# “Neuro-renal syndrome” related to anti-contactin-1
antibodies

Guillaume Taieb, Moglie Le Quintrec, Amandine Pialot, Ilan Szwarc, Hélène
Perrochia, Pierre Labauge, Jérôme Devaux

► To cite this version:

Guillaume Taieb, Moglie Le Quintrec, Amandine Pialot, Ilan Szwarc, Hélène Perrochia, et al. "Neuro-renal syndrome" related to anti-contactin-1 antibodies. Muscle & Nerve, 2019, 59 (3), 10.1002/mus.26392. hal-02347676

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Distributed under a Creative Commons Attribution 4.0 International License
myofiber necrosis was detected by chance. Patients presenting with asymptomatic hyperCKemia should be followed with regular CK levels for a period of time; rising CK levels or development of clinical symptoms should lead to consideration of additional evaluations, including investigations for NAM.

Ethical Publication Statement: All authors confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Drs. Triplett, Pamphlett, Wang, and Yiannikas have no disclosures.

James D. Triplett, FRACP ID<fnref n="1" />

Roger Pamphlett, MD, FRACP, FRCPATH<fnref n="2" />,<fnref n="3" />

Min-Xia Wang, MD<fnref n="4" />

Con Yiannikas, FRACP<fnref n="1" />,<fnref n="2" />

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Published online 29 November 2018 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.26388

## "NEURO-RENAL SYNDROME" RELATED TO ANTI-CONTACTIN-1 ANTIBODIES

Since 1973, a few cases of concomitant inflammatory demyelinating polyradiculoneuropathy and nephrotic syndrome have been reported. The neuropathy was either an acute inflammatory demyelinating polyneuropathy (AIDP) or a chronic inflammatory demyelinating polyneuropathy (CIDP), and the nephrotic syndrome was related to either a focal segmental glomerulosclerosis (FSGS) or a membranous glomerulonephritis (MGN).<fnref n="1" />⁻<fnref n="4" /> Time course, severity, and response to treatment were heterogeneous, and evolution of neuropathy and nephropathy could be independent. This suggests that common epitopes are targeted by autoantibodies within the peripheral nerve and the glomerular filtration barrier. However, the antigenic targets are unknown. Here, we report a patient who developed CIDP associated with anti-contactin-1 immunoglobulin G4 (IgG4) antibodies and nephrotic syndrome.

## CASE REPORT

A 75-year-old man developed numbness in all four extremities, unsteady gait, and bilateral proximal lower-limb muscle weakness over 1 month. These symptoms started 15 days after anti-influenza vaccination. Strength was 4/5 bilaterally (Medical Research Council scale) in proximal lower limb muscles and normal elsewhere. Deep tendon reflexes were absent in the lower limbs and normal in the upper limbs. Proprioceptive and vibratory modalities were impaired in all 4 limbs. Romberg's sign was positive, and tandem walking was impaired. General physical examination was normal, and blood pressure was 126/76 mm Hg. Motor nerve conduction studies (NCS) fulfilled the modified electrophysiological criteria for AIDP with prolongation of F-wave latencies in more than two nerves (Table 1).⁵ Sensory NCS in the sural, median, ulnar, and radial nerves were normal bilaterally. Needle electromyography showed neuropathic recruitment in the psoas muscles. Blood count, serum albumin, and renal and liver function tests were normal. Dipstick urinalysis did not detect albumin. Magnetic

**Abbreviations:** AIDP, acute inflammatory demyelinating polyneuropathy; CIDP, chronic inflammatory demyelinating polyneuropathy; FSGS, focal segmental glomerulosclerosis; IgG4, immunoglobulin G4; MGN, membranous glomerulonephritis; NCS, nerve conduction studies; PLA₂R, phospholipase A₂ receptor

**Key words:** anti-contactin-1 IgG4 antibodies; anti-neurofascin-186 IgG4 antibodies; chronic inflammatory demyelinating polyradiculoneuropathy; nephrotic syndrome; nodopathy; paranodopathy

**Conflicts of Interest:** None of the authors has any conflict of interest to disclose.

**Correspondence to:** G. Taieb, e-mail: taiebguillaume@gmail.com

© 2018 Wiley Periodicals, Inc.

<footnote n="1">¹Concord Hospital, Sydney, Hospital Road, Concord, NSW 2137, Australia</footnote>

<footnote n="2">²Faculty of Medicine, The University of Sydney, Sydney, Australia</footnote>

<footnote n="3">³Department of Neuropathology, Royal Prince Alfred Hospital, Sydney, Australia</footnote>

<footnote n="4">⁴Department of Neurology, Royal Prince Alfred Hospital, Sydney, Australia</footnote>
<table><caption>**Table 1.** Motor nerve conduction studies performed at 1 month, 3 months, and 5 months after disease onset.</caption><thead><tr><th></th><th>1 month<br>Right / left</th><th>3 months<br>Right / left</th><th>5 months<br>Right / left</th><th>Normal values</th></tr></thead><tbody><tr><td colspan="5"><strong>Median nerve</strong></td></tr><tr><td>DML</td><td>4.9 / 3.8</td><td>5.9 / 4.8</td><td>6.9* / 5.0</td><td>≤4.2 ms</td></tr><tr><td>CMAP</td><td>7.2 / 5.9</td><td>5.6 / 5.0</td><td>4.3 / 6.5</td><td>≥6.0 mV</td></tr><tr><td>CV</td><td>51.8 / 53.8</td><td>45.0 / 53.2</td><td>46.1 / 45.0</td><td>≥48 m/s</td></tr><tr><td>FWL</td><td>35.7 / 34.0</td><td>48.0* / 49.6*</td><td>56.3* / 57.8*</td><td>≤ 30 ms</td></tr><tr><td colspan="5"><strong>Ulnar nerve</strong></td></tr><tr><td>DML</td><td>2.4 / 2.5</td><td>2.6 / 3.0</td><td>3.3 / 3.1</td><td>≤3.2 ms</td></tr><tr><td>CMAP</td><td>6.7 / 8.1</td><td>3.8 / 5.0</td><td>3.6 / 5.3</td><td>≥6.0 mV</td></tr><tr><td>CV</td><td>58.1 / 59.0</td><td>53.9 / 55.7</td><td>45.5 / 45.0</td><td>≥48 m/s</td></tr><tr><td>FWL</td><td>37.0 / 39.9*</td><td>46.0* / 44.0*</td><td>50.0* / 55.1*</td><td>≤ 30 ms</td></tr><tr><td colspan="5"><strong>Peroneal nerve</strong></td></tr><tr><td>DML</td><td>4.9 / 4.7</td><td>7.1 / 6.3</td><td>NO / NO</td><td>≤5.0 ms</td></tr><tr><td>CMAP</td><td>2.9 / 3.8</td><td>0.5 / 0.9</td><td>NO / NO</td><td>≥3.0 mV</td></tr><tr><td>CV</td><td>37.9 / 38.2</td><td>31.0 / 28.8*</td><td>NO / NO</td><td>≥42 m/s</td></tr><tr><td>FWL</td><td>72.2* / NO</td><td>NO / NO</td><td>NO / NO</td><td>≤ 50 ms</td></tr><tr><td colspan="5"><strong>Tibial nerve</strong></td></tr><tr><td>DML</td><td>6.5 / 4.5</td><td>9.0* / 8.3*</td><td>7.8 / 8.1</td><td>≤5.5 ms</td></tr><tr><td>CMAP</td><td>5.9 / 6.8</td><td>1.7 / 1.8</td><td>0.6 / 0.5</td><td>≥6.0 mV</td></tr><tr><td>CV</td><td>37.8 / 41.5</td><td>26.6* / 32.4</td><td>NO / NO</td><td>≥42 m/s</td></tr><tr><td>FWL</td><td>79.6* / 71.2</td><td>79.0 / 70.4</td><td>NO / NO</td><td>≤ 55 ms</td></tr></tbody></table>

DML, distal motor latency; CMAP, compound muscle action potential; CV, conduction velocity; FWL, F-wave latency; NO, not obtained.

resonance imaging of the whole spinal cord was normal. Cerebrospinal fluid analysis showed albuminocytologic dissociation with a protein level of 150 mg/dL (normal <45 mg/dl) and a white blood cell count below 1/mm³ (normal <3/mm³). Serology for cytomegalovirus showed past infection, and serology for *Campylobacter jejuni* was negative. Detection of anti-ganglioside antibodies showed IgM anti-GM2 antibodies. At this stage, the diagnosis of AIDP was made and intravenous immunoglobulin (0.4 g/kg/day for 5 days) was given without clinical improvement.

Lower limb muscle weakness worsened gradually over 5 months, requiring a wheelchair. Strength was 2/5 proximally and distally in lower limbs and 3/5 distally in upper limbs. Deep tendon reflexes were absent, and hypoesthesia involved all sensory modalities and affected all limbs. Three months after the initial onset, motor NCS showed worsening of the demyelinating features fulfilling the

European criteria for a definite CIDP (Table 1).⁶ No conduction block or temporal dispersion was detected. At 5 months, motor and sensory NCS revealed mixed axonal and demyelinating features (Table 1). Acute denervation in tibialis anterior muscles was present on electromyography. Concomitantly, the patient developed high blood pressure (170/110 mmHg) and lower-limb edema. Laboratory tests revealed a nephrotic syndrome with hypoalbuminemia (22 g/L; normal, 38–48 g/L) and nephrotic-range proteinuria (5.4 g/24h; normal < 0.3 g/24 h) without elevated creatinine (48 µmol/L; normal, 45–90 µmol/L).

MGN at an early stage was diagnosed on renal biopsy. The glomeruli appeared normal by light microscopy. Immunofluorescence revealed marked subepithelial IgG4 deposits (Fig. 1). Complement staining intensity was weak for C3 and absent for C1q. Anti-M-type phospholipase A₂ receptor (PLA₂R) immunostaining on paraffin-embedded tissue sections was negative, and serum anti-PLA₂R antibodies were not detected. Anti-neurofascin-155 and -186 antibodies were also negative, but anti-contactin-1 IgG4 antibodies were detected by enzyme-linked immunosorbent assay and confirmed by cell-based assay (Fig. 1) and staining of myelinated axons. Prednisone (1 mg/kg/day) was started. While renal function improved, the neuropathy worsened. After 5 ineffective plasma exchanges, rituximab (1g) was started. One week later, the patient presented with nausea most likely related to rituximab, and died from aspiration pneumonia, with no obvious bulbar weakness.

## DISCUSSION

We describe a patient with acute-onset CIDP associated with anti-contactin-1 IgG4 antibodies and with nephrotic syndrome. By contrast to previously reported CIDP cases associated with anti-contactin-1 antibodies, the demyelinating features were primarily proximal rather than diffuse, with prolonged F-wave latencies.⁷,⁸ Similar to the previously reported case of MGN with anti-contactin-1 CIDP, the nephrotic syndrome improved after steroid treatment, but the neuropathy worsened rapidly and axonal involvement appeared despite usual therapies.⁹ Of interest, 2 cases of acute-onset CIDP related to anti-neurofascin-186 IgG4 antibodies with nephrotic syndrome have been reported

<figure><img src="image_2.png" /><figcaption>**FIGURE 1.** (A) Immunofluorescence section showed granular deposits of IgG4 along the outer aspect of the glomerular capillary walls (arrows). Scale bar = 20 µm. (B) Serological test revealed IgG4 reactivity (green) against contactin-1 (red) expressed on HEK cells. Scale bar = 10 µm.</figcaption></figure>

<footnote>*Demyelinating features fulfilling the European criteria for a definite CIDP.</footnote>
recently. In contrast to anti-contactin-1 patients, these patients were responsive to steroids, and renal biopsy showed a FSGS.¹⁰ Neurofascin-186 and contactin-1 are present in the nodal and paranodal compartments of myelinated axons, respectively, but also in podocytes.¹¹,¹² We speculate that autoantibodies to contactin-1 and neurofascin-186 could promote alterations in the glomerulus and in paranodes.

Consistent with this, immunofluorescence staining on renal biopsy revealed predominantly IgG4 deposits in our patient. This argues for a primary MGN, which is an IgG4-mediated autoimmune disease. However, while glomerular staining for anti-PLA₂R and serum anti-PLA₂R antibodies are usually present in primary MGN, both were absent in our case.¹³ Considering that anti-contactin-1 antibodies are mainly of the IgG4 subclass, we cannot exclude that MGN is secondary to elevated serum IgG4 concentration and could result from either deposition of circulating immune-complexes or other unknown mechanisms. An alternative could be that anti-contactin-1 IgG4 antibodies specifically affect podocyte structure and PLA₂R immunostaining. The high intensity of IgG4 staining on glomeruli together with the paucity of C3 deposits and the absence of Clq staining strongly argue against a complement-mediated glomerulopathy. In support of this, IgG4 subclass antibodies exhibit a low affinity for complement, and no complement deposition was observed at paranodes in nerve biopsy specimens from CIDP patients with anti-contactin-1 IgG4.¹⁴

In conclusion, the combination of demyelinating neuropathy and nephrotic syndrome should prompt a search for anti-neurofascin-186 and contactin-1 IgG4, in addition to tests for diabetes, amyloidosis, connective tissue diseases (e.g., systemic lupus erythematosus), paraneoplastic syndrome, and inverted form 2 mutations related to Charcot-Marie-Tooth disease.¹⁵ This latter mutant protein is expressed by both Schwann-cells and podocytes, suggesting the existence of "neuro-renal syndrome." Our data suggest that other renal proteins are involved in immune-mediated "neuro-renal syndrome."

Ethical Publication Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Guillaume Taieb, MD<fnref n="1" />

Moglie Le Quintrec, MD, PHD<fnref n="2" />

Amandine Pialot, MD<fnref n="2" />

Ilan Szwarc, MD<fnref n="2" />

Hélène Perrochia, MD<fnref n="3" />

Pierre Labauge, MD, PHD<fnref n="1" />

Jérôme J. Devaux, PHD<fnref n="4" />

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Published online 29 November 2018 in Wiley Online Library
(wileyonlinelibrary.com). DOI 10.1002/mus.26392

<footnote n="1">¹Department of Neurology, CHU Montpellier, Hopital Gui de Chauliac, 80 avenue Augustin Fliche, 34295, Montpellier Cedex 5, France</footnote>

<footnote n="2">²Department of Nephrology, CHU Montpellier, Hopital Lapeyronie, Montpellier, France</footnote>

<footnote n="3">³Department of Pathology, CHU Montpellier, Hopital Gui de Chauliac, Montpellier, France</footnote>

<footnote n="4">⁴Institute for Neurosciences of Montpellier, INSERM U1051, Montpellier University, Hopital Gui de Chauliac, Montpellier, France</footnote>