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


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COVID -19 Research finding rare brain inflammation.

A lot more research carried out is included in the paper, but I've included some of the neuroinflammatory findings here.
Neuroinflammatory syndromes
Twelve patients (Patients 11–22, 27–66 years old; eight female, four male; four White, three Black, three Asian; two other/mixed) presented with inflammatory CNS syndromes. Two had an encephalitis; one (Patient 11, Vignette B) had features of an autoimmune encephalitis with opsoclonus, stimulus sensitive myoclonus and convergence spasm. Although brain imaging, EEG and CSF were normal, the clinical picture was highly suggestive of an autoimmune brainstem encephalitis. The second encephalitis patient (Patient 12) presented with confusion and a single seizure, with MRI abnormalities suggestive of autoimmune or ‘limbic’ encephalitis in the thalami, medial temporal regions and pons (Fig. 1A–D, Table 3 and Supplementary material).

Figure 1

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Imaging from Patients 12, 13 and 15 (COVID-19 autoimmune and haemorrhagic encephalitis). Axial MRI from three individuals with para-/post-infectious central syndromes. (AD) Patient 12: axial fluid-attenuated inversion recovery (FLAIR) images show bilateral hyperintensity in the mesial temporal lobes (A and B), hypothalamus (C) temporal lobes and thalamus (D). (EH) Patient 13: axial T2-weighted (E), diffusion weighted imaging (DWI) (F), susceptibility weighted imaging (SWI) (G) and post-contrast T1-weighted (H) images show multifocal clusters of lesions involving the deep white matter of both cerebral hemispheres, intralesional cyst-like areas of varied sizes, and some peripheral rims of restricted diffusion (F), some haemorrhagic changes (G), and T1 hypointense ‘black holes’ without contrast enhancement (H). (IP) Patient 15: axial images at the level of the insula and basal ganglia (IL) and at the level of the temporal lobes and upper pons (MP). T2-weighted images (I and M), SWI images (J and N), DWI images (K and O) and contrast-enhanced images (L and P). There are extensive confluent areas of T2 hyperintensity (I and M), with haemorrhagic change on SWI imaging (J and N), restricted diffusion on DWI images (K and O) and peripheral contrast-enhancement (arrows in L and P) in the insular region, basal ganglia and left occipital lobe (IL) as well as in the medial temporal lobes and upper pons (MP).


Nine patients were categorized within the spectrum of ADEM (e.g. Vignette C, Fig. 1E–H). Four patients had haemorrhagic change on imaging, including microbleeds; and one had necrosis. Two patients had myelitis in addition to brain imaging changes, and one further had myelitis with normal brain imaging. Patient 17 (Vignette D) with acute haemorrhagic leucoencephalitis (based on clinical and imaging features) failed to respond to corticosteroids and required decompressive craniectomy for incipient brain herniation; a brain biopsy at the time of surgery showed evidence of perivenular inflammation supporting aggressive hyper-acute ADEM. She made significant recovery after the decompression followed by intravenous immunoglobulin (IVIG), but requires ongoing rehabilitation. Patient 15 developed a severe necrotizing encephalitis (Fig. 1I–P) that resulted in death. Patient 16 was unusual in presenting with a GBS and subsequently developed an ADEM-like illness (Fig. 2H–O, Vignette E).

Figure 2

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Axial MRI (A–D) and histopathology (E–G) from Patient 17, diagnosed with ADEM, and imaging (H–O) from Patient 16, with combined CNS and PNS disease. (AG) Patient 17: axial T2-weighted (A), SWI (B), post-gadolinium (C and D) images show extensive confluent ‘tumefactive’ lesions involving the white matter of the right cerebral hemisphere, corpus callosum and corona radiata with mass effect, subfalcine herniation (A), clusters of prominent medullary veins (B, short arrows) and peripheral rim enhancement (D, arrows). (E) The white matter shows scattered small vessels with surrounding infiltrates of neutrophils and occasional foamy macrophages extending into the parenchyma (arrow). The endothelium is focally vacuolated but there is no evidence of vasculitis or fibrinoid vessel wall necrosis in any region. There were a few perivascular T cells in the white matter but the cortex appears normal (not shown). (F) CD68 stain confirms foci of foamy macrophages in the white matter, mainly surrounding small vessels. There was no significant microgliosis in the cortex (not shown). (G) Myelin basic protein stain (SMI94) shows areas with focal myelin debris in macrophages around vessels in the white matter (arrows) in keeping with early myelin breakdown. There is no evidence of axonal damage on neurofilament stain (not shown). Scale bars: E =45 µm; F and G =70 µm. (HO) Patient 16: axial post-gadolinium fat-suppressed T1-weighted images (H) demonstrating pathologically enhancing extradural lumbosacral nerve roots (arrows). Note physiological enhancement of nerve root ganglia (short arrows). Coronal short tau inversion recovery (STIR) image (L) shows hyperintense signal abnormality of the upper trunk of the right brachial plexus (arrow). Initial axial T2 (I and J) and T2*-weighted images (K) show multifocal confluent T2 hyperintense lesions involving internal and external capsules, splenium of corpus callosum (I), and the juxtacortical and deep white matter (J), associated with microhaemorrhages (K, arrows). Follow-up T2-weighted images (M and N) show marked progression of the confluent T2 hyperintense lesions, which involve a large proportion of the juxtacortical and deep white matter, corpus callosum and internal and external capsules. The follow-up SWI image (O) demonstrates not only the previously seen microhaemorrhages (arrows) but also prominent medullary veins (short arrows).


Despite the striking imaging findings of these patients (Figs 13), the CSF parameters were abnormal in only half. In none of the cases tested were specific antibodies (e.g. to NMDAR, MOG, AQP4, LGI1 or GAD) identified in the serum or CSF. Treatments were with corticosteroids in nine, and IVIG in three. A full clinical response was seen in 1 of 12, partial recovery at the time of writing in 10 of 12, and one patient died.

Figure 3

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Patients 19 and 20 (ADEM including spinal cord). Patient 19: axial T2 (A and C) and DWI (B and D) images show multifocal lesions involving corpus callosum and corona radiata. Patient 20: axial T2-weighted images of brain MRI and sagittal T2-weighted of the spinal cord acquired on admission (EH) and after 26 days (IL). Axial T2-weighted images show multifocal hyperintense lesions in the brainstem (E and I), basal ganglia and supratentorial white matter (F and J). The pontomedullary hyperintensities have become more confluent (I) since admission (E). After 26 days, the signal abnormalities in the basal ganglia and the supratentorial white matter (J) are grossly similar to the baseline MRI scan (F). Sagittal and axial T2-weighted images show diffuse high T2-weighted signal intrinsic to the spinal cord at baseline (G and H). After 26 days, the cord oedema has reduced, and the spinal cord lesions appear less confluent and more discrete (K and L).


Vignette B: post-infectious probable brainstem and cortical autoimmune encephalitis
A 65-year-old female (Patient 11), with a 2-year history of cognitive decline and presumed sporadic early onset Alzheimer’s disease, presented with right hand and then widespread involuntary movements, 6 days after fever, cough and myalgia. She had difficulty speaking and became disorientated and confused, complaining of well-formed visual hallucinations of people inside her house and objects flying around the room. She complained of deteriorating vision, with difficulty reading, and intermittent double vision. On admission she had widespread stimulus sensitive myoclonus involving the tongue and all four limbs with marked hyperekplexia. There was episodic opsoclonus and prominent convergence spasm on visual fixation. She had a non-fluent aphasia with oral apraxia, difficulty repeating sentences and was only able to follow single stage commands. MRI brain, EEG and CSF examination were normal. SARS-CoV-2 PCR was positive on nasopharyngeal swab. Levetiracetam and clonazepam were used to treat her myoclonus, and 2 weeks after onset of neurological symptoms, she received a course of steroids for a clinical diagnosis of presumed post-infectious autoimmune encephalitis affecting cortex and brainstem. Cognition and visual symptoms improved although there are on-going symptoms at the time of writing.

Vignette C: ADEM with haemorrhage in a critically ill patient
A 52-year-old male (Patient 13) presented with a 10-day history of cough, fever, dyspnoea and myalgia. On admission he was hypoxic and non-invasive ventilation was commenced. He had bilateral chest X-ray changes consistent with COVID-19 and SARS-CoV-2 RNA PCR was positive. Oxygen requirements increased and mechanical intubation was required. On Day 17 of intensive care admission he was slow to wean from sedation. His conscious level was impaired (responding to pain only) despite a prolonged withdrawal from sedation. He was hyper-reflexic with lower limb clonus. Brain MRI showed bilateral white matter changes with haemorrhage (Fig. 1E–H). There was slow and still on-going neurological improvement over 4 weeks with supportive treatment alone, which continues at the time of writing.

Vignette D: acute haemorrhagic leukoencephalopathy form of ADEM requiring decompressive craniectomy
A 47-year-old female (Patient 17), previously well and who worked in a high-risk occupation for COVID-19, presented with right-sided headache and left hand numbness. This was preceded by 7 days of cough, fever and shortness of breath. On the day of presentation, she had persistent severe headache and progressive onset of left-sided numbness followed by left-sided weakness including the face. A few hours later, she was drowsy, with severe left upper limb weakness, mild left leg weakness and hemisensory loss. CT head imaging demonstrated marked right hemisphere vasogenic oedema with midline shift. She required 4 l of oxygen and had lower zone chest X-ray and CT chest changes compatible with probable COVID-19 as well as lymphopenia, and elevated D-dimer. Head MRI demonstrated severe right hemispheric vasogenic oedema with a leading edge on contrast imaging, and smaller areas of T2 hyperintense changes in the left hemisphere, in keeping with a diagnosis of an acute haemorrhagic leukoencephalopathy form of ADEM. She was treated with high dose intravenous methylprednisolone (1 g daily for 5 days). After 48 h of treatment her conscious level fell, she developed a fixed dilated right pupil and underwent emergency right hemi-craniectomy. She subsequently received oral prednisolone 60 mg daily and 5 days of IVIG. She was extubated 4 days postoperatively and continues to improve clinically, and is able to weight bear with support. Pathological findings from brain biopsy taken at surgery supported a diagnosis of hyperacute ADEM (Fig. 2E–G). The brain tissue was negative in PCR for SARS-CoV-2.

Vignette E: sequential para-infectious involvement of central and peripheral nervous systems
A 52-year-old male (Patient 16) presented with a 3-day history of headache, back pain, vomiting and progressive limb weakness. There was bilateral facial and neck weakness, symmetrical upper and lower limb flaccid (proximal > distal) weakness, generalized areflexia, extensor plantar responses and preserved sensation. MRI of the neuroaxis was normal except for gadolinium enhancement of the cervical and lumbar roots (Fig. 2H and L). CSF was acellular, with a raised protein. Nerve conduction studies supported a diagnosis of GBS and he was treated with IVIG. On Day 3 of admission, he deteriorated with increasing weakness, dysphagia, ophthalmoplegia, and lymphopenia. Due to type-2 respiratory failure, he required ventilation. The patient became febrile (38.9°C), with increasing oxygen requirements, and antibiotics were commenced. Chest CT showed bilateral pulmonary infiltrates. SARS-CoV-2 RNA PCR was positive on throat swab, but negative in CSF. On Day 5, he became unresponsive and a repeat brain MRI showed a pattern of T2 symmetrical widespread white matter hyperintensities, which progressed further on Day 12 (Fig. 2I–K and M–O). Intravenous methylprednisolone (IVMP, 1 g/day) was given for 5 days, with neurological improvement following treatment on Day 3: eyes opened spontaneously, he could obey commands, mouth words, and move both hands. Two weeks after completion of IVMP the patient was alert, breathing without assistance, talking and able to flex both arms.
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