By Alan Z. Segal, MD

Associate Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Segal reports no financial relationships relevant to this field of study.

SYNOPSIS: As the COVID-19 pandemic grows and spreads around the world, investigators in multiple countries are reporting patients with myriad cranial and peripheral nerve disorders that have some, but not all, features of Guillain-Barré syndrome.

SOURCE: Zhao H, Shen D, Zhou H, et al. Guillain-Barré syndrome associated with SARS-CoV-2 infection: Causality or coincidence? Lancet Neurol 2020;19:383-384.

Guillain-Barré syndrome (GBS) is an autoimmune neuropathy, seen following infections, most classically gastroenteritis from Campylobacter jejuni. It also has followed outbreaks of other infectious diseases, such as Zika virus, influenza, and, more rarely, the influenza vaccine. With the onset of the COVID-19 pandemic, it was not unexpected that a flurry of GBS would follow. This review highlights the earliest published reports of GBS and associated syndromes, such as Miller Fisher syndrome (MFS), related to SARS-CoV-2 infection.

In the first reported case, on Jan. 23, 2020, a middle-aged woman in Shanghai (who had just returned from Wuhan) was diagnosed with GBS after presenting with acute weakness in both legs and severe fatigue. She had mild initial weakness, which progressed to 3/5 in the legs and 4/5 in the arms, with areflexia and an elevated cerebrospinal fluid (CSF) protein, without cells. Nerve conduction studies revealed a demyelinating neuropathy. A complete blood count showed depressed lymphocyte and platelet counts. Of note, these hematological findings subsequently have been determined to be more prevalent in COVID-19 patients with neurological complications compared to those without. Eight days into GBS illness, this first Chinese patient developed symptoms of a viral upper respiratory tract infection, with subsequent ground glass lung opacities and a positive nasal SARS-CoV-2 swab. She was treated with intravenous immunoglobulin (IVIG) and fully recovered from both COVID and GBS within two to three weeks.

Further reports from the next epicenter of COVID-19 (Northern Italy) detailed a series of five cases of GBS. Lower extremity weakness was the first symptom in four of these patients, with one showing facial diplegia and ataxia. The interval between COVID-19 onset and GBS ranged from five to 10 days. All patients showed an absence of CSF white blood cells, with three of the five showing increased protein. None of the patients had positive CSF polymerase chain reaction (PCR) for SARS-Co-V-2. Electrophysiological studies were notable for low compound muscle action potential (CMAP) amplitude, with prolonged distal latencies and significant muscle fibrillation responses. There was no dysautonomia. The GBS was classified as an axonal variant in three patients and demyelinating in two. Treatments included IVIG, with a subset of patients requiring repeat IVIG and/or plasmapheresis. Magnetic resonance imaging (MRI) showed enhancement of caudal spinal nerve roots in two of the four patients who had a primarily lower extremity presentation, and a unilaterally enhancing facial nerve in the patient with diplegia. The authors could not draw any conclusions regarding GBS-related respiratory failure, but they hypothesized that this would be suggested when overall respiratory deficiencies outweighed pulmonary disease as defined by chest imaging.¹

Neuro-ophthalmological presentations were the focus of additional reports made by groups in Spain and New York City (including my own institution, NewYork-Presbyterian, Weill Cornell Medical College). The first Spanish patient was characterized as having a variant of MFS, while the second patient was alternatively diagnosed as “polyneuritis cranialis.” Neurological findings in case one included anosmia, ageusia, a right internuclear ophthalmoplegia (INO), a partial right third nerve palsy, ataxia, and areflexia. Testing for anti-GQ1b antibodies (typically associated with MFS) was negative, but there was a positive titer of anti-GD1b antibodies. The second case also had ageusia, along with bilateral abducens palsies, ataxia, and areflexia. Both patients had cytoalbuminologic dissociation in CSF. The first patient received IVIG, while the second was stable enough to be sent home for observation without treatment. The time lag from COVID-19 symptoms to onset of neurological deficits was three to five days, which is similar to the Italian report.²

In contrast to the Spanish patients, the two New York City patients were not diagnosed with MFS or polyneuritis specifically, but rather with multiple cranial neuropathies — a less speculative, conservative characterization. The first patient, who had a history of infantile strabismus, presented with left ptosis, diplopia, and bilateral distal leg paresthesias. Formal cranial nerve examination showed a partial third nerve palsy and bilateral sixth nerve weakness along with ataxia and hyporeflexia. Peripheral lymphocytes were significantly depleted, with an absolute count of 900/ml. The second patient had diplopia with complete right abducens palsy. MRI findings included gadolinium enhancement of the oculomotor nerve in case one and of the optic nerve sheaths in case two. As in previous reports, there was an approximately three- to five-day lag between the onset of viral symptoms (cough, fever, and myalgias) and the first neurological findings.³

COMMENTARY

The spectrum of CNS disease in COVID-19 includes stroke and encephalitis, often with necrotizing and hemorrhagic components. Given the prominent symptoms of anosmia and dysgeusia, it is thought that the olfactory bulb may serve as a portal of entry for the virus into the nervous system. Although not a consistent finding, sporadic cases with positive SARS-CoV-2 in CSF have been identified.

Taking another perspective, the cases in this review focus on manifestations of COVID primarily affecting the peripheral nervous system. Ascending paralysis with neuropathy has been highly suggestive of GBS, while cranial nerve abnormalities have raised a question of MFS or a less well defined “neuritic” syndrome. Given the limited case numbers described here, more questions are raised than are actually answered.

Do these syndromes reflect the typical post-infectious disorder of GBS, which may lag behind viral infection by many days or even a few weeks? Or does the nearly simultaneous onset of both COVID-19 and the GBS-like syndromes described here suggest that there is more of a “para-infectious” effect? Nerves may be directly infected with the virus or perhaps nerves are bystanders, injured as a consequence of the profound immune reaction and marked inflammatory state in severe COVID cases.

With so few cases, finding a set of clinical features that identify a unique signature of COVID-related neuropathy is difficult. Although typical GBS is demyelinating more often than axonal, it appears that this may be the reverse in COVID. The likelihood of the most protean GBS outcomes, such as autonomic instability or neuromuscular respiratory failure, also remains unclear. In addition, the cases reported here may not be purely peripheral, but rather may have central findings mixed in.

The INO in the first Spanish case would be atypical for MFS, and the optic nerve leptomeningeal enhancement in the second New York City patient had no clinical correlate. Although the finding of typical cytoalbuminologic dissociation was common, none of the cases here showed a positive CSF PCR for SARS-CoV-2. Anti-ganglioside antibodies, which are a frequent but not invariable finding in sporadic GBS and imply an autoimmune process, were very rare here. There was only one positive result, but about half of the patients went untested.

Tremendous uncertainty persists regarding the natural history of SARS-CoV-2 and its ongoing pandemic. With the likely accumulation of massive cohorts of COVID patients, larger series of GBS, MFS, and other associated syndromes are sure to follow.

REFERENCES

1. Toscano G, Palmerini F, Ravaglia S, et al. Guillain-Barré syndrome associated with SARS-CoV-2. N Engl J Med 2020; April 17. doi: 10.1056/NEJMc2009191. [Online ahead of print].
2. Gutierrez-Ortiz C, Mendez A, Rodrigo-Rey S, et al. Miller Fisher syndrome and polyneuritis cranialis in COVID-19. Neurology 2020; April 17. doi: 10.1212/WNL.0000000000009619. [Online ahead of print].
3. Dinkin M, Gao V, Kahan J, et al. COVID-19 presenting with ophthalmoparesis from cranial nerve palsy. Neurology 2020; May 1. doi: 10.1212/WNL.0000000000009700. [Online ahead of print].