2.2.1. General neurological symptoms

Given the global nature of SARS‐CoV‐2, the lack of any large‐scale observational studies investigating the CNS involvement of the novel coronavirus is surprising. Numerous individual case reports exist which suggests that some patients exhibit neuropsychiatric complications of the virus such as altered consciousness 5 and encephalopathy 6 ; however, such reports are limited by their power. Of the limited published research available, most centre in China from the beginning of the SARS‐CoV‐2 pandemic. An early study from city of Wuhan, China, of 214 hospitalized patients with SARS‐CoV‐2 reported that over a third (36.4%) of patients had some degree of neurological involvement suggesting that this may be an underreported and overlooked component of the disease course. They noted that headache and dizziness were the two most reported CNS manifestations at 17% and 13%, respectively. The incidence of more severe neurological sequelae such as cerebrovascular accidents and seizures was low at 3% and 0.5%, respectively. Those with “severe” infections with SARS‐CoV‐2 were found to be more likely to suffer from neurological complications; however, the authors did not specify the methodology of distinguishing between a severe and non‐severe infection with SARS‐CoV‐2. 7

Interestingly, they noted that most neurological manifestations occurred early on in the disease which may pose to be an important early predictor of future clinical deterioration. Another similar such retrospective series by Chen et al from the city of Wuhan described that confusion (9%) and headache (8%) were symptoms reported by such patients; importantly however, neurological complaints were significantly less prevalent than the typical respiratory symptoms of cough (82%) and dyspnoea (31%). 8 More significant and potentially long‐lasting neurological complications of SARS‐CoV‐2 were highlighted by Li et al in a study of 221 patients, and 6% developed severe neurological disease: ischaemic stroke, haemorrhage of cerebral vein thrombosis, of which a significant proportion died as a result. 9

2.2.2. Stroke

Worryingly, Oxley et al 10 reported five cases of large vessel stroke in patients younger than 50 who had a diagnosis of SARS‐CoV‐2. The youngest two patients, aged 33 and 37, had no previous medical history. Two further studies detailing the rate of thromboembolic complications in patients with SARS‐CoV‐2 noted the incidence of ischaemic stroke to be 1.6% 11 and 2.5%, 12 respectively. Both authors recognized that the incidence of thrombotic complications was remarkably high for their particular institutions. There are clearly additional risk factors predisposing patients with SARS‐CoV‐2 to develop thromboembolic stroke beyond the traditional cardiovascular and metabolic co‐morbidities and those pertinent to a protracted stay within intensive care settings.

The thrombo‐inflammatory nature that SARS‐Cov‐2 predisposes patients to, was described by Connor and colleagues who reported the coagulative parameters in 16 critically ill patients. 13 They found that fibrinogen (94%), platelet (62%) and D‐dimer (100%) levels were increased, as well as interleukin‐6 (IL‐6) (100%). They propose a correlation between inflammation and subsequent coagulopathy, by IL‐6 and fibrinogen, respectively. 13 Upon damage to the alveoli, an inflammatory state is generated, and as a result, the production of inflammatory cytokines is released, including IL‐6.

The downstream effects are broadly categorized into two sequelae: firstly, the production of pro‐coagulative factors and, secondly, damage to capillary endothelium resulting in dysregulation of its anti‐thrombotic properties. Both of which result in the formation of microvascular thrombosis, that in turn have the potential to embolize systemically. 13 The pathophysiology of pro‐thrombotic states following viral infection has been extensively documented and mirrors the proposed mechanism by Connor et al However, we must also consider the possibility that the predisposition to coagulopathy and thrombotic events may well be explained by the long stays in ITU and consequent immobility.

2.2.3. Guillain‐barre syndrome

There have also been eleven confirmed case reports and another potential report of Guillain‐Barre syndrome (GBS) as being a significant neurological sequelae of SARS‐CoV‐2. Of the eleven cases in published literature, there is considerable variability in the onset of features of GBS and the typical respiratory symptoms of SARS‐CoV‐2. One paper reported symptoms of GBS at initial presentation to healthcare settings alongside only mild fever, 14 whereas a further nine patients reported symptoms of GBS, five to eleven days post‐diagnosis with the novel coronavirus 15 , 16 , 17 , 18 , 19 ^.Despite the inconsistent onset of symptoms in relation to the diagnosis of COVID‐19, it is reassuring that the majority of reports describe consistent clinical features of marked lower limb weakness over upper limb and loss of deep tendon reflexes with variable sensory abnormalities. Interestingly however, raised cerebrospinal fluid protein was not universal in this cohort of patients, and in patients with significant respiratory compromise from SARS‐CoV‐2, measuring vital capacity due to neuromuscular failure from GBS to further support the diagnosis may not be plausible.

Another report by Zhao et al suggests GBS as a presenting symptom of the novel coronavirus but it is unclear whether this is a true association or merely coincidental. 20 It is well documented that GBS is associated with recent inoculation from a potential range of pathogens, which in itself can explain the clinical heterogenicity of the disease. 21 Several mechanisms by which a virus induces an acute areflexic state in GBS have been proposed. Most likely is that antibodies against surface glycoproteins are produced against a pathogen which also respond to similar native protein structures found of the surface of neurones leading to the clinical features seen in GBS. 19 Other plausible theories include one described by McGonagle et al who describe a “macrophage activation syndrome,” also known as cytokine storm, and the subsequent hyperinflammation may also be implicated in the pathogenesis of GBS in patients with SARS‐CoV‐2. 22

A clear time lag between infection with the primary causative pathogen and development of neurological sequelae is the classic phenotype of GBS and has been described as the “post‐infectious” presentation. However, it is clear that from some case reports, this post‐infectious phenotype may not explain why a select number of patients present with either concurrent symptoms of SARS‐CoV‐2 and neurological involvement or those that present with GBS initially. Zhao et al 20 proposed a so‐called “parainfectious” profile pattern whereby GBS occurs at the same time of an acute episode of infection. This may go some way to explain some of the early onset cases of GBS, some of which preceded without significant respiratory involvement and in the absence of a history of any other plausible infection known to cause GBS.

Toscano et al 15 raised an important point in being able to distinguish between GBS and critical illness polyneuropathy, particularly in patients with SARS‐CoV‐2 who have prolonged admission to intensive care. These consequences of extended intensive care are typically seen later in the course of major illness than GBS but as we have explored, relying on purely time as a differentiator may prove to be difficult.

Historical research has shown that coronaviruses do have the potential to induce demyelinating disease in mice, albeit a central demyelination type picture. 23 There has been an interesting case of GBS overlapping with Bickerstaff's encephalitis documented in the previous MERS‐CoV 24 outbreak and a report of a 5‐year‐old developing GBS after contraction of coronavirus OC43. 25 So, in combination with animal models, previous reports of neurological involvement in sister viruses and current emerging reports, it does seem that GBS is associated with the ongoing SARS‐CoV‐2 pandemic. But due to so few published reports and the difficulty in proving a direct cause and effect relationship between a single pathogen, it may be complex to explore this further in clinical practice. The neurological symptoms reported by patients are represented in Figure 2.

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Figure 2

Illustration of reported neurological manifestations of SARS‐CoV‐2