COVID-19-associated stroke differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

COVID-19-associated stroke should be differentiated from other causes of muscle weakness and paralysis such as botulism, guillian-Barre syndrome, Eaton Lambert syndrome, myasthenia gravis, electrolyte disturbance, organophosphate toxicity, tick paralysis (Dermacentor tick), tetrodotoxin poisoning, stroke, poliomyelitis, transverse myelitis, neurosyphilis, muscular dystrophy, multiple sclerosis exacerbation, amyotrophic lateral sclerosis, and inflammatory myopathy.

Differential Diagnosis

COVID-19-associated stroke should be differentiated from other causes of muscle weakness and paralysis such as botulism, guillian-Barre syndrome, Eaton Lambert syndrome, myasthenia gravis, electrolyte disturbance, organophosphate toxicity, tick paralysis (Dermacentor tick), tetrodotoxin poisoning, stroke, poliomyelitis, transverse myelitis, neurosyphilis, muscular dystrophy, multiple sclerosis exacerbation, amyotrophic lateral sclerosis, and inflammatory myopathy.

Diseases	History and Physical								Diagnostic tests		Other Findings
	Motor Deficit	Sensory deficit	Cranial nerve Involvement	Autonomic dysfunction	Proximal/Distal/Generalized	Ascending/Descending/Systemic	Unilateral (UL) or Bilateral (BL) or No Lateralization (NL)	Onset	Lab or Imaging Findings	Specific test
Stroke	+/-	+/-	+/-	+/-	Generalized	Systemic	UL	Sudden	MRI +ve for ischemia or hemorrhage	MRI	Sudden unilateral motor and sensory deficit in a patient with a history of atherosclerotic risk factors (diabetes, hypertension, smoking) or atrial fibrillation.
Acute Flaccid Myelitis	+	+	+	-	Proximal > Distal	Ascending	UL/BL	Sudden	MRI (Longitudinal hyperintense lesions)	MRI and CSF PCR for viral etiology	Drooping eyelids Difficulty swallowing Respiratory failure
Adult Botulism	+	-	+	+	Generalized	Descending	BL	Sudden	Toxin test	Blood, Wound, or Stool culture	Diplopia, Hyporeflexia, Hypotonia, possible respiratory paralysis
Infant Botulism	+	-	+	+	Generalized	Descending	BL	Sudden	Toxin test	Blood, Wound, or Stool culture	Flaccid paralysis (Floppy baby syndrome), possible respiratory paralysis
Guillian-Barre syndrome	+	-	-	-	Generalized	Ascending	BL	Insidious	CSF: ↑Protein ↓Cells	Clinical & Lumbar Puncture	Progressive ascending paralysis following infection, possible respiratory paralysis
Eaton Lambert syndrome	+	-	+	+	Generalized	Systemic	BL	Intermittent	EMG, repetitive nerve stimulation test (RNS)	Voltage gated calcium channel (VGCC) antibody	Diplopia, ptosis, improves with movement (as the day progresses)
Myasthenia gravis	+	-	+	+	Generalized	Systemic	BL	Intermittent	EMG, Edrophonium test	Ach receptor antibody	Diplopia, ptosis, worsening with movement (as the day progresses)
Electrolyte disturbance	+	+	-	-	Generalized	Systemic	BL	Insidious	Electrolyte panel	↓Ca++, ↓Mg++, ↓K+	Possible arrhythmia
Organophosphate toxicity	+	+	-	+	Generalized	Ascending	BL	Sudden	Clinical diagnosis: physical exam & history	Clinical suspicion confirmed with RBC AchE activity	History of exposure to insecticide or living in farming environment. with : Diarrhea, Urination, Miosis, Bradycardia, Lacrimation, Emesis, Salivation, Sweating
Tick paralysis (Dermacentor tick)	+	-	-	-	Generalized	Ascending	BL	Insidious	Clinical diagnosis: physical exam & history	-	History of outdoor activity in Northeastern United States. The tick is often still latched to the patient at presentation (often in head and neck area)
Tetrodotoxin poisoning	+	-	+	+	Generalized	Systemic	BL	Sudden	Clinical diagnosis: physical exam & dietary history	-	History of consumption of puffer fish species.
Poliomyelitis	+	+	+	+/-	Proximal > Distal	Systemic	BL or UL	Sudden		PCR of CSF	Asymmetric paralysis following a flu-like syndrome.
Transverse myelitis	+	+	+	+	Proximal > Distal	Systemic	BL or UL	Sudden	MRI & Lumbar puncture	MRI	History of chronic viral or autoimmune disease (e.g. HIV)
Neurosyphilis	+	+	-	+/-	Generalized	Systemic	BL	Insidious	MRI & Lumbar puncture	CSF VDRL-specifc CSF FTA-Ab -sensitive	History of unprotected sex or multiple sexual partners. History of genital ulcer (chancre), diffuse maculopapular rash.
Muscular dystrophy	+	-	-	-	Proximal > Distal	Systemic	BL	Insidious	Genetic testing	Muscle biopsy	Progressive proximal lower limb weakness with calf pseudohypertrophy in early childhood. Gower sign positive.
Multiple sclerosis exacerbation	+	+	+	+	Generalized	Systemic	NL	Sudden	↑CSF IgG levels (monoclonal)	Clinical assessment and MRI	Blurry vision, urinary incontinence, fatigue
Amyotrophic lateral sclerosis	+	-	-	-	Generalized	Systemic	BL	Insidious	Normal LP (to rule out DDx)	MRI & LP	Patient initially presents with upper motor neuron deficit (spasticity) followed by lower motor neuron deficit (flaccidity).
Inflammatory myopathy	+	-	-	-	Proximal > Distal	Systemic	UL or BL	Insidious	Elevated CK & Aldolase	Muscle biopsy	Progressive proximal muscle weakness in 3rd to 5th decade of life. With or without skin manifestations.

• Stroke associated with COVID-19 should be differentiated from other diseases that can have similar presentation as stroke. These include-
  • Other COVID-19 associated neurological complications: Encephalitis, Encephalopathy, Meningitis, Seizure, Guillain-Barre syndrome, polyneuritis cranialis
  • Neurologic in non-COVID patients: Transient Ischemic Attack, Brain abscess, Hemiplegic Migraine, Seizures, Postictal paralysis, Cerebral venous sinus thrombosis, Cerebral neoplasm, Cerebral Infections (Meningitis, Encephalitis, Brain Abscess, Progressive multifocal leukoencephalopathy)
  • Traumatic: Epidural hematoma, Subdural hematoma, Traumatic brain Injury
  • Toxic and/or Metabolic: Hypoglycemia, Hyponatremia, Drug intoxication
  • Syncope
  • Lyme's disease
  • Ear and Nose diseases: Benign Paroxysmal Positional Vertigo, Vestibular Neuronitis, Meniere's Disease
  • Psychiatric: Malingering, Conversion disorder
  • Paraneoplastic syndromes
  • Autoimmune disorders: Multiple Sclerosis, Acute inflammatory demyelinating polyradiculoneuropathy(Guillain-Barre syndrome)

• Stroke in COVID-19 positive patients vs. Stroke in non-COVID-19 patients: A retrospective cohort study (15th March,2020 to 19th April,2020) conducted by Yaghi et. al. in hospitalized patients in New York Healthcare systems compared stroke characteristics in patients with and without COVID-19. This study included 3,556 COVID-19 positive patients, out of which 32 patients were diagnosed with ischemic stroke based on imaging. These COVID-19 positive stroke patients were then compared with 46 hospitalized stroke patients without COVID-19. Based on findings of this study-
  • Younger patient population (average age-63 years) as compared to relatively older patient population (average age-70 years) in non-COVID-19 patients.
  • Severe stroke (National Institutes of Health Stroke Scale- average score 19) as compared to non-COVID patients with lesser average score (8) seen on National Institutes of Health Stroke Scale
  • Higher D-dimer levels which point towards severe blood clotting (10,000 in this study). Relatively lower D-dimer levels (525 in this study) were seen in non-COVID patients.
  • Mostly Cryptogenic stroke seen in COVID-19 patients.
  • Increased mortality seen in COVID-19 patients.
  • Most of COVID-19 patients did not have any history of prior stroke (only 3.1% reported stroke history) as opposed to non-COVID patient group in which prior history of stroke was reported in 13%.
  • Non-COVID patients were more likely to have higher blood pressure levels.

• Further studies are going on to understand the clinical characteristics specific to stroke in COVID-19 patients. It has been observed that the findings vary in different countries possibly due to racial/ethnicity variations. Since strokes have been reported in critically ill COVID-19 patients, hence, it is difficult to diagnose stroke in intubated and sedated COVID-19 patients.

• Stroke in COVID-19 positive patients vs. Stroke in Influenza patients: Out of 1916 COVID-19 patients (Emergency Department visits or were hospitalized with COVID-19) in retrospective cohort study which included patients from two academic hospitals in New York, 31 patients (1.6%) with median age 69 years, experienced acute ischemic stroke. The majority of these patients were men (58%). 8 patients (26%] had initial presentation as stroke while 23 had stroke over the course of the disease after testing positive for COVID-19.

• Based on this study, the COVID-19 patients have much higher incidence of stroke when compared to influenza patients.