Report of a fulminant anti‐pan‐neurofascin‐associated neuropathy responsive to rituximab and bortezomib

Abstract

Inflammatory neuropathies with pathogenic involvement of the nodes of Ranvier through autoantibodies have been increasingly characterized in the past years.The so-called anti-pan-NF-associated neuropathies caused by the simultaneous existence of anti-Neurofascin-186/-140 and -155-antibodies are extremely rare and cause life-threatening symptoms. Therapeutic strategies are needed as symptoms may be life-threatening and may not respond to standard first-line CIDP treatment. We report a case of a 52-year-old male with a rare anti-pan-neurofascin (NF) (-155, -186/-140)-associated neuropathy. The initial presentation was subacute with mild paresthesia leading to a fulminant "locked-in"-like syndrome requiring mechanical ventilation within the first eight weeks despite treatment with intravenous immunoglobulins. Nerve conduction studies revealed non-excitable nerves with acute spontaneous activity in electromyography. High titers of anti-Neurofascin-155, À186/À140-antibodies were detected in serum and cerebrospinal fluid. A combination of aggressive immunotherapy consisting of intravenous immunoglobulins, plasma exchange, rituximab and bortezomib resulted in clinical improvement with ambulation and non-detectable anti-neurofascin-antibodies within the following 3 months. The follow-up nerve conduction studies showed normalized amplitudes of the peripheral nerves with signs of reinnervation in electromyography. We conclude that an early aggressive immunotherapy consisting of a combination of rituximab and bortezomib could be considered as a therapeutic option for anti-pan-NF-associated neuropathies.

IgG4 Autoantibodies in Organ-Specific Autoimmunopathies: Reviewing Class Switching, Antibody-Producing Cells, and Specific Immunotherapies

“…Among IgG4-AID, bortezomib was described as a good therapeutic option for CIDP patients ( 228 ) with severe relapses or an acute progression who did not respond adequately to regular immunosuppression treatment and rituximab ( 228 ). Additionally, in a patient with anti-pan-NF-associated neuropathy (predominantly of the IgG4 isotype) with severe clinical manifestations, it has also being shown reduction in antibody titer leading to clinical improvement after receiving a combination of IVIG, PLEX, rituximab and bortezomib ( 229 ). Bortezomib was beneficial in patients with relapsed/refractory TTP with an acceptable adverse event profile ( 230 ).…”

Anti-pan-neurofascin antibodies induce subclass-related complement activation and nodo-paranodal damage

“…The others received rituximab, in one case in combination with bortezomib. 27 They showed major motor improvement (ΔMRC 43/48/58) and sNF-L levels < 70 ng/ml in follow-up intervals of 4–11 months, with one of them reaching sNF-L levels within the normal range of healthy controls (3 standard deviations) 9 months after the onset of disease. Supplementary Video 1 shows one of them happily leaving the rehabilitation clinic.…”

“… 12 , 20–27 A distinct clinical phenotype has been proposed in this subset: they present with a severe, GBS-like onset and after initial short recovery, develop a fulminant course of disease with tetraplegia, autonomic instability, cranial nerve involvement, respiratory failure with prolonged ventilation, insufficient response to standard treatment and a high mortality. 12 , 20 , 21 , 26 , 27 …”

Anti-NF155/NF186 IgG4 Antibody Positive Autoimmune Nodopathy

“…The so-called anti-pan-NF-associated neuropathies caused by the co-existence of anti-NF186/140 and NF155 antibodies were extremely rare and caused life-threatening symptoms such as almost locked-in syndromes [ 9 , 11 , 12 , 19 , 20 , 28 ]. Burnor et al [ 10 ] reported a 50-year-old man who developed rapidly progressive weakness and paresthesias, which evolved into extraocular weakness, ptosis, facial diplegia, dysarthria, almost complete ophthalmoplegia, quadriplegia, and oscillating sympathetic hypersensitivity with labile blood pressure.…”

“…In this case, the symptoms were quite mild and revealed an effective clinical response to IVIG, so no further immunotherapy was required. Fels et al [ 28 ] described a case of fulminant anti-pan-NF-associated neuropathy as IgG4 and IgG3-mediated disease with severe clinical damage. The patient presented with progressive tetraplegia, sensory impairment, cranial nerve involvement, autonomic dysregulation and respiratory insufficiency.…”