Infectious/parainfectious, nonvascular, nonhypoxic central nervous system disease in 48 COVID-19 patients.

To the Editor,

It is now well appreciated that severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) not only affects the respiratory system but almost all organs to variable degrees. SARS‐CoV‐2 can be also found in the central (CNS) and peripheral nervous system. CNS manifestations of SARS‐CoV2 include meningitis/encephalitis, ventriculitis/endothelialitis, myelitis, encephalopathy, autoimmune encephalitis (AIE), acute, hemorrhaghic, necrotizing encephalopathy (AHNE), acute disseminated encephalomyelitis (ADEM), ischemic/hemorrhaghic stroke, sinus venous thrombosis, and cerebral hypoxia. This literature review aims at summarizing and discussing recent advances concerning infectious and parainfectious, nonvascular, and nonhypoxic CNS disease in SARS‐CoV‐2‐infected (coronavirus disease‐2019 [COVID‐19]) patients.

Altogether, 28 articles reporting 48 patients with infections or parainfectious, nonvascular, and nonhypoxic SARS‐CoV‐2‐associated CNS disease were included. A report about an Indian patient with AHNE is currently in press. Patients originated from Turkey (n = 11), France (n = 9), USA (n = 9), China (n = 4), UK (n = 4), Italy (n = 2), Switzerland (n = 2), Spain (n = 2), Japan, (n = 1), India (n = 1), Germany (n = 1), Ecuador (n = 1), and Dubai (n = 1). Age ranged from 22 to 79 years (Table 1). There was male preponderance. In 43 patients, CNS disease started after onset of the COVID‐19 disease and in four patients before onset of COVID‐19 (Table 1). Clinical manifestations included seizures (n = 11), confusion (n = 7), impaired consciousness (n = 6), headache (n = 5), psychosis/delirium (n = 5), muscle weakness (n = 4), and dysphagia (n = 2). Among patients with infectious CNS disease (n = 14), one presented with meningitis, five with encephalitis, five with meningo‐encephalitis, and three with myelitis , (Table 1). In a single patient meningo‐encephalitis was the sole manifestation of SARS‐CoV‐2. In a single patient SARS‐CoV‐2‐associated meningo‐encephalitis was accompanied by intracerebral bleeding, subarachnoid bleeding, and subdural hematoma. One patient with encephalitis additionally had ventriculitis. Parainfectious CNS disease was more frequent than infectious CNS disease (Table 1). Among patients with parainfectious CNS disease (n = 34), 18 had encephalopathy, 11 AIE, 3 ADEM, and 2 AHNE. Among the 40 patients with a spinal tap, mild lymphocytic pleocytosis was found in seven with infections and two with parainfectious CNS disease. The cerebrospinal fluid (CSF) was tested for SARS‐CoV‐2 in 40 patients and was positive for virus‐RNA in four patients with infectious CNS disease but negative in all patients with parainfectious CNS disease. Fifteen patients received virostatics, 21 antibiotics, 11 steroids, 5 immunoglobulins, 7 plasma exchange, 8 AEDs, 8 chloroquine, and 11 required mechanical ventilation (Table 1). In patients with AIE, particularly plasma exchange had a beneficial effect. Twenty‐two patients recovered, two did not, and six died.

Table 1

Patients with SARS‐CoV‐2‐associated infectious/parainfectious nonvascular CNS disease so far reported

Age (y)	Sex	Onset	OO (d)	M/E	LP	CIC	CM	Imaging	Treatment	OC	Country	Reference
24	m	B	5	E	NR	Yes	HA, IC, and SE	Edema and ventriculitis	VS, AB, MV, S, and AED	NR	Japan	Moriguchi et al 3
44	f	A	3	E	Yes	NR	CON and SE	E and bleeding	VS, AB, AED, and S	Death	India	Ghosh et al 4
NR	NR	NR	NR	E	NR	Yes	SE and hiccups	Normal	VS, AB, and AED	NR	China	Xiang et al 5 ,a
41	f	AB	0	ME	Yes	No	SE, CON, and HL	Normal	VS, AB, CHLO, AED, and S	REC	USA	Duong et al 6
36	m	A	4	ME	NR	Yes	HA	SAB, ICB, and SDH	Surgery	NR	Dubai	Al‐Olama et al 7
64	f	A	6	ME	Yes	No	SE and psychosis	Normal	VS	REC	Swiss	Bernard‐Valnet et al 8
67	f	A	17	ME	Yes	No	HA, CON, HAN and HN	Normal	VS and AB	REC	Swiss	Bernard‐Valnet et al 8
69	m	A	7	ME	Yes	No	HA, CON, and fall	Normal	VS, AB, and CHLO	REC	France	Chaumont et al 9
66	m	A	>5	Myelitis	NR	NR	Paraparesis	NR	VS, AB, S, and IVIG	REC	China	Zhao et al 10
60	m	A	8	Myelitis	Yes	No	Paraparesis	Myelitis	VS, AB, and S	REC	German	Munz et al 11
49	m	A	NR	AIE	No	No	NR	E	AB and PE	REC	Turkey	Dogan et al 12
59	m	A	NR	AIE	No	No	NR	E	AB and PE	REC	Turkey	Dogan et al 12
59	m	A	NR	AIE	No	No	NR	Normal	AB and PE	Death	Turkey	Dogan et al 12
51	f	A	NR	AIE	No	No	NR	Normal	AB and PE	REC	Turkey	Dogan et al 12
55	m	A	NR	AIE	No	No	NR	Normal	AB and PE	ICU	Turkey	Dogan et al 12
22	m	A	NR	AIE	No	No	NR	E	AB and PE	REC	Turkey	Dogan et al 12
71	m	A	NR	ADEMb	NR	NR	NR	NRc	ICU and S	Death	USA	Reichard et al (2020) 13
40	f	A	11	ADEM	No	No	Bulbar signs	Demyel	AB, IVIG, and CHLO	REC	USA	Zhang et al (2020) 14
54	f	A	Days	ADEM	No	No	SE	Demyel	AED and S	REC	Italy	Zanin et al (2020) 15
∼55	f	A	3	AHNE	NR	No	CON	AHNE	IVIG	NR	USA	Poyiadji et al (2020) 16
59	f	A	10	AHNE	No	No	SE and IC	Edema	MV and S	Death	UK	Dixon et al (2020) 17
74	m	A	1	EP	No	No	HA and CON	Old stroke	VS AB, CHLO, and AED	ICU	USA	Filatov et al (2020) 18
8 pat.	NR	A	NR	EP	NR	No	NR	LEE	NR	NR	France	Helms et al (2020) 19
60	m	B	2	EP	Yes	No	IC and akinetic	Normal	VS, AB, and S	REC	Italy	Pilotto et al (2020) 20
23	m	AB	0	EP	No	NR	Psychosis	Normal	AB, S, IVIG, and neuroleptics	REC	Ecuador	Panariello et al (2020) 21
31	f	A	18	EP	Yes	NR	Coma	Edema	VS, AB, CHLO, and MV	Death	USA	Benameur et al (2020) 22
34	m	A	9	EP	No	NR	Coma and SE	Edema	CHLO and MV	NR	USA	Benameur et al (2020) 22
64	m	A	NR	EP, CH	No	NR	SE	T2HI	CHLO and MV	REC	USA	Benameur et al (2020) 22
46	m	B	2	EP	No	No	Delirium and SE	Inflammation	VS, AB, AED, and MV	REC	UK	Hosseini et al (2020) 23
79	f	B	2	EP	No	No	SE and delirium	Limbic E	AED	REC	UK	Hosseini et al (2020) 23
77	m	A	6	EP	NR	NR	Delirium	Normal	VS and AB	Death	UK	Butt et al (2020) 24
69	f	A	8	myelitis	Yes	No	Weakness	Myelitis	S and PE	REC	Spain	Sototca et al (2020) 25
nr	m	A	14	E	No	No	E	Normal	Supportive	REC	China	Ye et al (2020) 26
56	f	A	15	M	No	No	TEPA and dysph	LEE	IVIG	REC	Spain	Sancho‐Soldana (2020) 27
64	m	A	2	EP	No	No	IC and CON	Normal	VS and supportive	REC	China	Yin et al (2020) 28
5 pat.	NR	A	NR	AIE	No	No	NR	CSA	MV	NR	Turkey	Kandemirli et al (2020) 29
40	f	A	NR	E	NR	Yes	Syncope	NR	CHLO	REC	USA	Huang et al (2020) 30

Abbreviations: A, onset of ME after onset of non‐neurological manifestations; AB, antibiotics; AED, antiepileptic drugs; AHNE, acute, hemorrhaghic, necrotizing encephalopathy; AIE, autoimmune encephalitis; B, onset of ME before onset of non‐neurological manifestations; CC, CSF culture; CH, cerebral hypoxia; CHLO, chloroquine; CIC, SARS‐CoV‐2 in CSF; CM, clinical manifestations; CON, confusion; COVID‐19, coronavirus disease‐2019; CSA, cortical signal abnormality; Demyel, demyelination; dysph, dysphagia; E, encephalitis; EP, encephalopathy; f, female; HA, headache; HAN, hemianopia; HL, hallucinations; HN, hemineglect; IC, impaired consciousness; ICB, intracerebral bleeding; ICU, intensive care unit; IVIG, intravenous immunoglobulins; LEE, leptomeningeal enhancement; LP, lymphocytic pleocytosis; M, meningitis; m, male; MB, microbleeds; MV, mechanical ventilation; ND, not done; NR, not reported; OO, latency between onset of meningitis/encephalitis and COVID‐19, respectively vice versa; PE, plasma exchange; REC, recovery; S, steroids; SAB, subarachnoid bleeding; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2; SDH, subdural hematoma; SE, seizures; T2HI, hyperintensity on T2‐images; TEPA, quadruparesis; VS, virostatics.

Reported in Ramoli et al.

On autopsy.

ADEM‐like lesions.

This review shows that the CNS is only rarely directly attacked by SARS‐CoV‐2, but more commonly, by the immune response to the virus. This is why immunosuppressive and immune‐modulating treatment (steroids, immunoglobulins, and plasma exchange) have a strong role in the management of infectious/parainfectious, nonvascular, and nonhypoxic CNS disease in SARS‐CoV‐2‐infected patients. The virus was found in the CSF in only four patients with infectious CNS disease. The reason for this phenomenon remains speculative but it can be assumed that the virus either is traceable in the CSF only shortly or predominantly located intracellular, why it cannot be found in the CSF. Since the virus has been found in neurons and endothelial cells of the frontal lobe, it is conceivable that the virus directly invades motor and sensory neurons. There are even speculations that the CNS could be a reservoir for the virus in the absence of clinical manifestations. These considerations implicate that virus‐negative infectious CNS disease is in fact immune mediated. Probably, an autoimmune pathogenesis is underlying even if there is pleocytosis.

Arguments in favor of an immune‐mediated pathogenesis of virus‐negative/positive CNS disease in COVID‐19 are that several patients responded favorably to steroids, immunoglobulins, or plasma exchange, and that CNS inflammatory proteins are increased in COVID‐19 encephalopathy. This corresponds with the general hyperinflammatory state (cytokine storm and dysregulated immune response) with massive release of cytokines and chemokines that impair blood‐brain barrier permeability and thus could activate neuroinflammatory cascades. , Furthermore, SARS‐CoV‐2 infection is more severe if the number of CD8 T‐killer cells is low. Elevation of neutrophils reduces CD8 T‐killer cells. The immunologic pathogenesis is further supported by several reports presenting only nonspecific CNS abnormalities in COVID‐19 patients, such as impaired consciousness, confusion, disorientation, dizziness, delirium, hallucinations, psychosis, headache, ataxia, or seizures.

In conclusion, SARS‐CoV‐2 rarely causes infectious/parainfectious CNS disease, including meningitis/encephalitis, ventriculitis/endothelialitis, myelitis, encephalopathy, AIE, AHNE, or ADEM. Virus‐RNA is absent in SARS‐CoV‐2‐associated parainfectious CNS disease and present only in some cases with infectious CNS disease, suggesting that CNS disease in COVID‐19 is immune mediated. Treatment relies on virostatics, antibiotics, antiepileptics, steroids, immunoglobulins, plasma exchange, and mechanical ventilation. The outcome of infectious/parainfectious CNS disease in COVID‐19 is usually fair but can be fatal in single cases.

CONFLICT OF INTERESTS

The authors declare that there are no conflict of interests.

AUTHOR CONTRIBUTIONS

JF: concept, writing literature search, and discussion; FS: literature search, critical remarks, and discussion.

ETHICS STATEMENT

The research has been given ethical approval.

DATA AVAILABILITY STATEMENT

All data are available.