The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings.

Preliminary clinical data indicate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with neurological and neuropsychiatric illness. Responding to this, a weekly virtual coronavirus disease 19 (COVID-19) neurology multi-disciplinary meeting was established at the National Hospital, Queen Square, in early March 2020 in order to discuss and begin to understand neurological presentations in patients with suspected COVID-19-related neurological disorders. Detailed clinical and paraclinical data were collected from cases where the diagnosis of COVID-19 was confirmed through RNA PCR, or where the diagnosis was probable/possible according to World Health Organization criteria. Of 43 patients, 29 were SARS-CoV-2 PCR positive and definite, eight probable and six possible. Five major categories emerged: (i) encephalopathies (n = 10) with delirium/psychosis and no distinct MRI or CSF abnormalities, and with 9/10 making a full or partial recovery with supportive care only; (ii) inflammatory CNS syndromes (n = 12) including encephalitis (n = 2, para- or post-infectious), acute disseminated encephalomyelitis (n = 9), with haemorrhage in five, necrosis in one, and myelitis in two, and isolated myelitis (n = 1). Of these, 10 were treated with corticosteroids, and three of these patients also received intravenous immunoglobulin; one made a full recovery, 10 of 12 made a partial recovery, and one patient died; (iii) ischaemic strokes (n = 8) associated with a pro-thrombotic state (four with pulmonary thromboembolism), one of whom died; (iv) peripheral neurological disorders (n = 8), seven with Guillain-Barré syndrome, one with brachial plexopathy, six of eight making a partial and ongoing recovery; and (v) five patients with miscellaneous central disorders who did not fit these categories. SARS-CoV-2 infection is associated with a wide spectrum of neurological syndromes affecting the whole neuraxis, including the cerebral vasculature and, in some cases, responding to immunotherapies. The high incidence of acute disseminated encephalomyelitis, particularly with haemorrhagic change, is striking. This complication was not related to the severity of the respiratory COVID-19 disease. Early recognition, investigation and management of COVID-19-related neurological disease is challenging. Further clinical, neuroradiological, biomarker and neuropathological studies are essential to determine the underlying pathobiological mechanisms that will guide treatment. Longitudinal follow-up studies will be necessary to ascertain the long-term neurological and neuropsychological consequences of this pandemic.

Characterisation and mechanisms of bradykinin-evoked pain in man using iontophoresis.

Bradykinin (BK) is an inflammatory mediator that can evoke oedema and vasodilatation, and is a potent algogen signalling via the B1 and B2 G-protein coupled receptors. In naïve skin, BK is effective via constitutively expressed B2 receptors (B2R), while B1 receptors (B1R) are purported to be upregulated by inflammation. The aim of this investigation was to optimise BK delivery to investigate the algesic effects of BK and how these are modulated by inflammation. BK iontophoresis evoked dose- and temperature-dependent pain and neurogenic erythema, as well as thermal and mechanical hyperalgesia (P < 0.001 vs saline control). To differentiate the direct effects of BK from indirect effects mediated by histamine released from mast cells (MCs), skin was pretreated with compound 4880 to degranulate the MCs prior to BK challenge. The early phase of BK-evoked pain was reduced in degranulated skin (P < 0.001), while thermal and mechanical sensitisation, wheal, and flare were still evident. In contrast to BK, the B1R selective agonist des-Arg9-BK failed to induce pain or sensitise naïve skin. However, following skin inflammation induced by ultraviolet B irradiation, this compound produced a robust pain response. We have optimised a versatile experimental model by which BK and its analogues can be administered to human skin. We have found that there is an early phase of BK-induced pain which partly depends on the release of inflammatory mediators by MCs; however, subsequent hyperalgesia is not dependent on MC degranulation. In naïve skin, B2R signaling predominates, however, cutaneous inflammation results in enhanced B1R responses.

Multiple somatotopic representations of heat and mechanical pain in the operculo-insular cortex: a high-resolution fMRI study.

Whereas studies of somatotopic representation of touch have been useful to distinguish multiple somatosensory areas within primary (SI) and secondary (SII) somatosensory cortex regions, no such analysis exists for the representation of pain across nociceptive modalities. Here we investigated somatotopy in the operculo-insular cortex with noxious heat and pinprick stimuli in 11 healthy subjects using high-resolution (2 × 2 × 4 mm) 3T functional magnetic resonance imaging (fMRI). Heat stimuli (delivered using a laser) and pinprick stimuli (delivered using a punctate probe) were directed to the dorsum of the right hand and foot in a balanced design. Locations of the peak fMRI responses were compared between stimulation sites (hand vs. foot) and modalities (heat vs. pinprick) within four bilateral regions of interest: anterior and posterior insula and frontal and parietal operculum. Importantly, all analyses were performed on individual, non-normalized fMRI images. For heat stimuli, we found hand-foot somatotopy in the contralateral anterior and posterior insula [hand, 9 ± 10 (SD) mm anterior to foot, P < 0.05] and in the contralateral parietal operculum (SII; hand, 7 ± 10 mm lateral to foot, P < 0.05). For pinprick stimuli, we also found somatotopy in the contralateral posterior insula (hand, 9 ± 10 mm anterior to foot, P < 0.05). Furthermore, the response to heat stimulation of the hand was 11 ± 12 mm anterior to the response to pinprick stimulation of the hand in the contralateral (left) anterior insula (P < 0.05). These results indicate the existence of multiple somatotopic representations for pain within the operculo-insular region in humans, possibly reflecting its importance as a sensory-integration site that directs emotional responses and behavior appropriately depending on the body site being injured.

Identifying brain activity specifically related to the maintenance and perceptual consequence of central sensitization in humans.

Central sensitization (CS) refers to an increase in the excitability of spinal dorsal horn neurons that results from, and far outlasts the initiating nociceptive input. Here, functional magnetic resonance imaging was used to examine whether supraspinal activity might contribute to the maintenance of CS in humans. A crossover parametric design was used to distinguish and control for brain activity that is related to the consequence of increased pain experienced during CS. When the intensity of pain during CS and normal states were matched, only activity within the brainstem, including the mesencephalic pontine reticular formation, and the anterior thalami remained increased during CS. Further analyses revealed that activity in the isolated brainstem area correlated positively with the force of noxious stimulation only during CS, whereas activity in the isolated thalamic area was not modulated parametrically in either CS or normal states. Additionally, the mean activity in the isolated brainstem area was increased only during CS, whereas the mean activity in the isolated thalamic area was increased in both states, albeit less so in the normal state. Together, these findings suggest a specific role of the brainstem for the maintenance of CS in humans. Regarding brain areas related to the consequence of increased pain perception during CS, we found that only cortical activity, mainly in the primary somatosensory area, was significantly correlated with intensity of pain that was attributable to both the force of noxious stimulation used and state in which noxious stimulation was applied.