Neurological complications after COVID-19: A narrative review

Abstract

COVID-19 is primarily classified as a respiratory disorder; however, various neurological symptoms have been reported in COVID-19 patients. Neurological manifestations may be the initial signs of COVID-19 and can develop in patients of different age groups and with or without underlying disease. COVID-19 causes a broad range of complications in the central nervous system. These include headaches, altered mental status, dizziness, seizures, cerebrovascular events, encephalitis, and other encephalopathies. Moreover, a broad spectrum of peripheral nervous system symptoms such as olfactory and gustatory dysfunctions, neuropathy, visual impairments, neuralgia, cranial nerves palsy, and muscle involvement could manifest as symptoms. Despite various efforts, the exact pathogenesis of the COVID-19 neurological complications has not been clarified yet. Moreover, the reason for the development of neurological manifestation in only some COVID-19 patients has not been determined. This review focuses on the different neurological symptoms associated with COVID-19 and the possible pathological mechanisms hoping to provide new insights for diagnosis, therapies, or other forms of intervention.

Highlights

• •Numerous studies, including cohorts and case reports, investigated the neurological symptoms in COVID-19 patients.
• •COVID-19 causes a broad range of complications in the central nervous system.
• •Despite various efforts, the exact pathogenesis of the COVID-19 neurological complications has not been clarified yet.
• •Comprehensive information is essential to elucidate the spectrum of the neurological complications caused by SARS-CoV-2.

1. Introduction

Emerging and re-emerging diseases have significant implications for public health and society as a whole. These diseases are characterized by their sudden appearance or resurgence in a population, often with a high potential for rapid spread and severity. Coronavirus disease 2019 known as COVID-19 is one of the emerging diseases and Ebola Virus Disease (EVD) [1] and Mpox (monkeypox) disease [2] are two re-emerging diseases in the recent years. The clinical symptoms for EVD are Fever, Fatigue, Headache, Muscle and Joint Pain, Sore Throat, Gastrointestinal Symptoms, Skin Rash, Impaired Kidney and Liver Function, and Hemorrhagic Manifestations and for Mpox are Skin Lesions, Fever, Lymphadenopathy, Fatigue, Headache, Muscle Aches, and Chill. Ebola usually has a high mortality rate but in the current Ebola outbreak the rate ranges between 55% and 60% [3]. According to the World Health Organization (WHO), the death rates for monkeypox have been reported to be around 3% to 6% in recent years. However, historical data suggests that the death rates for monkeypox can be as high as 11% [4].

COVID-19 was first discovered in China in December 2019 [5,6]. It is developed due to the infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). WHO and the Institute for Health Metrics and Evaluation (IHME) have estimated that 14.9 and 18.2 million excess deaths from COVID-19 happened globally [7]. Although the disease is a respiratory illness characterized primarily by pulmonary complaints, the disease also affects other body organs [8]. COVID-19 commonly presents with symptoms such as fever, cough, shortness of breath, muscle or body pains, headache, fatigue, loss of taste or smell, sore throat, nasal congestion or runny nose, and gastrointestinal symptoms like nausea, vomiting, and diarrhea. In addition, COVID-19 can lead to complications affecting the neurological, renal, and gastrointestinal systems in a significant number of patients [9].

The neurological manifestations are one of the most concerning issues for the SARS-CoV-2 infected individuals. Headache, fever, and anosmia can happen during the onset of the disease. Other neurological symptoms, such as hypogeusia, polyneuropathy, and cerebrovascular stroke, may also occur [10,11]. Neurological symptoms are also among the primary manifestations in SARS-CoV-2-infected children [5].

Numerous studies, including cohorts and case reports, investigated the neurological symptoms in COVID-19 patients. However, most of these studies do not provide adequate information regarding the possible pathogenesis. These studies have been performed sparsely on various neurological symptoms worldwide. Comprehensive information about these symptoms is essential to elucidate the spectrum of the neurological complications caused by SARS-CoV-2 infection. Therefore, in this study, we comprehensively discussed the neurological symptoms of COVID-19 related to the peripheral and central nervous systems. In addition, we have addressed the possible pathological mechanisms of neurological symptoms caused by COVID-19 disease and estimated the pooled prevalence of these symptoms based on our included studies.

2. Methods

This review was based on MEDLINE searches including (in various combinations) the terms “COVID-19”, “SARS-COV-2”, “neurological complications”, “neurological signs”, “neurological manifestations”, “central nervous system (CNS)”, “ peripheral nervous system (PNS)”, “pathogenesis”, “clinical manifestations”, “neurological symptoms”, “pathological mechanisms”.

3. Nervous system manifestations and hypothetical pathological mechanisms

3.1. Direct invasion of SARS-CoV-2

There is a possibility that SARS-CoV-2 can enter the central nervous system (CNS), as neurovirulence and neuroinvasion were observed in animal models and cell culture [12]. Despite other betacoronaviruses, there are scarce documents that affirm the SARS-CoV-2 neural invasion in vivo [13]. It is not yet determined by which neuroinvasive potential COVID-19 infiltrates the CNS. However, there are two proposed pathways: the hematogenous expansion of the virus to cerebral circulation and neural retrograde dissemination through the olfactory bulb and cribriform plate [14,15]. The in vivo real-time imaging investigation of mice revealed an alternative route to the brain by the neurovascular element of the respiratory mucosa's connective tissue [16]. The hematogenous path might mediate the SARS-CoV-2 diffuse to the CNS via a harmed blood-brain barrier (BBB). The virus-infected cells cross the BBB, potentially invading the brain via perivascular spaces called Virchow-Robin. In these fluid-filled sites, there is an interaction between lymphocytes and macrophages to initiate an immune response in viral encephalitis patients [12]. It has been proven that Angiotensin-converting Enzyme 2 (ACE2) is an influential receptor for SARS-CoV-2. It mediates the entry of the virus into cells [17]. ACE2 expression was reasonably high in some significant brain areas, like the piriform cortex, brain ventricles, and substantia nigra. Moreover, ACE2 expression is observed in many neurons, such as inhibitory and excitatory neurons, and some non-neuron cells, such as oligodendrocytes and astrocytes in the posterior cingulate cortex and the middle temporal gyrus [18]. Accordingly, SARS-CoV-2 can invade different brain areas if it can cross the BBB, entering the brain.

The second route can be considered in patients in the early phase of COVID-19 that lose their taste and smell [10]. Besides ACE2 as a SARS-CoV-2 receptor, TMPRSS2 (transmembrane protease, serine 2) could simplify the fusion of cellular membranes and SARS-CoV-2 by cleaving the spike (S) protein of SARS-CoV-2. TMPRSS2 and ACE2 are expressed in the liver, digestive tract, heart, brain, kidney, and other organs [17], as well as in the astrocytes of the substantia nigra and cortex, oligodendrocyte precursor cells, and the non-neuronal cells comprising olfactory bulb pericytes and sustentacular cells [19,20]. These essential genes are expressed in olfactory epithelial cells and not in bulb neurons and olfactory sensory. It suggests the engagement of other dissemination mechanisms independent of axonal transport [12] or involvement of other molecules, like neuropilin-1, BSG, or PIKfyve, in the entry of SARS-CoV-2 [21]. Moreover, the studies suggested that the virus can have accessibility to the CNS through specific neurotransmitter pathways, including the serotoninergic dorsal raphe system or dissemination via the lymphatic systems. Further surveys are needed to verify these hypotheses and test in vivo models [12].

The TMPRSS2 and ACE2 expressions in the peripheral nervous system have also been reported in limited studies [20]. Therefore, the development of peripheral neurological symptoms (PNS) complications in COVID-19 patients can be occurred by direct invasion of SARS-CoV-2 with some other receptors or due to indirect mechanisms.

3.2. Indirect mechanisms

The advent of neurological signs and symptoms in advanced stages of COVID-19 may be because of respiratory and metabolic acidosis and hypoxia [10]. Loss of oxygen or hypoxia in the brain causes acute or permanent alterations in the brain regions [22]. Moreover, the coagulation system is activated through the vigorous inflammatory response. It leads to cerebral infarctions in addition to deep pulmonary embolisms, venous thrombosis, and renal failure [23]. The PNS and CNS damages may be due to the innate and adaptive immune responses to infection. Despite the capability of some enteroviruses, herpes simplex virus, and some arthropod-borne viruses in neuron death induction, the neurovirulence abilities of SARS-CoV-2 have not been fully confirmed yet [15].

The synthesis of intrathecal IgG, identical oligoclonal bands in CSF and serum, in some COVID-19 patients discloses a systemic inflammation [24]. The CSF of Neuro-COVID subjects (COVID-19 patients who develop neurological sequelae) demonstrated the development of exhausted CD4+ T cells and dedifferentiated monocytes. The CSF leukocytes of Neuro-COVID individuals contained an increased interferon signature but were still less conspicuous than in virus-caused encephalitis. Moreover, the crossed-off interferon response and vast clonal T cell expansion were observed in severe compared to mild Neuro-COVID patients [25]. Screening on CSF of 58 patients with COVID-19 accompanied by the advent of neurologic symptoms revealed the elevation albumin quotient in 40% of patients proposing devastated blood-brain barrier integrity. Moreover, the CSF- specific IgG oligoclonal band was observed in 5 (11%) cases, offering an intrathecal synthesis of IgG.

Moreover, 26 (55%) patients showed identical oligoclonal bands in CSF and serum. RT-PCR showed the positive SARS-CoV-2 in CSF of 4 (7%) patients [26]. The neurological symptoms in COVID-19 may be due to the “cytokine storm” induced neuroinflammation or comorbidities [13]. The leptomeningeal inflammatory cytokines in the lack of viral neuroinvasion were found in cancer patients with neurologic consequences of COVID-19. Type II interferon drives most of these inflammatory mediators. They can also cause neuronal injury. In these patients, the correlation between the neurologic dysfunction and the matrix metalloproteinase-10 levels within the spinal fluid was observed. Besides, this neuroinflammatory process remained several weeks after recovery from an acute respiratory infection. These long-time neurologic consequences result in prolonged neurocognitive dysfunction [27]. Symptoms and signs of CNS impairment may be associated with the evidence of cytokine release syndrome (CRS), an increase of IL-6 in the serum, and elevation of BBB permeability as specified by the attendance of hyperalbuminorrachia. The increase of the astroglial protein S100B with hyperalbuminorrachia proposed the dysfunction of BBB [28]. The hematogenous propagation of SARS-CoV-2 to the brain is of interest, which may result in a synergistic impact of a direct incursion of SARS-CoV-2 and inflammatory reactions.

The potential for remarkable neurological deficiency is one of the main concerns after observing the lack of involuntary control of breathing in a COVID-19 patient. It is likely because of the involvement of the inspiratory region in the brainstem [29]. The electrophysiological test proved the functional role of the brain stem in COVID-19 patients and its contribution to respiratory failure and, afterward, developing severe periods of the disease [30]. However, there is still an essential question of whether the brain infection caused by COVID-19 has a role in respiratory problems or contrariwise. The respiratory center, positioned in the medulla oblongata and pons (brainstem), can also be attacked by COVID-19, promoting breathing troubles [22]. Given that the entrance route of SARS-CoV-2 through the respiratory tract has been affirmed, the development of respiratory problems followed by direct invasion of the virus or hypoxia is expected. Therefore, different brain regions, like the brain stem, may be involved in the progression of a severe respiratory state of disease.

4. The manifestations of the central nervous system

The patients with COVID-19 have shown a 9.9–65% prevalence of neurological symptoms [[31], [32], [33]], and severe neurological impairment was found among 7% of 56 children hospitalized with COVID-19 [34]. The patients may also manifest severe neurologic symptoms, like stroke and impaired consciousness, even without common symptoms of COVID-19 [35]. Also, another study showed that COVID-19 presentations usually appear a few days before the virus infection diagnosis [36]. Hospitalized patients with COVID-19 commonly showed peripheral neurological symptoms and CNC complications, especially in the ICU, and often represent a critical illness [37]. However, some studies have observed a prevalence higher than the actual number in a small sample size. Patients with COVID-19 indicated an extensive range of CNS symptoms. For example, the highly documented symptoms include headache, dizziness, impaired consciousness, seizure, delirium, cerebrovascular disease, hypoxic-ischemic brain injury, encephalopathy, and encephalitis. A study reported the CNS symptoms in almost 24.76% of COVID-19 patients [33]. According to a cohort study in Wuhan, CNS-related symptoms were reported in 23.3% of patients with severe disease [31]. Among 1261 hospitalized COVID- 19 patients, 19.8% were found to be fatalities with neurological indications, which increased to 32.6% in patients with acute CNS involvement [38]. According to a study on 54 ICU patients, there were meningoencephalitis, major neurological events of sensory changes, and cerebral hemorrhage in 2, 5, and 1 complicated cases, respectively [39]. These outcomes may not be generalized because of the small number of specimens in most studies. The probability of progressing neurologic manifestations in cases with intense infection is higher [33]. The great attendance of D-dimer in deceased patients and those with severe infection with the virus makes it a potential prognostic factor [33,39]. Maybe because of this factor, the probability of developing cerebrovascular diseases in patients with severe infection is higher [33]. It is supposed that neuroimaging findings help to discover CNS involvement, particularly in detecting infarction, encephalopathy, intracranial hemorrhage, and edema [40]. The COVID-19 patients that show apparent neurological disorders present indiscoverable or meager amounts of SARS-CoV-2 RNA in the cerebrospinal fluid. It discloses that the clearance of the virus is performed before the neurological involvement [41]. Therefore, the CSF analysis for the attendance of SARS-CoV-2 is not beneficial for diagnostic purposes. NSE as a cerebrospinal fluid biomarker has been proposed as a potential prognostic/diagnostic biomarker for neuroinflammation in COVID-19, particularly for those with neurological symptoms, such as encephalopathy [42]. Details on neurological signs may help to clarify their pathogenesis. Table 1 indicates the CNS involvement in patients with COVID-19.

Table 1.

The CNS manifestation of COVID-19.

Study	Sample size	The CNS complications		gender	(mean) age	Ref.
Mao et al.	214 hospitalized patients with confirmed SARS-CoV-2 infection	24.8%	Headache (13.1%)	M: 87 F: 127	52.7	[33]
			Dizziness (16.8%)
Vacchiano et al.	108 hospitalized COVID-19 patients	Headache (43%) Dizziness (10%)		57% males	59	[86]
Ghaffari et al.	361 adult patients with confirmed diagnosis of COVID-19	Headache (30.2%) Dizziness (9.4%) Vertigo (15%) Encephalopathy (3%) Seizure (2.8%) Ischemic stroke (2.2%) Intracerebral hemorrhage (1.1%)		M: 214 F: 147	61.90 ± 16.76	[87]
Amanat et al.	873 Patients with SARS-CoV-2 infection	Headaches (n = 110) Dizziness (n = 104)		M: 556 F: 317	60.71 ± 18.14	[88]
Kacem et al.	646 confirmed COVID-19 patients (466 with neurological symptoms)	Headache (41.1%) 51.3% associated with fever		M: 348 F: 298	42.17 ± 17.58	[89]
Flores-Silva et al.	1072 patients hospitalized with moderate to severe COVID-19	Headache (41.7%) Dizziness (1.2%) Altered mental status (1.7%)		M: 697 F: 375	53.2 ± 13.7	[90]
Cleret de Langavant et al.	26 neurological cases of COVID-19	encephalitis (N = 8) encephalopathy (N = 6) cerebrovascular events (ischemic strokes N = 4 and vein thromboses N = 2) Other CNS disorders (N = 4)		M: 19 F: 7	58.3 ± 19.3	[36]
García-Azorín et al.	233 COVID-19 cases	Stroke (27%) Altered mental status (23.6%) Headache (12.9%) Seizures (11.6%)		42.1% women	61.1	[91]
some case reports	case reports	PRES		F:3 M:1	[[52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64]]	[43,45,92]
		Diffuse leukoencephalopathy and microhaemorrhages		F	27	[93]
				M	59	[94]
		Encephalopathy		M:4 F:2	[[54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79]] 85, 86	[49,51,[95], [96], [97], [98]]
		CVST (n = 3)	Presented with encephalopathy (n = 2)	F: 3	25, 68, 79
			Presented with visual symptoms (n = 1)
		TM, ADEM-like, acute flaccid myelitis		M: 3	50 or older	[54,55,58]
		Meningitis		F	49	[99]
		Acute Ischemic Stroke		M: 5 F: 2	[[36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88]]	[[100], [101], [102], [103]]
		Multiple (multifocal) strokes		M: 4	[[39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65]]	[59,68,104]
		bilateral massive ischemic stroke		M	70	[105]
		(SDH), (SAH), and (IPH), transtentorial herniation		F	75	[106,107]
		Right olfactory gyrus ICH		M	72
		Critical illness-associated cerebral microbleed		F	56	[108]
		Brain microvascular occlusive disorder		M	68	[109]
		Encephalitis (n = 5)		F: 2 M: 12	[[13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82]]	[[70], [71], [72], [73], [74], [75],[110], [111], [112], [113], [114], [115], [116], [117]]
		Rhombencephalitis; ANE (n = 2)
		symptomatic seizures (n = 6)
		Afebrile seizures		F: 2	3 months
		OMA-like syndrome (without opsoclonus)		M	44	[118]
		Status epilepticus		M	24	[119]
		Multiple sclerosis		M: 1 F: 1	27, 28	[120,121]
		Parkinsonism in close temporal association with encephalitis		F: 2	70, 73	[122]
		Tremors and Gait Disturbance		M	46	[123]
		slurred speech, dizziness, and left-sided weakness		F	42	[124]
		drowsiness, poor suction and mild hypotonia		M	39 weeks	[125]
Delorme et al. & Muccioli et al.	9 cases of COVID-19-related encephalopathy	Encephalopathy		M: 5 F: 4	60 or older	[46,53]
Chen et al.	5 critically ill patients with COVID-19 who underwent EEG monitoring	Status epilepticus		M: 2 F: 3	[[37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60]]	[47]
Abenza-Abildúa et al.	30 patients with severe SARS-CoV-2 infection with neurological symptoms	Acute confusional syndrome (93.33%)		M: 21 F: 9	57.41	[126]
		Headache (16.66%)
		CVD (13.33%)
		Encephalopathies/encephalitis (13.33%)
Abdel-Mannan et al.	4 Patients with SARS-CoV-2 infection who presented with new-onset neurological symptoms	encephalopathy (n = 4)		M: 2 F: 2	8, 9, 15, 15	[5]
		headache (n = 3)
		brainstem signs with dysarthria or dysphagia (n = 2)
		meningism (n = 1)
		cerebellar ataxia (n = 1)
Studart-Neto A et al.	89 neurological consults, requested among 1208 COVID-19 patients	Encephalopathy (44.4%)		M: 55 F: 34	57.4	[127]
		Stroke (16.7%)
		Seizures (9.0%)
Pinna et al.	50 patients with COVID-19	Altered mental status (60%)		M: 29 F: 21	59.6	[128]
		Seizures (26%)
		Headache (24%)
		Acute ischemic stroke (20%)
		Intracerebral hemorrhage (8%)
		SAH (8%)
		PRES (4%)
Karadaş et al.	239 patients with COVID-19	Headache (26.7%)		M: 133 F: 106	46.46	[82]
		Impaired consciousness-confusion (9.6%)
		Dizziness (6.7%)
		CVD (3.8%)
		Pain with eye movements (1.3%)
Iltaf et al.	350 patients with SARS-CoV-2 infection	Headache (6%), followed by vertigo (3.4%)		M: 245 F: 105	49.5	[69]
		Altered level of consciousness (2%)
		Encephalitis (0.9%)
		Stroke (0.6%)
		Seizure (0.3%)
Varatharaj et al.	125 patients with COVID-19 and neurological or psychiatric disease	CVD 62%		F: 44 M: 73 (NE for 8 patients)	71	[61]
Guilmot et al.	15 patients with COVID-19 and neurological manifestations	CVD (n = 3)		M: 12 F: 3	62	[81]
		Cranial neuropathy (n = 2)
		Associated seizures (n = 2)
Lodigiani et al.	388 cases of COVID-19	Ischemic stroke 2.5%		M: 264 F: 124	66	[63]
Herna'ndez-Ferna'ndez et al.	1683 patients with COVID-19	CVD 1.4%		78.3% male among patients with CVD and COVID-19	with a cut-off point set at 63 years of age	[62]
Ashrafi et al.	6 patients with a diagnosis of stroke and a confirmed diagnosis of COVID- 19	5 in MCA versus 83.3%		M: 3 F: 3	younger than 55 years	[64]
		1 in basal ganglia 16.7%
Perrin et al.	5 patients with severe COVID-19	central hypothyroidism (n = 3)		M:3 F:2	[[51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71]]	[28]
Morassi et al.	6 patients with a diagnosis of stroke and a confirmed diagnosis of COVID-19	Ischemic stroke 67%		M: 5 F: 1	69	[129]
		hemorrhagic stroke 33%

SDH: Subdural hematoma, SAH: Subarachnoid hemorrhage, IPH: Intraparenchymal hemorrhage.

CVST: Cerebral Venous Sinus Thromboses, OMA: opsoclonus-myoclonus-ataxia.

4.1. Encephalopathy & acute necrotizing encephalopathy (ANE)

Encephalopathy, as a pathobiological process in the brain, often proceeds within hours to days. It can be specified as altered behavior, personality, consciousness, or cognition (including clinical manifestation of coma or delirium). In encephalopathy and COVID-19 patients with no proven brain inflammation, various other causes should be noted, including drugs, hypoxia, metabolic arrangements, and toxins [15]. About 7% of the hospitalized cases with COVID-19 in Wuhan, China, presented Encephalopathy [33]. There are some reported cases of reversible encephalopathy syndrome (PRES). Characteristics of PRES include acute impairment in consciousness, headache, seizures, and visual disturbances with subcortical/cortical vasogenic edema, which involve the occipital and parietal regions bilaterally. There is an association between PRES and renal failure, blood pressure fluctuations, sepsis, autoimmune conditions, preeclampsia or preeclampsia, and immunosuppressive-cytotoxic drugs resulting from endothelial dysfunction [[43], [44], [45]]. A case study on eight COVID-19 patients with PRES showed impaired consciousness in 5 cases, focal neurological signs in 3 cases, seizures in 7, and visual disturbances in one [44]. Patients may not show Magnetic Resonance Imaging (MRI) characteristics of encephalitis or remarkable CSF abnormalities. The RT-PCR result for the SARS-CoV-2 in the CSF may be negative. A consistent brain FDG-PET/CT pattern of anomalies, i.e., cerebellar hypermetabolism and frontal hypometabolism, can be observed by patients [46]. The attendance of epilepsy in two of five highly diseased patients undergoing electroencephalography (EEG) monitoring was also reported. The EEG monitoring in high-risk COVID-19 patients with encephalopathy is substantial [47]. EEG was the most sensitive test for patients with developed encephalitis or encephalopathy, and very few cases showed changes in neuroimaging studies [48]. Therefore, EEG has a high level of usefulness in encephalopathy patients. CSF analysis in the infected subjects with SARS-CoV-2 assists the ruling other reasons for altered mental status [49]. According to the research findings, the encountered encephalopathy patterns chiefly involved the posterior circulation and watershed areas. It proposes the vulnerability of these areas to hypoperfusion. Thus, they have higher exposure to this disease. Deficient adrenergic sympathetic innervations in the vertebrobasilar system compared to the carotid system would be a plausible explanation. A suggestion for a higher occurrence of thromboembolic phenomena and stroke in COVID-19 could also be cytokine storm syndrome, which is connected to the prothrombotic impact of the inflammatory response [50]. The presence of COVID-19-related encephalopathy with acute lingual disturbances as the earliest characteristic has been suggested [51]. Several weeks after clearance of the initial COVID infection, patients may present a steroid-responsive encephalopathy [52]. IVIg could obtain a practical and safe treatment for COVID-19-related encephalopathy [53]. The best method for detecting encephalopathy resulting from COVID-19 is to consider alterations in the patient's behavior, cognition, consciousness, and clinical manifestations. CSF analysis is efficacious in ruling out other reasons for encephalopathy. Negative SARS-CoV-2 in the CSF could indicate less probability of direct incursion of the brain by the virus or precedence of the viral clearance from CSF to the neurological symptoms.

4.2. Acute disseminated encephalomyelitis (ADEM) and myelitis

ADEM is the multifocal demyelination syndrome, which typically happens several weeks after infection, and focal neurological symptoms with encephalopathy accompany its general presentation. Myelitis and ADEM are generally regarded as post-infectious problems, and corticosteroids or other immunotherapies are often used for their treatment [15]. There are rare case reports of this complication described in COVID-19, including ADEM, acute flaccid myelitis, transverse myelitis (TM), and a complex case with two differential diagnoses of neuromyelitis-optica spectrum disorder (NMOSD) or ADEM [[54], [55], [56], [57]]. Additionally, an (ADEM)-like pathology was found in the gross postmortem investigation of the brain in a COVID-19 patient [58]. All the case reports examined in this neurological manifestation class were related to male cases. MRI seems helpful in detecting patterns, extending, and locations of lesions.

4.3. Cerebrovascular accident (CVA)

There might be an association between cerebral infarction in patients with COVID-19 and a hypercoagulable state linked to a systemic inflammatory response; however, the diagnosis could be challenging [59]. Various studies describe the virus's potential impact on inducing venous thromboembolism and disseminated intravascular coagulation, which results in cerebrovascular indications, such as hemorrhage and cerebral thrombosis [14]. The significant sign of multiple brain infarctions in patients with severe COVID-19 might be the changed mental status. It must be particularly considered in cases with suspected COVID-19-related coagulopathy [59]. According to previous works, 2.8–62% of patients with COVID-19 showed a cerebrovascular occurrence [33,60,61].

Moreover, based on the findings of Spanish retrospective research, 1.4% of COVID-19 patients represented cerebrovascular disease (CVD) over 50 days [62]. Hemorrhagic and ischemic strokes, transient ischemic attacks, and intracerebral hemorrhages (ICH) were patients' most widely reported CVDs. Less widely reported VCDs were CNS vasculitis and cerebral venous thrombosis [60,61]. About 2.5% of hospitalized COVID-19 subjects in a study had a stroke [63]. Besides, a study in Iran shows that the middle cerebral artery (MCA) can be the most affected region [64]. Research findings indicated that 0.25% of COVID-19 patients presented ICH [65].

On the other hand, the abnormal distribution of microbleeds with a particular propensity for the corpus callosum was found in MR images of 9 COVID-19 patients with the postponed recovery of consciousness or significant agitation. The middle cerebellar peduncles and internal capsule were other unusual locations of microbleeds. In most patients, subcortical regions were also influenced [66]. Patients with a simultaneous diagnosis with cerebral venous sinus thrombosis (CVST) and SARS-CoV-2 infection were studied. CVST must be regarded as a possible comorbidity in SARS-CoV-2 patients with neurological symptoms. Thus, it was implied that in comparison with non-SARS-CoV-2 infected cases, older patients represent CVST, with fewer rates of known CVST risk factors. It could result in more unsatisfactory results in the group of subjects who were infected by SARS-CoV-2 [67]. Despite a higher rate of acute cerebrovascular in severe patients with COVID-19 [33], CVDs could be observed in those patients that were also out of the ‘at risk’ group (that is, younger patients with no underlying conditions or intense respiratory infection) [64,68]. Debatably, despite the possibility of coagulopathy and stroke as the severe COVID-19 complication, coagulopathy might be a consequence of hospitalization in the ICU.

4.4. Encephalitis

Encephalitis is characterized as brain parenchyma inflammation, generally resulting from an infection or the body's immune responses. Although it is a pathological diagnosis, clinical evidence of brain inflammation is embraced for practical purposes, like imaging changes, a CSF pleocytosis, or focal abnormalities on EEG. The diagnosis of encephalitis is not confirmed without clues of brain inflammation, even if a virus is detected in the CSF [15]. Table 1 summarizes the studies discussing encephalitis in patients with COVID-19. Hyperinflammation state secondary to SARS-CoV-2 infection, with the considerable liberation of cytokines, such as granulocyte colony-stimulating factor (G-CSF), IL-2, IL-6, IL-7, tumor necrosis factor (TNF), free radicals connected with the severity of COVID-19, and interferon-gamma (IFN-γ), which might change the BBB permeability [69,70]. It might activate the neuroinflammation cascade. Also, SARS-CoV-2 might be hypothetically persuaded by molecular mimicry-associated mechanisms, the antibodies' generation against glial or neural cells, as shown for EBV, HSV-1, or Japanese encephalitis [70]. Altered mental status, unusual speech or behavior, abnormal motor movement, altered body temperament, and focal neurological abnormalities, like paresthesia, flaccid paralysis, seizures, or hemiparesis are symptoms of severe viral encephalitis [8]. It must be noted in the differential diagnosis in those patients with neurological symptomatology or sensory disorder in the COVID-19 pandemic context [71]. Furthermore, autoimmune encephalitis could occur in the post-acute phase of SARS-CoV-2 infection [72]. Besides, it has been presented in a rare case with acute necrotizing encephalitis as the only manifestation of COVID-19. A rare consequence of influenza and other viral infections is ANE linked to intracranial cytokine storm, resulting in breaching in BBB and encephalitis [73]. COVID-19 patients can present acute symptomatic seizures, which probably have a multifactorial origin, including cortical irritation because of the breakdown of BBB and accelerated by the cytokine reaction as a sector of the viral infection [74]. The hyperimmune response observed in adults with COVID-19 can also be observed in infants, even with no respiratory symptoms. Additionally, COVID-19 in infants may manifest as non-febrile seizures that trigger the primary initiation of seizures in infants with a genetic predisposition [75]. Research findings show that the severe patients and mortalities in the recurrent seizure and new-onset seizure groups showed a higher proportion than the general population and epilepsy history group. There were 30 patients diagnosed with COVID-19 and epilepsy, 13 of whom (43.4%) developed new-onset epileptic seizures with no epilepsy history. An epilepsy history with a recurrent epileptic seizure was observed in 10 subjects (33.3%). Moreover, an epilepsy history was observed in 7 patients (23.3%), but there was no seizure during the COVID-19 course (epilepsy history group) [76]. Two cases with acute symptomatic seizures were reported in non-epileptic patients in another study, which was related to severe COVID-19 [74]. EEG was conducted on eight patients, and all of them represent typical background slowing. The generalized epileptiform discharges with triphasic morphology were observed in three patients. One case with focal epilepsy history developed focal electrographic seizures, observed in another case without any such history. A previous diagnosis of epilepsy was observed in 5 of 8 cases. It implies that pre-existing epilepsy might be a risk factor for COVID-19-related neurological presentations [77]. A distributed vasculitis (endotheliitis) with different segmental and total endothelial destruction levels was observed in a 20-year-old man dying from the acute SARS-CoV-2-related hemorrhagic necrotizing encephalopathy in adults with distinct endothelial dysfunction. It was also affirmed by the virological test of the autopsy material and the brain structures [78]. According to findings of a consecutive chain of COVID-19 encephalopathy, there were (i) neuroradiological symptoms (high rate of gadolinium increase in large intracranial arteries), (ii) clinical results (high incidence of headache in patients with severe disease), (iii) biological properties (increased CSF QAlb indicative of disruption in blood-brain barrier), which might imply a pathophysiological mechanism associated with the vessel wall inflammation for development of COVID-19 encephalopathy– the endothelial hypothesis [79]. Besides, in a study, a case report was presented related to a pregnant woman with SARS-CoV-2 showing sudden blindness and seizures, proposing the possibility of promoting brain endothelial damage by SARS-CoV-2 infection, inducing the cited neurological complications in the patient. Subsequently, this study reported a COVID-19 patient indicating preeclampsia related to eclampsia versus posterior reversible leukoencephalopathy with no symptoms [80]. It is still polemical if the seizure risk is elevated by a previous history of epilepsy in adult patients with COVID-19. Nevertheless, it seems that genetic history is a predisposing factor in infants.

4.5. Headaches and dizziness

Headache is a shared clinical sign in multiple diseases and a sign of CNS implication. However, isolated non-severe headache has not been considered in the CNS involvement [81]. In some studies, headache was reported as the most repetitious neurological symptom in COVID-19 patients [69,82]. The isolated headache can be continued several weeks after recovering from acute COVID-19 disease and may be a sign of wide CVST [83]. A remarkably higher expression of IL-6 was observed in patients with headaches [82]. In another study on patients with neurological symptoms, dizziness and headache were reported in 0.9% and 12.8% of patients, respectively [84]. A case report also suggested that dizziness might be a primary clinical advent for COVID-19 infection [85]. Although headache is reported as a manifestation of the CNS involvement in COVID-19 patients, it can be a consequence of dehydration in patients with diarrhea, or if it is a tension headache, it may be caused by the inflammation and spasm of the muscles surrounding the skull, not a CNS complication.

4.6. The peripheral nervous system (PNS) manifestations

There are many PNS symptoms like neuropathy, smell and taste impairment, vision impairment, GBS and its variants, neuralgia, and muscle involvement in COVID-19 patients, as the prevalence of PNS symptoms has been reported at 8.9% and 22.6% in two studies. [33,60] Moreover, the PNS of pregnant women could be affected due to infection by SARS-CoV-2 [130]. In a cohort of 54 patients admitted to ICU, neuropathy and paresis were observed in 2 and 3 cases, respectively [39]. The COVID-19 patients usually have neurologic appearances. However, muscle and hyposmia involvement is more frequent than other flu illnesses [131]. The PNS manifestations in patients with COVID-19 are summarized in Table 2.

Table 2.

Peripheral nervous system manifestations of COVID-19.

Study	Sample size	The PNS complications		gender	(mean) age	Ref.
Mao et al.	214 hospitalized patients with confirmed SARS-CoV-2 infection	8.9%	TDs [5.6%]	M: 87 F: 127	52.7	[33]
			ODs [5.1%]
Iltaf et al.	350 patients with SARS-CoV-2 infection	Numbness/ paresthesia (3.1%)		M: 245 F: 105	[[17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88]]	[69]
		Hyposmia/ anosmia (1.4%)
		GBS (0.3%)
Karadaş et al.	239 patients with COVID-19	ODs (7.5%)		M: 133 F: 106	46.46	[82]
		TDs (6.7%)
		Numbness on the tongue (1.7)
		Numbness in the face area (3.3%)
		GBS (0.4%)
Pinna et al.	50 patients with COVID-19	Dysautonomia (12%)		M: 29 F: 21	59.6	[128]
		Muscle injury (12%)
		Hypogeusia/Dysgeusia (10%)
		Hyposmia (6%)
		Extraocular muscle abnormalities (10%)
		Facial palsy (6%)
Studart-Neto A et al.	89 neurological consults, requested among 1208 COVID-19 patients	Neuromuscular disorders (5.6%)		M: 55 F: 34	57.4	[127]
		Anosmia (9.9%)
		Dysgeusia (4.8%)
Guilmot et al.	15 patients with COVID-19 and neurological manifestations	Associated anosmia (n = 2)		M: 12 F: 3	62	[81]
García-Azorín et al.	233 COVID-19 cases	Neuromuscular symptoms (23.6%) Anosmia (17.6%)		42.1% women	61.1	[91]
Cleret de Langavant et al.	26 neurological cases of COVID-19	GBS (N = 2)		M: 19 F: 7	58.3 ± 19.3	[36]
Flores-Silva et al.	1072 patients hospitalized with moderate to severe COVID-19	Muscle pain (38.5%) Myopathy (9.9%) Anosmia (7%) Dysgeusia (8%)		M: 697 F: 375	53.2 ± 13.7	[90]
Ghaffari et al.	361 adult patients with confirmed diagnosis of COVID-19	Paresis (3.3%) Anosmia (19.1%) Ageusia (19.1%) Sensory (3.6%) Hearing loss (0.8%) Dysphasia (3.6%) Ataxia (5.5%)		M: 214 F: 147	61.90 ± 16.76	[87]
Amanat et al.	873 Patients with SARS-CoV-2 infection	Smell and taste dysfunctions (n = 561) Myalgia (n = 217)		M: 556 F: 317	60.71 ± 18.14	[88]
Abdel-Mannan et al.	4 Patients with SARS-CoV-2 infection who presented with new-onset neurological symptoms	Global proximal muscle weakness (n = 4)		M: 2 F: 2	8, 9, 15, 15	[5]
		Reduced reflexes (n = 2)
Abenza-Abildúa et al.	30 patients with severe SARS-CoV-2 infection with neurological symptoms	Neuromuscular disease (50%)		M: 21 F: 9	57.41	[126]
Kacem et al.	646 confirmed COVID-19 patients (466 with neurological symptoms)	Smell impairment (37.9%)		M: 348 F: 298	42.17 ± 17.58	[89]
		Taste impairment (36.8%)
		Myalgia (37.3%)
		Visual loss/blurred vision (7.4%)
		Focal weakness (2.5%)
Vacchiano et al.	108 hospitalized COVID-19 patients	ODs (37%) TDs (61%) Muscle pain (34%)		57% males	59	[86]
Case reports	NE	GBS AMSAN (n = 1) Facial diplegia (n = 1) Bell's palsy (n = 1)		11, 15, 17, 30, 35, 36, 39, 41 twelve patients: 48 or older	M: 14 F: 6	[[135], [136], [137], [138], [139], [140],[142], [143], [144], [145], [146], [147], [148],[165], [166], [167], [168], [169], [170]]

ODs: olfactory disorders, TDs: taste disorders.

4.7. Olfactory and gustatory dysfunctions (OGDs)

According to current observations, the SARS-CoV-2 genes in the gustatory, olfactory, and chemesthetic systems are mainly expressed in support, epithelial, and stem cells, not primary or secondary neurons. It proposes the indirect changing of neural function because of SARS-CoV-2 infection of peripheral support cells, including local inflammation and alterations in ciliary structure and olfactory sensory neuron (OSN) gene expression. The alterations in olfactory bulb MRI intensity due to COVID-19 propose the role of CNS in a subgroup of patients. These alterations are transient and are possibly the result of inflammatory cytokines distributing from the dorsal epithelium across the perforations in the cribriform plate or local inflammatory processes. It is also feasible that SARS-CoV-2 directly infects bulb neurons or OSNs [21]. Anosmia also displays a frequentative neurological apparition during COVID-19. However, it is temporary in most patients [132]. Anosmia and dysgeusia are helpful for diagnosis and treatment [133]. Various studies reported the occurrence of taste disorders (TDs) and olfactory disorders (ODs) differently. They are listed in Table 2. ODs were notably more common in patients with TDs than those without TDs. ODs were not linked to IL-6, CRP levels, and rhinorrhea.

Furthermore, patients with ODs less often needed oxygen therapy [86]. It is conceivable that the SARS-CoV-2 enters and proliferates in these patients' epithelial cells around the taste buds and the olfactory neurons. However, SARS-CoV-2 has a milder invasion of lung cells. Therefore, they emerge with less severe respiratory symptoms.

4.8. Guillain-Barré syndrome (GBS) and its variants

GBS contains a spectrum of polyneuropathies specified by occasional cranial nerve involvement, acute increasing motor infirmity, mild or moderate sensory abnormalcies, and radicular or muscle pain [134]. The most joint subtypes of GBS are acute motor axonal neuropathy (AMAN), acute inflammatory demyelinating polyneuropathy (AIDP), and the Miller Fisher syndrome (MFS), characterized by acute gait ataxia, ophthalmoplegia, and areflexia [134]. Most patients were over 50 years old, but GBS has also been reported in children and younger patients [[135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145], [146], [147], [148]]. A study reported the immunological and clinical characteristics in a patient of SARS-CoV-2-induced GBS (Si-GBS) and then proposed (1) Si-GBS can progress after paucisymptomatic COVID-19 infection; (2) a specified cytokine repertoire and an increase in the concentration of IL-8 in CSF as well as mildly elevation of TNF-α, IL-6, and IL-8 in serum are related to this autoimmune complication; (3) a specific genetic predisposition may also be related, whereas the patient carried several human leukocyte antigens)HLA(alleles including distinctive class I (HLA-A33) and class II alleles (DQB1*05:01 and DRB1*03:01) which are related to GBS [138]. The nerve conduction studies in a cohort study reported revealed a typical demyelinating pattern (AIDP) [141]. Another study presented GBS in association with leptomeningeal enhancement, a distinctive characteristic of GBS. It also could be a biomarker of its intercommunity with SARS-CoV-2 infection [143]. In a study, the development of a rare variant of GBS known as sensory axonal neuropathy (AMSAN) and acute motor was reported in a COVID-19 patient. Signs and symptoms included pinprick sensation and declined muscle strength in both lower extremities [135].

Moreover, a case without prior clinically relevant background developed facial diplegia as a rare variant of GBS after ten days of confirmation of SARS-CoV-2 infection [139]. A study reported the first case of COVID-19 post-vaccine-associated GBS (during the first week after obtaining the first dose of Pfizer COVID-19 vaccine) which can be related to autoimmune processes [149]. In another study, a case was diagnosed with MFS (anti-GQ1b syndrome) two weeks after COVID-19; however, the antibody study was negative [150]. Moreover, the function of ganglioside antibodies against GD1b instead of QG1b in MFS was detected. COVID-19 spike protein attaches to sialic acid-containing glycoproteins for cell entrance. Also, the involvement of anti-GD1b antibodies in peripheral nerve glycolipids, cross-reactivity among COVID-19–bearing gangliosides, and ataxic neuropathy was addressed [151].

4.9. Other neuropathy

The sudden numbness, limb pain, and weakness can manifest as peripheral neuropathy in COVID-19 patients. Furthermore, the sudden beginning of symptoms, lack of ascending pattern, and normal CSF can be debated against Guillain-Barre [152]. Among four involved patients in a study, three had polyneuropathy, and one patient had signs of the left brachial plexus affection [30]. A case report of peripheral neuropathy showed the effectiveness of plasma exchange therapy for severe COVID-19 with associated thromboinflammation and neurological manifestations [153]. In another study, among the 69 patients with severe COVID-19, 16% of them had a mononeuritis multiplex identified. This study clarifies that a neurological complication often occurs in patients with severe COVID-19, adversely affecting long-term results and noticeably efficacies of their rehabilitation needs [154]. The observed neuropathy may be due to indirect complications of severe illness or hospitalization in the ICU.

4.10. Autonomic nervous system complications

Dysautonomia is described as rapid fluctuations in vital signs. A study found dysautonomia in 12% of 50 COVID-19 patients. [128]. A prospective clinical study observed orthostatic hypertension in 3.3% of 239 patients [82]. Another longitudinal study reported dysautonomia in 2/5 patients [28]. In a case series of 4 patients, all four had the affection of the autonomic nervous system [30]. Acute onset dysautonomia may also declare AMAN during SARS-CoV-2 infection [155].

4.11. Muscle injury

Muscle injury was reported in 19.3% of patients in the severely ill group and 4.8% of cases in the non-severe group [33]. In a study in Wuhan, among 1682 patients with affirmed non-critically disease, myalgia was observed in 311 (18.5%) patients [84]. In another cohort in Wuhan, among 86 patients with affirmed COVID-19, six patients (7%) were found with neuromuscular involvement [31]. Muscle pain was not correlated with the elevation of LDH and CK compared to patients without CRP. However, it was notably more common in patients with arthralgia and headache [86].

4.12. Neuralgia

In a study on 239 patients with COVID-19, trigeminal neuralgia, glossopharyngeal neuralgia, and vasoglossopharyngeal neuralgia were detected in 3.3%, 3.7%, and 0.8% of patients [82].

4.13. Cranial nerves palsy

Facial nerve palsy is known to be associated with varicella-zoster, herpes simplex, human immunodeficiency virus infections, and Lyme disease [156,157]. Isolated unilateral peripheral facial palsy was beheld in 6% of COVID-19 patients in a cohort [128]. A study on eight COVID-19 patients who progressed peripheral facial palsy during infection disclosed that facial palsy was the initial symptom in three patients. Nerve damage led to mild dysfunction in five patients and moderate in three. Moreover, the PCR did not show SARS-CoV-2 in the CSF [158]. In a case report, a patient developed Bell's phenomenon and left weakness of the lower and the upper face [156]. In another case, a pregnant patient was diagnosed with COVID-19 after confirming the isolated peripheral facial palsy [159].

Moreover, in a case report performed on the five COVID-19 patients with neurological symptoms, neurological inspections showed a flaccid paresis in four patients with lower or upper limb predominance. A unidirectional mild facial nerve implication confined to the muscles of the lower face, with sparing of the forehead muscles, was figured out [160]. Pseudo bulbar palsy was reported as a scarce complication related to COVID-19 infection, which is also treated as a stroke [161]. A case report introduced a 24-year-old man case with unilateral hypoglossal nerve palsy (HNP) with severe COVID-19 complications [162]. Cranial nerve palsy can happen in elderly and young patients without any other diseases. It may be the prime sign in the detection of COVID-19. The SARS-CoV-2 may not be found in CSF, and the clinical manifestation can be considered the proper diagnostic factor.

4.14. Ocular muscles abnormalities

Ocular muscle abnormalities, including pain with eye movements, extraocular movement abnormalities, Adie's pupil, diplopia, and strabismus, were reported in elderly and young COVID-19 patients. Extraocular movement abnormalities were identified in 10% of 50 COVID-19 patients [128]. Pain with eye movements was found in 1.3% of 239 patients [82]. A confirmed COVID-19 patient with acute onset of diplopia and strabismus of the left eye was reported. These symptoms happened three days after the start of typical symptoms, and third cranial nerve palsy was suspected [163]. A study reported a case of concurrent trochlear nerve palsy and tonic pupil, and a 0.125% pilocarpine test affirmed Adie's pupil diagnosis. Adie's pupil is a tonic mydriatic pupil, resulted from an improper reproduction of parasympathetic nerve fibers after the ciliary ganglion detriment [164]. Ocular muscles abnormalities can be due to inflammation and direct damage to the muscle or can result from cranial nerves palsy.

5. Discussion

According to our systematic review, neurological symptoms may be due to hypoxia or systemic inflammation associated with COVID-19. On the other hand, there is a hypothesis that damage to the nerves gives rise to the known COVID-19 symptoms since, in some patients, the neurological symptoms and signs may present the first manifestation of COVID-19. While some patients' CSF sample has shown the virus's presence, the direct degeneration of neurons by SARS-CoV-2 remains unclear. The prevalence of central and peripheral nervous system involvement in COVID-19 patients of different ages has been reported differently. This study investigated all of the CNS and PNS complications in COVID-19 patients. The CNS complications are encephalopathy, ADEM, headaches and dizziness, CVA, encephalitis, and myelitis. The PNS involvements include GBS, OGDs, their variants, neuropathy, cranial nerves palsy, autonomic nervous system complications, neuralgia, muscle injury, and ocular muscle abnormalities. Human coronaviruses (HCoV) may present in human brains, so it is supposed that long-time sequelae can progress due to the emergence or aggravation of chronic neurological diseases, as it is already reported for the human coronaviruses HCOV-OC43 and HCOV-229E. The latter has also been identified in different neurological disorders, including multiple sclerosis [171]. Several recent articles reported the associated cases of acute flaccid paralysis, encephalitis, and other neurological symptoms, such as ADEM or GBS, as possible complications of an HCoV infection [172]. A case report was presented regarding four patients who developed GBS, polyneuropathy, and Bickerstaff's encephalitis overlapping with GBS during treatment of the Middle East respiratory syndrome (MERS) [173].

Moreover, current information, mostly from Chinese brain autopsy reports, affirms SARS-CoV's invasion of the CNS [174,175]. Epilepsy, Status epilepticus, infarction in the cerebral artery, neuropathy, rhabdomyolysis, and myopathy are reported as neurological manifestations related to the SARS-CoV infection [176]. The current pandemic has implicated more people than SARS and MERS. Although various studies have been carried out on the neurological presentations in COVID-19 patients, data regarding neuronal pathogenesis is scarce. Therefore, further research is essential to fully perceive the mechanism of neuronal damage that sheds light on the course and pathogenesis of COVID-19.

6. Conclusion

This systematic review suggests that neurological symptoms in COVID-19 patients may arise from hypoxia or systemic inflammation. Some patients experience neurological symptoms as the first manifestation of COVID-19. The prevalence of central and peripheral nervous system involvement varies across different age groups. Neurological complications include encephalopathy, ADEM, headaches, CVA, encephalitis, myelitis, GBS, OGDs, neuropathy, cranial nerves palsy, autonomic nervous system complications, neuralgia, muscle injury, and ocular muscle abnormalities. Human coronaviruses have been found in human brains, and long-term sequelae and chronic neurological diseases may be associated with COVID-19. Further research is needed to understand the mechanism of neuronal damage and its relationship to COVID-19.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Funding

Not applicable.

Code availability

Not applicable.

Authors' contributions

GM: Data extraction, text writing, table preparation, discussion; ZK: Revision and final edition of the manuscript; MS: Data extraction; AS: Revision and final edition of the manuscript; S-HM: Data extraction and discussion; MG: concept, discussion, and supervision of manuscript.

CRediT authorship contribution statement

Ghazale Molaverdi: Validation, Conceptualization, Data curation, Investigation, Writing – original draft. Zahra Kamal: Investigation. Mahshid Safavi: Resources. Arman Shafiee: Writing – review & editing, Conceptualization. Sayed-Hamidreza Mozhgani: Writing – review & editing, Validation, Conceptualization. Mohadeseh Zarei Ghobadi: Writing – review & editing, Supervision. Mahdi Goudarzvand: Writing – review & editing, Supervision, Conceptualization.

Declaration of Competing Interest

All authors declare that they have no conflicts of interest and have never published the manuscript.

Data availability

All data generated or analysed during this study are included in this article.