SARS‐CoV‐2–associated Guillain‐Barre syndrome in 62 patients

Dear Editor,

We read with interest the review article by De Sanctis et al. about 18 patients with Guillain‐Barre syndrome (GBS) associated with the SARS‐CoV‐2 infection (COVID‐19) [1]. Acute, inflammatory, demyelinating polyneuropathy (AIDP) was the most frequent subtype of GBS. We have the following comments and concerns.

The number of patients experiencing GBS in the context of COVID‐19 is much higher than reported by De Sanctis et al. Currently (12 August 2020), at least 62 COVID‐19 patients with polyradiculitis have been reported in 48 articles (Table 1). Ages ranged from 11 to 94 years (Table 1). Twenty patients were female and 36 were male (Table 1). In 58 patients, GBS began after onset of clinical manifestations of COVID‐19. Latency between onset of COVID‐19 and GBS ranged from 3 to 33 days. Forty‐two patients were diagnosed with AIDP, six with acute motor axonal neuropathy, five with Miller‐Fisher syndrome and three with acute motor sensory axonal neuropathy. In six patients, the subtype was not specified (Table 1). SARS‐CoV‐2 in the cerebrospinal fluid (CSF) was detected in none of the patients (Table 1). Fifty patients received intravenous immunoglobulin and eight plasmapheresis (Table 1). Two patients received steroids exclusively (Table 1). Eighteen patients required artificial ventilation (Table 1). Twenty‐four patients recovered completely and 23 partially. Only two patients died.

Table 1.

Patients with SARS‐CoV‐2–associated polyradiculitis so far reported

Age (years)	Sex	Onset	LOO (days)	Subtype	CIC	CM	IVIG	AV	Recovery	Country
61	F	B	9	AIDP	NR	None	Yes	No	Yes	China
65	M	A	9	AMSAN	ND	DM	Yes	No	NR	Iran
54	M	A	8	AIDP	NR	None	Yes	Yes	Yes	USA
70	F	A	23	AIDP	ND	None	Yes	Yes	NR	Italy
66	F	A	7	AIDP	No	NR	Yes	Yes	Yes	Italy
54	F	A	21	AIDP	ND	None	Yes	No	Yes	Germany
70	F	A	3	AMSAN	No	RA	Yes	No	No	Morocco
20	M	A	5	AMAN	ND	None	Yes	No	Yes	India
71	M	A	4	AIDP	No	AHT, AAR, LC	Yes	Yes	Death	Italy
64	M	A	11	AIDP	ND	None	Yes	Yes	NR	France
NR	NR	A	7	AIDP	No	NR	Yes	No	No	Italy
NR	NR	A	10	AIDP	No	NR	Yes	No	Yes	Italy
NR	NR	A	10	AMAN	No	NR	Yes	Yes	No	Italy
NR	NR	A	5	AMAN	No	NR	Yes	No	No	Italy
NR	NR	A	7	AMAN	No	NR	Yes, PE	No	No	Italy
50	M	A	3	MFS	No	None	Yes	No	Yes	Spain
39	M	A	3	MFS	No	None	No	No	Yes	Spain
61	M	A	10	MFS	No	None	S	No	Yes	Spain
76	F	A	8	GBS*	ND	None	No	NR	Death	Spain
~75	M	B	10	AIDP	No	None	Yes	No	Yes	Swiss
43	M	A	10	AIDP	NR	NR	Yes	No	Yes	Spain
64	M	A	23	AIDP	No	NR	Yes	No	Yes	France
72	M	A	7	AIDP	No	AHT, CHD, AL	Yes	Yes	Partial	USA
~65	M	A	17	AIDP	No	None	Yes	No	Yes	Italy
67	F	A	10	NR	No	Breast cancer	PE	Yes	Partial	USA
54	M	A	14	AIDP	ND	NR	Yes	No	Partial	USA
43	M	A	21	AIDP	No	NR	Yes	No	Yes	France
71	F	A	10	AIDP	No	NR	Yes	No	Partial	France
36	M	A	4	MFS	NR	NR	Yes	No	Yes	USA
55	M	A	20	AIDP	No	NR	Yes	Yes	Partial	Italy
60	M	A	3	AMSAN	No	NR	Yes	Yes	Partial	Italy
58	M	B	0	AIDP	No	No	Yes	No	Partial	Canada
52	F	A	15	AIDP	No	NR	Yes	No	Partial	Switzerland
63	F	A	7	AIDP	NR	NR	Yes	No	Yes	Switzerland
61	F	A	22	AIDP	No	NR	Yes	No	Partial	Switzerland
53	F	B	NR	AIDP	No	No	PE	No	Partial	Turkey
51	F	A	14	MFS	NR	NR	Yes	No	Partial	Spain
56	F	A	15	AIDP	No	NR	Yes	Yes	Partial	Spain
68	M	A	14	AIDP	NR&	NR	Yes, PE	Yes	Partial	Austria
55	F	A	14	AIDP	NR	No	Yes	Yes	Partial	Spain
53	M	A	24	AIDP	No	No	Yes	No	Yes	the Netherlands
57	M	A	6	AIDP	No	AHT, psoriasis	Yes	Yes	Partial	UK
21	M	A	16	AIDP	NR	AHT, DM	PE	No	Yes	USA
41	M	A	10	AIDP	NR	DM	Yes	No	Partial	Iran
38	M	A	16	AIDP	NR	AHT	PE	No	Yes	Iran
14	F	A	NR	GBS	NR	No	Yes	No	Yes	Iran
49	M	A	14	AIDP	No	No	Yes	No	Yes	UK
68	M	A	5	AIDP	NR	AHT, HLP	Yes	No	Yes	Italy
11	M	A	21	AIDP	NR	No	Yes	No	Yes	Saudi Arabia
15	M	A	NR	AMAN	No	No	Yes	No	Partial	Brazil
72	M	A	18	AIDP	No	NR	Yes	Yes	Partial	Italy
72	M	A	30	AIDP	No	NR	Yes	Yes	Partial	Italy
49	F	A	14	AIDP	No	NR	Yes	No	Partial	Italy
94	M	A	33	AIDP	NR	NR	S	No	Partial	Italy
76	M	A	22	AIDP	No	NR	Yes	Yes	Partial	Italy
64	M	A	NR	GBS?	NR	DM	Yes	Yes	Yes	Japan
77	M	A	NR	AIDP	NR	AHT, HLP	Yes	No	Yes	Spain
58	F	A	6	AIDP	No	NR	PE	No	Yes	USA
56	F	A	7	AIDP	No	AHT, thyroxin ↓	NR	NR	Partial	Germany
61	F	A	14	AMAN	No	AHT, HLP	PE	No	Yes	USA
75	M	A	NR	NR	No	Spinal trauma	Yes	No	Yes	USA
37	NR	A	10	NR	NR	NR	NR	NR	NR	Belgium

A, onset of GBS after onset of non‐neurological manifestations; AAR, aortic aneurysm repair; AHT, arterial hypertension; AIDP, acute inflammatory demyelinating polyneuropathy; AL, alcoholism; AMAN, acute motor axonal neuropathy; AMSAN, acute motor sensory axonal neuropathy; AV, artificial ventilation; B, onset of GBS before onset of non‐neurological manifestations; CHD, coronary heart disease; CIC, CoV‐2 in CSF; CM, comorbidities; DM, diabetes mellitus; F, female; GBS, Guillain Barre syndrome; HLP, hyperlipidaemia; IVIG, intravenous immunoglobulin; LC, lung cancer; LOO, latency between onset of GBS and COVID‐19, respectively, vice versa; M, male; MFS, Miller‐Fisher syndrome; NCSs, nerve conduction studies; ND, not done; NR, not reported; PE, plasma exchange; RA, rheumatoid arthritis; S, steroids and antibodies positive in cerebrospinal fluid.

The authors regard SARS‐CoV‐2 as causative for GBS in the 18 included patients. However, proof for this speculation was not provided. They reported that the CSF was negative for the virus in all included cases. Immunological parameters (cytokines, lymphocyte counts and specification) were provided only in one article [2].

A further argument against a causal relation between the virus and GBS is that in four cases, clinical manifestations of GBS started before clinical manifestations of the viral infection (Table 1). However, it cannot be excluded that in these cases the viral infection remained subclinical for several days prior to onset of clinical manifestations.

A further argument against a causal relation between SARS‐CoV‐2 and GBS is that the overall prevalence of GBS did not increase since the outbreak of the pandemic, as was the case with Zika. During the Zika endemic, the prevalence of GBS dramatically increased [3]. Thus, other triggering factors for GBS in COVID‐19 patients should be considered. Frequently, it is not easy to differentiate between concomitant disease and a dominating other disease as may be the case with GBS in COVID‐19 patients.

Whether hypogeusia/hyposmia, frequently observed in COVID‐19 patients, is due to radiculitis of the seventh, ninth, and tenth cranial nerve remains speculative. Considering hypogeusia/hyposmia as a manifestation of a radiculitis, the prevalence of GBS would dramatically increase, as 5.1% to 85% of the COVID‐19 patients reported hypogeusia/hyposmia [4]. Prolonged latency and reduced compound muscle action potentials on nerve conduction studies of the facial nerve argues in favour of polyradiculitis [5].

Overall, this interesting review lacks inclusion of a number of SARS‐CoV–infected patients with GBS. Furthermore, a causal relation between SARS‐CoV‐2 and GBS remains unproven. Whether the immune reaction against SARS‐CoV‐2 triggers the development of GBS requires further investigations.

Disclosure of conflicts of interest

The authors declare no financial or other conflicts of interest.