A patient (65-year-old female) who has a history of cognitive decline and Alzheimer’s disease presented with widespread involuntary movements, difficulty speaking, disorientation, confusion, visual hallucinations, and deteriorating vision, 6 days after the onset of COVID-19 symptoms. On admission, she had the following behavioural and cognitive abnormalities:

- Widespread stimulus sensitive myoclonus involving the tongue and all four limbs with marked hyperekplexia
- Episodic opsoclonus and prominent convergence spasm on visual fixation 
- Non-fluent aphasia with oral apraxia (difficulty repeating sentences and was only able to follow single stage commands)

Her myoclonus was treated with levetiracetam and clonazepam, and her presumed post-infectious autoimmune encephalitis affecting cortex and brainstem was treated with a course of steroids. At the time of writing, her cognition and visual symptoms were still ongoing, but they had improved. 

Case Study: Post-infectious Probable Brainstem and Cortical Autoimmune Encephalitis

A patient (47-year-old female) presented with right-sided headache followed by  persistent severe headache, left-sided numbness followed by left-sided weakness, and drowsiness (with severe left upper limb weakness, mild left leg weakness and hemisensory loss), 7 days the onset of COVID-19 symptoms. The CT head imaging demonstrated marked right hemisphere vasogenic oedema with midline shift. The 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, therefore a diagnosis of an acute haemorrhagic leukoencephalopathy form of ADEM was made. After 48 hours of being treated with high dose intravenous methylprednisolone (1 g daily for 5 days), her level of consciousness dropped and her right pupil became fixed and dilated. Because of her decline, she underwent emergency right hemi-craniectomy. During the operation, a brain biopsy was taken that suggested hyperacute ADEM. After the procedure, she was treated with oral prednisolone (60 mg daily), IVIG (for 5 days), and was extubated (4 days). Her clinical condition and physical strength continue to improve, with brain tissue that is negative in PCR for SARS-CoV-2.

Case Study: Acute Haemorrhagic Leukoencephalopathy Form of ADEM Requiring Decompressive Craniectomy

A patient (52-year-old male) presented with a headache, back pain, vomiting and progressive limb weakness. He had bilateral facial and neck weakness, symmetrical upper and lower limb flaccid (proximal > distal) weakness, generalized areflexia, extensor plantar responses, and preserved sensation. His MRI of the neuroaxis demonstrated gadolinium enhancement of the cervical and lumbar roots and, his CSF was acellular (with an elevated protein level). He was diagnosed with GBS and was treated with IVIG. Three days after admission, his weakness, dysphagia, ophthalmoplegia, and lymphopenia increased. He had type-2 respiratory failure (requiring ventilation) and became febrile. He was treated with antibiotics. A chest CT showed bilateral pulmonary infiltrates and SARS-CoV-2 RNA PCR was positive on a throat swab but negative in CSF. Five days after admission, he became unresponsive and an MRI showed a pattern of T2 symmetrical widespread white matter hyperintensities. He was treated with Intravenous methylprednisolone (IVMP, 1 g/day) for 5 days, improved by the third day of treatment, and continued to improve.

Case Study: Sequential Para-infectious Involvement of Central and Peripheral Nervous System

Acute disseminated encephalomyelitis (ADEM), which can include acute haemorrhagic leucoencephalitis and ADEM-like illnesses, is a neuroinflammatory syndrome that may develop as a complication in COVID-19 patients.

Acute Disseminated Encephalomyelitis (ADEM) in COVID-19 Patients

In a case study of acute disseminated encephalomyelitis (ADEM) with haemorrhage, a critically ill 52-year-old male COVID-19 patient was hypoxic on admission, requiring non-invasive ventilation and eventually mechanical intubation. On Day 17 of intensive care, he was slow to wean from sedation, responded only to painful stimuli, exhibited hyper-reflexia with lower limb clonus, and a brain MRI revealed bilateral white matter haemorrhaging. He showed slow improvement with supportive treatment.

Case Study: ADEM with Haemorrhage in a Critically Ill Patient

Neuroinflammation is an innate immune response to percieved threats in the nervous system, which can lead to neurological complications. In a study of 43 patients, 12 developed neuroinflammatory syndromes, including:

- Encephalitis 
- Acute disseminated encephalomyelitis (including acute haemorrhagic leucoencephalitis and ADEM-like illnesses)
- Myelitis

Smith College

University of Michigan - Ann Arbor

- Encephalopathy (overall)
- Ischemic Stroke
- Multisystem Inflammatory Syndrome in Children (MIS-C)
- Induce brain and spine demyelinating lesions
- Mast cell activation
- Acute cerebrovascular disease 
- Intracranial hemorrhage
- Seizure (caused by meningitis)
- Neuroinflammatory syndromes 
- Post-infection cerebral changes

COVID-19 Reports on Patient Neurological Symptoms, Organized by Symptoms Affecting the CNS

Paterson, R. W., Brown, R. L., Benjamin, L., Nortley, R., Wiethoff, S., Bharucha, T.,... the UCL Queen Square National Hospital for Neurology and Neurosurgery COVID-19 Study Group. (2020). The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings. Brain: A Journal of Neurology, awaa240. https://doi.org/10.1093/brain/awaa240.

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

In studies conducted in Wuhan, China and France, 93 patients total were found with encephalopathy. Most of these patients experienced symptoms such as dizziness, headaches, and a reduced state of consciousness.

Encephalopathy in COVID-19 Patients.

- Encephalopathy
- Meningism
- Headaches
- Ataxia
- Dysarthria
- Dysphagia
- Splenium of the corpus callosum (SCC) lesions

Multisystem Inflammatory Syndrome in Children (MIS-C) in COVID-19 Patients: CNS Symptoms

SARS-CoV-2 is known to activate mast cells in affected patients, along with other immune cells including monocytes/macrophages, neutrophils, T cells, killer cells, and resident tissue epithelial and endothelial cells. These various groups cells have been thought to induce the "cytokine storm syndrome" that is experienced by COVID-19 patients. However, since mast cells are well-expressed throughout the body (including the CNS) and are involved in certain neuroinflammatory diseases, it is hypothesized that their activation by SARS-CoV-2 upregulates certain neuroinflammatory responses, which may result in some of the other symptoms observed in COVID-19 patients, including ischemic stroke.

Mast Cell Activation in COVID-19 Patients

In the study by Li et al., a majority of the 221 COVID-19 patients had ischemic infarcts in both small and large arterial vessels, and 13 (5.4%) had imaging-confirmed cerebrovascular disease. Another study by Oxley et al. reported 5 patients under age 50 with cerebrovascular disease and noted that even without presenting typical respiratory symptoms, young healthy patients with COVID-19 may experience large strokes. The 5 young patients were treated with either antiplatelet or anticoagulation.


Acute Cerebrovascular Disease in COVID-19 Patients

While a majority of COVID-19-related strokes have been ischemic, a few have been intercranial hemorrhage, although the causes of the latter are not yet understood. One potential explanation is that SARS-Cov2 binds to and downregulates ACE2, slowing the conversion of angiotensin II to angiotensin, and that since higher levels of angiotensin II are associated with vasoconstriction, this causes blood vessels in the brain to rupture. ACE2 polymorphism may explain the increased risk of intracranial hemorrhage among the East Asian population.


Intracranial Hemorrhage in COVID-19 Patients

As the meninges have high quantities of blood vessels and ACE2, damage to these blood vessels and meninges inflammation resulting from SARS-Cov2 can lead to symptoms of meningitis, such as acute headache, stiff neck, confusion, and seizure. 

Potential Link Between Seizure and Meningitis in COVID-19 Patients

Neuroinflammatory Syndromes in COVID-19 Patients 

Several studies have suggested that COVID-19 patients have long-term structural changes within certain structures in their brains. As an example, an MRI- and DTI-based 3-month follow up study from Lu et al. (2020) found that patients have significantly higher gray matter volumes in their olfactory cortices, hippocampi, insulas, left Rolandic operculum, left Heschl's gyrus, and right cingulate gyrus. General diffusivity had declined. Left hemisphere changes correlated with memory loses, while other right hemisphere changes correlated with smell loss. 

Post-Infection Cerebral Changes in COVID-19 Patients

- Impact of COVID-19 on Outcomes in Ischemic Stroke Patients in the United States
- COVID-19 Is an Independent Risk Factor for Acute Ischemic Stroke
- Prevalence and Outcomes of Acute Ischemic Stroke Among Patients ≤50 Years of Age With Laboratory Confirmed COVID-19 Infection
- Characteristics and Comparison of 32 COVID-19 and Non-COVID-19 Ischemic Strokes and Historical Stroke Patients
- Characteristics and Outcomes in Patients With COVID-19 and Acute Ischemic Stroke

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