key: cord-0876323-7n42u6pw
authors: Senel, Makbule; Abu‐Rumeileh, Samir; Michel, Detlef; Garibashvili, Tamara; Althaus, Katharina; Kassubek, Jan; Otto, Markus
title: Miller‐Fisher syndrome after COVID‐19: neurochemical markers as an early sign of nervous system involvement
date: 2020-08-11
journal: Eur J Neurol
DOI: 10.1111/ene.14473
sha: 186c93037b0bacc3ddc0270e95c37384fb5fde0a
doc_id: 876323
cord_uid: 7n42u6pw

The Miller Fisher syndrome (MFS) is classified as a variant of the Guillain–Barré syndrome (GBS), accounting for 5‐25% of all GBS cases. Since the coronavirus disease‐2019 (COVID‐19) outbreak, increasing evidence of the neurologic manifestations of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, affecting both central and peripheral nervous system, has been described. Here we report the clinical course, detailed cerebrospinal fluid (CSF) profile including CSF/blood antibody status, and neurochemical parameters of a case with a typical clinical presentation of MFS after being tested positive for SARS‐CoV‐2 infection.

nervous system, has been described. Here we report the clinical course, detailed cerebrospinal fluid (CSF) profile including CSF/blood antibody status, and neurochemical parameters of a case with a typical clinical presentation of MFS after being tested positive for SARS-CoV-2 infection.

A 61-years-old patient experienced mild breathing difficulties at the end of March 2020.

Three days later, he was tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA on RT-PCR with a nasopharyngeal swab. Given the mild symptoms the patient was in home quarantine. During this period, he developed fever for four days with heavy night sweat. Moreover, he reported a weight loss of 12 kg. At the end of quarantine, he experienced a slight unstableness during walking, a sensation of "pins and needles" on his fingertips and slight diplopia. Twenty-seven days after the first symptoms car driving was not possible anymore. Finally, the patient was admitted to our department presenting with slight sensitive ataxia, ophthalmoplegia, and general areflexia. In the electrophysiological examination, the F-wave was not detectable. Serum anti-ganglioside antibodies, including anti-GQ1b, were negative.

Cerebrospinal fluid (CSF) analysis revealed: normal cell count (one leukocyte per µL). Cell differentiation showed 90% lymphocytes, 6% monocytes, and 4% activated lymphocytes.

RT-PCR for SARS-CoV-2 in CSF and at nasopharyngeal swab was negative. CSF total protein levels and the corresponding albumin quotient were largely increased (1588 mg/L and 24.8, respectively). An intrathecal production of IgG (either by oligoclonal bands or in the Reiber diagram), IgA or IgM was not detectable (Quotient (Q)IgG: 12.1, QIgA: 7.0, QIgM: 1.1) ( Figure 1 ). Lactate was slightly elevated with 3.4 mmol/L, but the glucose quotient was within normal range (0.51). CSF total tau and amyloid-beta-42 were normal (265 and 1109 pg/ml, respectively). CXCL13, beta-microglobulin, and ferritin in CSF were not affected. CSFblood antibody indexes for varicella-zoster, Epstein-Barr virus, herpes-simplex virus were

This article is protected by copyright. All rights reserved normal. In blood, the antibody reaction against SARS-CoV-2 was positive for IgG and IgA.

The response was 8.6 (arbitrary units, AU) for IgG (cut-off 1.1, dilution 1:1000) and 2.3 for IgA (cut-off 1.1, dilution 1:1000, Euroimmun assay). At a CSF dilution of 1:10, a positive signal was observed for IgG (8.6 AU) and IgA (1.3 AU), corresponding to an antibody index below one, meaning no intrathecal production of SARS-CoV-2 antibodies. Phosphorylated neurofilament heavy chain protein (pNfH) was massively elevated in CSF with 2131 pg/ml (normal levels below 560 pg/mL). Neurofilament light chain (NfL) protein in blood measured by Simoa was clearly increased with 58 pg/mL (normal levels below 30 pg/mL).

After the lumbar puncture the patient was treated for five days with intravenous immunoglobulin (30 g/day). Two weeks after the treatment, the patient was free of symptoms. A second and third determination of NfL in blood, seven days and 23 after the lumbar puncture, still showed increased levels (61 pg/mL; 58 pg/mL, respectively).

MFS is classified as a variant of the GBS, presenting with ophthalmoplegia, ataxia, and areflexia [1] . In summary, here, we describe a patient with a typical clinical presentation of MFS 20 days after he was tested positive for SARS-CoV-2 infection. The latency between coronavirus disease-2019 (COVID-19) manifestations and MFS onset is in accordance with previous single case reports and suggests a typical post-infectious course [2] [3] [4] . Moreover, our patient shares the classical MFS clinical features and a good response to intravenous immunoglobulins with other reports [2] [3] [4] .

Most interestingly, we provide for the first time a detailed and comprehensive overview of the CSF profile in COVID-19-associated MFS. In detail, we found no evidence of intrathecal production of SARS-CoV-2 antibodies as disease-causing antibodies in CSF. However, we could show a significant rise of CSF p-NfH and serum NfL in this patient, reflecting the affection of the peripheral nerves. In addition, the absence of serum anti-ganglioside antibodies (including anti-GQ1b) in our and two other COVID-19-associated MFS cases [2] [3] , together with the positivity for anti-GD1b antibodies in another one [3] , might implicate different immune-mediated mechanisms compared to those of non-COVID-19 MFS, although serum anti-GQ1b antibody negative MFS cases have been described [5] .

This article is protected by copyright. All rights reserved

With the spreading of the SARS-CoV-2 pandemic worldwide, more of such cases will probably be described. Here the measurement of NfL in blood might be considered an easy tool to detect an early affection of the peripheral and central nervous system [6, 7]. demonstrate a blood-CSF barrier dysfunction without an intrathecal Ig production.

Diagnosis and management of

Guillain-Barre syndrome in ten steps

Miller-Fisher syndrome after SARS-CoV-2 infection

Miller Fisher Syndrome and polyneuritis cranialis in COVID-19

Guillain-Barre syndrome following COVID-19: new infection, old complication?

Usefulness of anti-GQ1b IgG antibody testing in Fisher syndrome compared with cerebrospinal fluid examination