Electrodiagnostic findings in COVID-19 patients: A single center experience.

OBJECTIVE: Neurological manifestations in patients with coronavirus disease 2019 (COVID-19) have been reported from early features of anosmia and dysgeusia to widespread involvement of the central nervous system, peripheral nervous system, as well as the neuromuscular junction and muscle. Our study objective is to evaluate the electromyography and nerve conduction study (EMG/NCS) findings among COVID-19 patients and look for possible correlations.
METHODS: This is a hospital-based retrospective observational study. All COVID-19 patients between the period of 1st January 2020 to 31st December 2020 undergoing an EMG/NCS were included.
RESULTS: Eighteen patients (12 male and 6 female) were included. Mean age was 55 ± 12 years. 11 patients required intubation for a mean period of 18.6 days (range: 3-37 days). Electrodiagnostic findings were consistent with a myopathy in a majority of these patients (82%). Five of them also had a concurrent axonal neuropathy. In the remaining patients who did not require intubation (n = 7), three patients had myopathic EMG changes and one had Guillain Barre syndrome.
CONCLUSION: At this time, there are no neuromuscular-specific recommendations for patients who contract COVID-19. Only time and additional data will unveil the varying nature and potential neurological sequelae of COVID-19. SIGNIFICANCE: Myopathic EMG changes are commonly seen in critically ill COVID-19 patients, especially with a prolonged hospital stay.

Introduction

The coronavirus disease 2019 (COVID-19) is a severe acute respiratory syndrome (SARS) caused by the SARS-CoV-2 coronavirus. More than 209 million confirmed cases and over 4.4 million deaths have been reported worldwide, as of August 20, 2021 (Johns Hopkins University Coronavirus Resource Center, 2021). Neurological manifestations in COVID-19 have been reported from early features of anosmia and dysgeusia to widespread involvement of the central nervous system (CNS), peripheral nervous system (PNS), as well as the neuromuscular junction and muscle (Román et al., 2020). Different neuromuscular manifestations have been reported in COVID-19 patients with myalgia being the most common symptom (Paliwal et al., 2020). Critical illness myopathy (CIM) has been frequently seen in patients with severe COVID-19 disease with a prolonged hospital stay (Cabañes-Martínez et al., 2020). Our study objective is to evaluate the electromyography and nerve conduction study (EMG/NCS) findings among COVID-19 patients presenting to our neurophysiology laboratory and look for possible correlations.

Methods

This is a hospital-based retrospective observational study. All COVID-19 patients between the period of 1st January 2020 to 31st December 2020 referred to the neurophysiology laboratory at the Aga Khan University Hospital Karachi, Pakistan for an EMG/NCS were eligible to be included in this study. EMG/NCS was ordered by the primary intensive care physician or a neurologist taking part in the clinical care of patients. Inclusion criteria included ≥ 18 years of age and a COVID-19 infection confirmed by a reverse transcriptase-polymerase chain reaction (RT-PCR) assay of a nasopharyngeal swab sample. Patients with pre-existing neuromuscular disorders were excluded. This study was approved by the Ethical Review Committee of the AKUH (Ref: 2020–5469) and the informed consent requirement was waived.

The electrodiagnostic study consisted of motor and sensory nerve conduction studies followed by concentric needle electromyography examination. Sensory NCS were conducted with antidromic stimulation. All studies were performed using a Nicolet Viking machine. Low‑ and high‑pass filters were set at 2 kHz and 20 kHz, and 20 Hz and 2000 Hz for motor studies and sensory studies, respectively, with a sweep speed of 2 ms/division. The stimulus duration was of 0.05 or 0.1msec, as needed. The acceptable limb temperature for performing NCS was ≥ 32 °C. In the event of low limb temperatures, the patients were warmed up using a heating pad or hot water bags to maintain the required temperature, as needed.

NCS: We studied motor and sensory NCS as per the protocol. In all patients, the nerves of the upper (median) and lower extremities (sural, peroneal, and posterior tibial nerves) were examined. In cases of peripheral neuropathy, a superficial peroneal or medial and lateral plantar nerves are additionally examined depending upon whether sural nerve was absent or present, respectively, in the lower extremities. Ulnar and/or radial nerves were also additionally performed in upper extremities in the peripheral neuropathy protocol.

EMG: Needle electrode examination was performed using disposable concentric needles. The number of muscles examined was determined by the patient’s clinical history and electrodiagnostic findings, however, at least seven muscles in the upper extremities and six muscles in the lower extremities (both distal and proximal muscles) were examined in every patient. Amplitude and duration of motor unit action potentials (MUAPs) along with polyphasic potentials and recruitment pattern were evaluated, in addition to the presence or absence of spontaneous activity.

Myopathy: Myopathy is defined on the basis of NCS/EMG findings. The EMG findings of short motor unit action potentials, with decreased amplitude and duration, along with normal sensory and motor NCS were seen. However in some of the patients, low compound muscle action potentials were also noted.

Guillain Barre syndrome (GBS): GBS and its variants i.e. acute idiopathic demyelinating polyneuropathy (AIDP) (Albers and Kelly, 1989), acute motor axonal neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAN) (Ho et al., 1995) are defined on the basis of electrodiagnostic criterions. (Please review Supplementary File for details.)

Intraspinal canal lesion: An intraspinal canal lesion is labelled when (i) sensory nerve action potentials (SNAPs) are normal; (ii) Motor NCS is either normal or shows decreased CMAPs in the corresponding region(s). (iii) Needle EMG examination reveals acute and/or chronic motor axon loss changes in a myotome pattern, without a distal-to-proximal gradient.

Results

Eighteen patients (12 male and 6 female) were included in our study (review Table 1, Table 2 for details). The mean age was 55 ± 12 years. A total of 2,426 adult patients (≥ 18 years) had a diagnosis of COVID-19 patients either at the time of admission or during the course of the hospital stay during the study period. Our study subjects had multiple comorbidities, with the most common comorbid condition being hypertension (67%, n = 12), followed by diabetes mellitus (50%, n = 9) and asthma (22%, n = 4). The mean duration from the diagnosis of COVID-19 infection to the performance of the electrodiagnostic study was variable, ranging between 4 to 180 days, with a mean duration of 41 days.

Table 1

Characteristics of COVID-19 patients with EMG/NCS findings.

		Total (n)	Intubated (n)	Non-Intubated (n)
No of patients (n)		18	11	7
Age ± SD (in years)		55 ± 12	54 ± 12	55 ± 13
Gender	MaleFemale	67% (12)33% (6)	73% (8)27% (3)	57% (4)43% (3)
Co-morbid	DMHTNAsthma	50% (9)67% (12)22% (4)	64% (7)64% (7)36% (4)	29% (2)71% (5)0
EMG/NCS Diagnosis	Myopathy	39% (7)	36% (4)	43% (3)
	Neuropathy	6% (1)	9% (1)	0
	Myopathy + Neuropathy	28% (5)	45% (5)	0
	GBS	11% (2)	9% (1)	14% (1)
	Intraspinal canal lesion	6% (1)	0	14% (1)
	Peroneal neuropathy	6% (1)	0	14% (1)
	Ulnar neuropathy + CTS	6% (1)	0	14% (1)
Mean CK Value in IU/L*Range		222(28–876)	246(66–876)	64(28–93).
Respiratory Symptoms	PresentAbsent	89% (16)11% (2)	100% (11)0	71% (5)29% (2)
COVID-19 Treatment	SteroidsTocliziumabPlasmapharesisAntiviralsNone	83% (15)44% (8)22% (4)11% (2)17% (3)	100% (11)55% (6)18% (2)9% (1)0	57% (4)29% (2)29% (2)14% (1)43% (3)
Outcome	ExpiredDischargedMean mRS score	28% (5)72% (13)3.9	46% (5)54% (6)4.3	0100% (7)3.8

Abbreviations: CK = Creatine kinase; CTS = Carpal tunnel syndrome; DM = Diabetes mellitus; EMG/NCS = Electromyography and nerve conduction studies; HTN = Hypertension; SD = Standard deviation.

CK values are only of the patients with myopathic EMG changes.

Table 2

Summary of all the patients.

No.	A/G	PMH	Respiratorysymptoms	Intubation (days)	Neurological symptoms	Bulk/Tone/DTR	Motor Power(MRC Grading)	Sensory Exam	Time*	Treatment	Clinical Diagnosis	EMG/NCS Findings@	Outcome (mRS)	Mean Peak CK (IU/L)
1	64M	DM, HTN	Fever and sore throat	Yes (7)	Quadriparesis	Normal/Decreased/Absent	UL:Proximal:3/5Distal: 3/5LL:Proximal: 2/5Distal: 3/5	Normal	23	HCQ, Steroids, Tocilizumab.	CIM/CIN	Myopathy(Non-irritable)	4	424
2	65M	DM, HTN	Fever, cough, and dyspnea	Yes (10)	Quadriparesis (prox. > distal)	Normal/Decreased/Absent	UL: Proximal:1/5Distal: 3/5LL:Proximal: 2/5Distal: 2/5	Normal	14	PP, Steroids, Tocilizumab.	CIM/CIN	Myopathy(Non-irritable) & motor axonal PN	4	117
3	44F	DM, Asthma	Fever, cough, and dyspnea	Yes (24)	Difficult to wean off/ Quadriparesis	Normal/Decreased/Absent	UL:Proximal: 0/5Distal: 0/5LL:Proximal: 1/5Distal: 1/5	N/A	20	Steroids, Tocilizumab.	CIM/CIN	Myopathy (Irritable) & sensorimotor axonal PN	Expired	189
4	56F	HTN, Asthma	Fever and dyspnea	Yes (15)	Difficult to wean off/ Quadriparesis	Normal/Decreased/Absent	UL:Not assessed due to stockings.LL:Proximal: 0/5Distal: 0/5	N/A	42	PP, Steroids, Tocilizumab.	CIM/CIN	Myopathy (Irritable)	Expired	876
5	59M	HTN	Fever and sore throat	No	Bilateral lower limb weakness	Normal/Normal/Absent ankle reflex; rest of the reflexes are normal (2 + )	UL:Proximal: 5/5Distal: 5/5LL:Proximal: 5/5Distal: bilateral dorsiflexion: 1/5Bilateral platerflexion: 3/5	Decreased sensations bil. lower limbs.	26	None	Radiculitis/CPN	Acute bil. L2 & L5,S1 intraspinal canal lesion	2	94
6	59F	HTN, Asthma	Fever and dyspnea	Yes (37)	Unable to wean off / Quadriparesis	Normal/Decreased/Decreased (1 + )	UL:Proximal: 1/5Distal: 1/5LL:Proximal: 1/5Distal: 1/5	N/A	40	Steroids	CIM	Sensorimotor axonal PN	5	75
7	38M	None	Sore throat and cough	No	Bilateral lower limb weakness	Normal/Normal/Decreased (1 + )	UL:Proximal: 5/5Distal: 5/5LL:Proximal: 3/5Distal: 3/5	Normal	35	PP, Steroids, Tocilizumab.	CIM	Myopathy (Irritable)	3	28
8	41M	Asthma	Fever and dyspnea	Yes (18)	Bilateral Lower limb weakness	Normal/Normal/Normal	UL:Proximal: 5/5Distal: 5/5LL:Proximal: 2/5Distal: 3/5	Normal	29	Steroids, IVIG	CIM	Myopathy (Irritable)	4	NA
9	77M	DM, HTN, IHD	Fever and dyspnea	Yes (31)	Difficult to wean off/ Quadriparesis	Normal /Normal/Decreased (1 + )	UL:Proximal: 3/5Distal: 3/5LL:Proximal: 2/5Distal: 3/5	Normal	15	Steroids	CIM	Myopathy (Non-irritable) & sensiromotor axonal PN	Expired	NA
10	64M	None	Dyspnea	Yes (18)	Difficult to wean off/ Quadriparesis	Normal/Normal/Absent	UL:Proximal: 0/5Distal: 0/5LL:Proximal: 0/5Distal: 0/5	N/A	16	Steroids, Tocilizumab	CIM/CIN	Myopathy(Non-irritable)	Expired	138
11	61M	DM, HTN	Fever, cough, and dyspnea	No	Left foot drop	Normal/Normal/Normal	UL:Proximal: 5/5Distal: 5/5LL:Proximal: 5/5Distal: 3/5 (dorsi 2/5, plantar 4/5)	Dec. sensations dorsum of the foot	39	Steroids	CPN/L5 radic.	Acute bil. common peroneal MN	3	138
12	46M	DM	Fever, cough, and dyspnea	Yes (12)	Quadriparesis	Normal/Normal/Decreased	UL:Proximal: 1/5Distal: 1/5LL:Proximal: 1/5Distal: 1/5	Decreased sensation in glove stocking pattern	120	Remdesivir, Steroids, Tocilizumab	CIM/CIN	Sensorimotor axonal PN + myopathy(Non-irritable)	5	NA
13	76M	DM, HTN	Fever, cough, and dyspnea	Yes (3)	Quadriparesis	Normal/Decreased/Absent	UL:Proximal: 0/5Distal: 0/5LL:Proximal: 0/5Distal: 0/5	N/A	10	Steroids	GBS	GBS (AMSAN)	5	NA
14	46F	None	None	No	Bil. Hand numbness	Normal/Normal/Normal	UL:Proximal: 5/5Distal: 4/5LL:Proximal: 5/5Distal: 5/5	Normal	180	None	GBS	Bil. ulnar neuropathy + CTS	2
15	64M	DM, HTN	None	No	Generalized weakness	Normal/Decreased/Decreased (1 + )	UL:Proximal: 3/5Distal: 4/5LL:Proximal: 2/5Distal: 4/5	Normal	45	None	CIM	Myopathy (Non-irritable)	4	68
16	47M	DM, HTN	Fever, cough, and dyspnea	Yes (30)	Difficult to wean off/ Quadriparesis	Normal/Decreased/Absent	UL:Proximal: 3/5Distal: 2/5LL:Proximal: 2/5Distal: 1/5	Decreased sensation in glove stocking pattern	35	Steroids	CIM/CIN	Sensorimotor axonal PN + Myopathy (Irritable)	Expired	66
17	54F	HTN	Fever, sorethroat and dyspnea	No	Quadriparesis	Normal/Decreased/Decreased (1 + )	UL:Proximal: 2/5Distal: 3/5LL:Proximal: 1/5Distal: 2/5	Normal	45	Remdesivir, Steroids, Tocilizumab	CIM	Myopathy(Non-irritable)	5	93
18	34F	HTN, Hypothyroid, SLE	Fever, dyspnea and abdominal pain	No	Quadriparesis	Normal/Decreased/Absent	UL:Proximal: 2/5Distal: 2/5LL:Proximal: 1/5Distal: 0/5	Normal	4	PP, Steroids	GBS	GBS (AMAN)	5	29

Time from the onset of symptoms to EMG/NCSs (Electromyography and nerve conduction studies). @ Irritable myopathy means presence of abnormal spontaneous activity (e.g. positive sharp waves, fibrillations or complex, repetitive discharges) on needle EMG examination; Non-irritable means absence of abnormal spontaneous activity.Abbreviations A = Age AF = Atrial fibrillation AKI = Acute kidney injury AMAN = Acute motor axonal polyneuropathy AMSAN = Acute motor and sensory axonal polyneuropathy Bil. = Bilateral CIM = Critical illness myopathy CIN = Critical illness neuropathy CPN = Common peroneal neuropathy CTS = Carpal tunnel syndrome DM = Diabetes mellitus DTR = Deep tendon reflexes F = Female G = Gender GBS = Guillain Barre syndrome HCQ = Hydroxychloroquine HTN = Hypertension IVIG = Intravenous immune globin LL = Lower limb M = Male MN = Mononeuropathy mRS = modified Rankin scale NA = Not available PN = polyneuropathy PP = Plasmapheresis Radic. = Radiculopathy SLE = Systemic lupus erythematosus UL = Upper limb.

Eleven patients suffered from severe COVID-19 infection and required intubation for a mean period of 18.6 days (range: 3–37 days). Indication for EMG/NCS in these intubated patients was either a difficulty to wean off the ventilator support or development of flaccid quadriparesis. Electrodiagnostic findings were consistent with a myopathy in a majority of these patients (82%, n = 9). Five of them also had a concurrent axonal neuropathy. In 4 out of 9 patients with myopathic EMG changes (44%), spontaneous activity consisting of fibrillations and positive sharp waves were seen. Mean peak creatine kinase (CK) value was 246 IU/L (range: 66–876 IU/L). Unfortunately, muscle biopsy was not performed in any of the patients, which is one of the major limitations of our study. One patient had chronic peripheral neuropathy without myopathic EMG changes, and one had an acute motor and sensory axonal neuropathy (AMSAN) variant of GBS. Understandably, these patients had multiple comorbidities and had poor outcome with a 46% mortality. All of the intubated patients received systemic steroids (100%) and half of them also received tocilizumab.

In the remaining patients who did not require intubation (n = 7), three patients had myopathic EMG changes (irritable in 1), one patient each had GBS (AMAN variant), bilateral common peroneal mononeuropathies, bilateral ulnar mononeuropathies along with bilateral carpal tunnel syndrome (CTS), and an active on chronic intraspinal canal lesion affecting L2 and L5-S1 myotomes. Interestingly, none of these patients had a large-fiber peripheral neuropathy. Mean peak CK value for patients with myopathic EMG changes was 64 IU/L (range: 28–93 IU/L). Half of the non-intubated patients received steroids and two patients (29%) also received tocilizumab. No mortality was seen in this non-intubated patient group.

Discussion

Neurological manifestations in COVID-19 occur in one-third of all COVID-19 infections (Mao et al., 2020). A drastic increase of critical illness myopathy (CIM) has been observed in COVID-19 survivors who have been exposed to long-term mechanical ventilation. The underlying mechanism is not well understood and may involve the release of factors affecting muscle secondary to immobilization (Lönnqvist et al., 2020). It is also proposed that cytokine release causes inactivation of sodium channels, thereby causing a slowing of muscle fiber conduction velocity and a simultaneous increase in calcium permeability that leads to myonecrosis (Friedrich et al., 2015).

Cabañes-Martínez et al. published the first study reporting neuromuscular involvement in critically ill COVID-19 patients. They diagnosed 11 patients electrodiagnostically with either CIP or CIM out of 225 COVID-19 patients, with the latter being present in the majority (Cabañes-Martínez et al., 2020). Another recently published study on six COVID-19 intubated patients afflicted with acute flaccid quadripalegia demonstrated CIM in almost all of them. Five of these patients recovered after receiving COVID-19 treatment while one succumbed to sepsis (Madia et al., 2020). In our study, it is difficult to ascertain whether the myopathic EMG changes were secondary to the critical-illness or due to direct virus-related effects. Laboratory parameters like LDH, CK, aldolase, ferritin may be elevated following post-COVID-19 myopathy. Another study revealed elevated CK in up to one-third of admitted patients (Wang et al., 2020). Manzano et al. reported a case of COVID-19 infection and myopathy in which a deltoid muscle biopsy showed raised levels of type 1 interferon, which may validate type 1 interferonopathy as a probable cause of myopathy in such individuals at a more cellular level (Manzano et al., 2020).

Growing evidence suggests that neuromuscular manifestations like GBS, rhabdomyolysis, and neuralgic amyotrophy are also on the rise (Guidon and Amato, 2020; Pergolizzi et al., 2021). In another systemic review, AIDP was reported to be the most common variant of GBS in COVID-19 patients (De Sanctis et al., 2020). There are also reports of the Miller Fischer variant of GBS being associated with COVID (Senel et al., 2020); (Ray, 2020); Lantos et al., 2020). Interestingly in our study, two patients who were diagnosed with GBS either had the AMAN and AMSAN variant, respectively. The pathogenesis of GBS in COVID-19 is still unclear. Whether COVID-19 produces antibodies against specific gangliosides still needs to be determined.

At this time, there are no neuromuscular-specific recommendations for patients who contract COVID-19. Only time and additional data will unveil the varying nature and potential neurological sequelae of COVID-19 (Guidon and Amato, 2020). Meanwhile, clinicians must keep a cautious low threshold for suspecting myopathy in patients who develop symmetrical muscle weakness in the setting of COVID-19 infection, lengthy ICU stay, or both combined. Ideally, longitudinal studies should undertake careful neurological imaging and electrophysiological examinations to understand the congruent interplay between COVID-19 induced myopathy and CIM. This can be followed by adequate access to rehabilitation facilities in patients who require rehabilitative services even after the resolution of infection.

Limitations

Lack of muscle biopsy and a small number of patients were the major limitations of our study. Due to the retrospective nature of this study and small numbers, a causal relationship cannot be determined. Further, drug adverse effects and other confounders, such as comorbid conditions, also could not be excluded.

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.”

CRediT authorship contribution statement

Sajid Hameed: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft, Writing - review & editing. Ayisha Farooq Khan: Data curation, Investigation, Methodology, Visualization, Writing - original draft, Writing - review & editing. Sara Khan:

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.