neurological adverse events, including demyelinating syndromes, that can be difficult to differentiate from multiple sclerosis (MS) and clinically isolated syndrome (CIS) as neither the clinical nor laboratory distinctive features have been reported. Usually clinicians mainly examine the diagnostic value of immunoglobulin G oligoclonal bands underestimating the value of other cerebrospinal fluid (CSF) parameters (such as CSF cytology). Case Report We present a case of a patient who acutely developed mild pyramidal and sensory impairment of lower limbs and urinary hesitancy during treatment with adalimumab, a monoclonal antibody to TNF-α, for psoriatic arthritis. Magnetic resonance imaging demonstrated a widespread area of hyperintense signal extending from C5 to D8 level in T2-weighted images. Two consecutive CSF examinations showed an intense activation of monocyte/macrophage lineage (88% and 90%, respectively) with some giant and binucleated cells that notably decreased five months after TNF-α blocker cessation. We compared the results of CSF examinations of our patient with CSF results of 20 patients with MS and 20 patients with CIS that demonstrated activation of both lymphocytic and monocytic lineage (MS: 48% and 52%, respectively, CIS: 54.5% and 43.5%, respectively) that were very different from the findings in adalimumab-related encephalomyelitis in acute phase (11% and 89%, respectively). CSF cytology in two patients with neuromyelitis optica during the relapse (n = 3) showed minor monocyte/macrophage activation (9%) and an increased number of granulocytes (77%). Conclusion Prominent activation of monocyte/macrophage lineage with some binucleated giant cells in CSF could be induced by anti-TNF-α treatment. The peculiar CSF pattern, never found in MS, CIS, and NMO, can help in differential diagnosis and stresses the importance of careful CSF cytology evaluation in the course of demyelinating diseases. Electronic supplementary material The online version of this article (doi:10.1007/s40120-015-0027-z) contains supplementary material, which is available to authorized users.


INTRODUCTION
Tumor necrosis factor-a (TNF-a) plays an important role in many aspects of immune system development, immune-response regulation, and T cell-mediated tissue injury, and is involved in many pathological conditions [1]. TNF-a inhibition represents a significant advance in the treatment of rheumatoid arthritis, and is approved for the treatment of ankylosing spondylitis and psoriatic arthritis, as well as Crohn's disease and ulcerative colitis [1].
Tumor necrosis factor-a blocking agent adverse events include peripheral and central nervous system (CNS) demyelination [1][2][3][4][5][6][7][8]; however, the role of anti-TNF-a drugs in the development of demyelination has not yet been well defined. It is still a matter of debate whether TNF-a blocking agents could cause de novo nervous system demyelination or unmask latent disease, or whether the use of these drugs and the development of neurological disorders is coincidental [9,10]. Any clinical, biological, or radiological evaluation can differentiate these conditions that have different prognosis and treatment. Here, we present a case of a patient who acutely developed mild pyramidal and sensory impairment of lower limbs and urinary hesitancy during treatment with adalimumab, a monoclonal antibody to TNF-a, for psoriatic arthritis.

CASE REPORT
Informed consent was obtained from the patient for being included in the study. A patient came to the authors' attention complaining of gait impairment and lower limb hypoesthesia, rapidly ascending up to the base of the neck, with dysesthesia and urinary hesitation. Symptoms had begun after the third injection of adalimumab, a recombinant human immunoglobulin (Ig) G1 monoclonal antibody that selectively binds TNF-a and blocks its interaction with the p55 and p75 cell surface TNF receptors [1], that was prescribed for psoriatic arthritis. Neurological examination showed mild proximal weakness at the lower limbs and mild hypopallesthesia at the left lower limb.
The patient underwent brain and spinal magnetic resonance imaging (MRI): T2weighted images showed a widespread area of hyperintense signal extending from C5 to D8 level and a clinically silent brain lesion adjacent to the left trigonum ( Fig. 1). Spinal cord diameters were slightly increased, mostly at C5-C7 levels ( Fig. 1). Both brain and spinal cord lesions were hyperintense on T1-weighted images after contrast enhancement.

DISCUSSION
Tumor necrosis factor-a, secreted by microglia and macrophages, has a critical role in demyelination [11]. A clinical trial in 1999 showed a worsening of the course in patients with MS during anti-TNF-a treatment [12]. Subsequently, central or peripheral nervous system demyelination was recognized as a well-known adverse event of anti-TNF-a therapy [1][2][3][4][5][6][7][8] reported only in few cases and mainly focused on oligoclonal bands, protein concentration Table 1 Results of CSF cytology in a patient with adalimumab-related encephalomyelitis in patients with CIS, MS, and NMO and IgG index [3,4,7]. To the best of our knowledge, CSF cytology has not been reported.
In our case, CSF cytology showed a pattern that was different from CIS, MS, and NMO, being characterized by a great number of activated cells of monocyte/macrophage lineage with large kidney-shaped nucleus (88% and 90%, respectively, in two subsequent CSF analyses during the acute phase), often forming large clusters with lymphocytes; moreover, a few cells were binucleated. This pattern was clearly different from both CIS and MS that showed a similar increased percentage and activation of both lymphocyte and monocyte lineages. NMO is characterized, during acute phase of the disease, by the presence of granulocytes [13]. Moreover, in any of the 42 cases of CIS, MS, and NMO we found binucleated giant cells as in the adalimumabrelated CNS inflammation.
The presence of binucleated cells in CSF can suggest a neoplastic origin and prompt testing for cellular expression or molecular tumoral markers. In the present case, the binucleated cells were not been assessed in regard to expression markers or molecular biology because the patient had two lesions, one in the spinal cord and one in the brain; bifocal lesions are very rarely of tumoral origin [14]. Besides, neoplastic origin for the binucleated cells was excluded by the negativity of the examinations performed to find a primary tumor, by the progressive reduction of the giant cells in the last lumbar puncture performed 5 months after the cessation of adalimumab, and by the absence of any neoplasia during 7 years of follow-up. A non-oncological origin of binucleated cells in CSF is the fusion of monocyte/macrophages, a well-known phenomenon occurring during granulomatous and herpetic infection [15], that in our patient were excluded by negativity of both viral PCR detection and tuberculosis tests. In theory, the presence of binucleated cells would also require bone-marrow assessment, but this was not performed as CNS tumors in the course of anti-TNF therapy have never been reported [11,16]. The mechanism causing the peculiar CSF pattern in our patient, that is a prominent activation of monocyte lineage, with increased number of macrophages and their fusion into binucleated cells during adalimumab treatment, is unknown; however, some data suggest an involvement of the CD36 receptor expressed on monocytes and a direct role of the monoclonal anti-TNF-a antibody [15,17]. In fact it has been demonstrated that, while TNF-a inhibits, on the contrary, adalimumab increases CD36 membrane expression on human monocytes [17] and CD36 can cause macrophages fusion [15].
The 7 years of follow-up without a second CNS inflammatory involvement, the absence of oligoclonal bands in CSF, the progressive attenuation of the symptoms, and the normal spinal cord and brain MRI performed during the follow-up strongly suggest that the CNS lesions were a single acute episode caused by the treatment with adalimumab, that did not unmask a preclinical demyelinating disease and was not triggered MS.

CONCLUSION
Our case indicates that CSF cytological examination must be included in the study of CNS adverse events occurring in anti-TNF-a- Compliance with ethics guidelines. Informed consent was obtained from the patient for being included in the study.
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