Remarkable Rituximab Response on Tremor Related to Acute‐Onset Chronic Inflammatory Demyelinating Polyradiculoneuropathy in an Antineurofascin155 Immunoglobulin G4–Seropositive Patient

Anti‐neurofascin (NF)‐155 antibodies characterize chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) phenotypes with severe polyradiculoneuropathy, ataxia, poor response to intravenous (IV) immunoglobulins (IVIg), and, in the majority of patients, disabling tremor.1 We present a 64‐year‐old woman who acutely developed gait disturbances with ataxia, followed by proximal and distal weakness, numbness, and tingling in the hands and feet over the next 2 weeks (April 2015). The Inflammatory Neuropathy Cause and Treatment (INCAT) disability score was 6/10 (four‐limb disability, 3 points). Nerve conduction studies (NCSs) disclosed a mainly demyelinating motor‐sensory polyradiculoneuropathy. Cerebrospinal fluid analysis showed albumin‐cytologic dissociation (total protein concentration, 1.42 g/L). The patient was diagnosed with Guillain–Barré syndrome (GBS) and was treated with plasma exchange without improvements. A subsequent IVIg cycle (0.4 g/kg/day for 5 days) led to partial improvements, given that she walked with bilateral support 8 weeks after rehabilitation. Six months after onset, she was wheelchair‐bound because of further neurological deteriorations, confirmed by electrophysiological studies. Accordingly, the diagnosis changed into acute‐onset CIDP. After an ineffective IVIg cycle, high‐dose IV corticosteroids (6‐methylprednisolone, 500 mg/day for 4 days) improved the clinical picture, allowing her to walk with bilateral support. From January 2016 onward, despite the oral steroid therapy (prednisone, 50 mg/day), the patient manifested a progressive clinical deterioration, with tetraparesis (Medical Research Council sum score, 44/60), hypoesthesia in a stocking‐glove distribution, distal apallesthesia, and areflexia. She was wheelchair‐bound, able to move only a few steps with ataxic gait and tremor when standing up and walking. A postural and intention tremor at the upper limbs prevented her from eating independently, in the absence of tremor in the head or facial muscles. INCAT disability score reached 8/10 points. We tested for serum anti‐contactin‐1 and anti‐NF‐155 antibodies, the latter resulting positive on both in‐house enzyme‐linked immunosorbent assays (total immunoglobulin G [IgG], predominant IgG4 isotype) and cell‐based assay (human NF‐155‐transfected HEK293 cells). The patient was treated with rituximab (375 mg/m2/weekly for 4 weeks). Three months after the end of the cycle, her tremor improved, she ate independently, and walked with bilateral support. Anti‐NF‐155 antibodies were negative. After 7 months, neurological examination disclosed further improvements in strength, numbness, and tingling; postural and intention tremor were minimal. She walked without assistance, regaining her self‐sufficiency (see Video). INCAT disability score dropped to 3/10 (lower limbs disability, 1 point). After 9 months, we repeated NCS, which showed slight improvements in motor nerve conduction velocity, distal latency, and F wave of the left ulnar nerve. As for the maintenance therapy, we checked levels of CD27⁺ memory B cells every 3 months, scheduling reinfusions whenever they exceeded 0.05% of peripheral blood mononuclear cells. At the last follow‐up (18 months), she needed one single infusion 11 months after the induction, with maintenance of the impressive improvements and without remarkable side effects.

Our patient manifested a severe clinical phenotype very similar to those typical of anti‐NF‐155 antibody–associated CIDP1, 2, 3, 4, 5. A GBS‐like onset of the disease,3, 4, 5 as well as good responses to rituximab,1, 2, 3, 4, 5 have also been reported. However, the heterogeneity in clinical severity and phenotypes (e.g., disabling tremor was absent in some cases5) makes the comparative evaluations of rituximab efficacy difficult. Moreover, in the 3 cases treated with this drug by Querol and colleagues, 1 patient had no tremor,1 and there is no clear mention about tremor evolution in the other 2.2 So, this is the first case of anti‐NF‐155 CIDP and tremor showing a remarkable response of tremor and other symptoms to rituximab. Such a response was somewhat unexpected, given that the deterioration of tremor, despite improvements of other symptoms, has been reported in rituximab‐treated patients with anti‐MAG neuropathy.6 Rituximab seemed effective as both induction and maintenance therapy. In IgG4‐related diseases, relapses are frequent after B‐cell reconstitution.7 In line with these experiences, our report suggests that titrating rituximab to circulating B cells might be effective in preventing relapses. As for the disappearance of anti‐NF‐155 antibodies after therapy, their meaning as biomarkers for monitoring the CIDP clinical course requires further studies.

Author Roles

1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

C.D.: 1B, 1C, 3A

D.F.: 1A, 1B, 1C, 3B

A.C.: 1A, 1B, 1C

I.C.: 1B, 1C

C.S.: 1A, 1B, 3B

G.M.: 1A, 1B, 3B

A.S.: 1A, 1B, 3B

A.L.: 1C, 3B

L.B.: 1A, 1B, 1C, 3B

Disclosures

Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. The authors obtained informed consent from the patient shown in the video. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for previous 12 months: The authors declare that there are no disclosures to report.

Supporting information

Supporting information may be found in the online version of this article.

Video 1. The video is divided into three parts. The first part shows the patient before rituximab treatment. She manifests postural and intention tremor with marked difficulty in object manipulation. The patient was severely disabled, being wheelchair‐bound, and able to walk only for a few steps, with an ataxic gait. The second part shows that the tremor markedly improved, the patient could crochet again and walked with bilateral support, three months after rituximab. The third part shows that the tremor was almost disappeared, and the patient regained her self‐sufficiency, walking independently, ten months after rituximab.