Rule Out Alternative Causes Before Attributing Acute, Haemorrhagic, Leukoencephalitis (AHLE) to COVID-19

We read with interest the article by Hutto et al. about a 22 years old male who developed rapidly sequential headache, numbness of both arms, gait disturbance, and respiratory insufficiency requiring mechanical ventilation, 2 months after a compound infection with SARS-CoV-2 and influenza A ¹ . COVID-19 had manifested with ageusia, anosmia, myalgia, and dyspnoea and had completely resolved without sequelae after 1 week under outpatient management ¹ . Neurological work-up revealed spino-medullary acute, haemorrhagic leukoencephalitis (AHLE, Weston Hurst syndrome) which partially resolved upon administration of steroids, plasmapheresis, cyclophosphamide, and intravenous immunoglobulins (IVIG) ¹ . The study is appealing but raises concerns that need to be discussed.

We do not agree with the notion that myelitis in the index patient was triggered by SARS-CoV-2 ¹ . Considering the latency of 2 months between onset of COVID-19 and the onset of neurological compromise, a causal relation is rather unlikely. Neurological abnormalities usually develop during the acute phase of COVID-19 within 4 weeks after onset of COVID-19 ² . If neurological abnormalities newly develop beyond this limit, they are usually due to alternative etiologies and not related to SARS-CoV-2.

Since a causative connection between COVID-19 and Weston Hurst syndrome is unlikely in the index case, alternative causes should be considered. These include tuberculosis, sarcoidosis, lymphoma, CLIPPERS, and HIV.

Missing is the determination of cytokine and chemokine profile in the cerebrospinal fluid (CSF). Particularly interleukin-6 (IL-6), IL-8, IL-1a, and TNF-alpha have been shown upregulated in patients with neuro-COVID ³ .

Unexplained remained the episode of non-responsiveness at hospital day 12. We should be told if the patient experienced a syncope, a transitory ischemic attack, or a seizure. We should be told if epileptiform discharges were recorded on electroencephalography (EEG). Did he ever receive anti-seizure drugs?

Manifestations of neuro-COVID not only include stroke, encephalopathy, encephalomyelitis, and Guillain-Barre syndrome (GBS) but a number of other neurological abnormalities. These include seizures, cerebral vasculitis, immune encephalitis, hypophysitis, cerebellitis, ventriculitis, intracerebral bleeding, subarachnoid bleeding, Tolosa Hunt syndrome, reversible, cerebral vasoconstriction syndrome (RCVS), posterior reversible encephalopathy syndrome (PRES), multiples sclerosis, neuromyelitis optica spectrum disorder, pontine myelinolysis, venous sinus thrombosis, Wernicke encephalopathy, pseudotumor cerebri, opsoclonus myoclonus syndrome, transverse myelitis, myasthenia, myasthenic syndrome, myositis, Parsonage Turner syndrome, and rhabdomyolysis.

Missing is the discussion if quadriplegia was clinically characteristic of a central nervous system (CNS) or peripheral nervous system (PNS) origin. We should be told if tendon reflexes were increased or reduced, if pyramidal signs were present or absent, and if muscle tone was increased or decreased.

Further arguments against AHLE in the index case are that CSF protein was normal and the cell count was normal.

Overall, the interesting study has several limitations and inconsistencies that call the results and their interpretation into question. Clarifying these weaknesses would strengthen the conclusions and could improve the status of the study. Given the latency of 2 months between onset of COVID-19 and onset of AHLE, alternative causes of the described spino-medullary abnormalities should be considered.

ORCID iD

Josef Finsterer https://orcid.org/0000-0003-2839-7305