Dear Sirs,

We report four cases of severe COVID-19 in male patients aged 50–70 with the combination of central and peripheral nervous system disorders occurring unexpectedly late after the first symptoms. Patients had comorbidities and were admitted for acute respiratory distress syndrome due to a proven SARS-CoV-2 infection. All required mechanical ventilation, among whom one needed an extracorporeal membrane oxygenation support.

Several acute neurological syndromes have been associated with SARS-CoV-2 infection, including anosmia and ageusia [1, 2], meningoencephalitis [3, 4], acute hemorrhagic necrotizing encephalopathy [5], axonal or demyelinating polyradiculoneuropathy [6,7,8], polyneuritis cranialis [8]. Like in most of the viral infections that involve nervous system, these manifestations occurred within the first ten days after infectious symptoms. Further away from the onset of the disease, when sedation and neuromuscular blocker were withheld, 67% of the patients with severe COVID-19 develop encephalopathy including prominent agitation, confusion and corticospinal tract signs [9].

In our cases neurological manifestations were detected after mechanical ventilation weaning and extubation (Fig. 1). They consisted of miscellaneous symptoms such as confusion, cognitive dysfunction (memory deficit, frontal syndrome), psychiatric disorders (paranoid delusion, hallucinations), weakness, pyramidal signs, dysautonomia, swallowing dysfunction, vertical supranuclear eye palsy, upper limbs myoclonus, fasciculation and focal muscle atrophy (Table 1). To note, before admission to intensive care unit, patients had no neurological symptom, except for anosmia or ageusia in two of them. One patient had a small acute sub-cortical ischemic stroke on brain MRI. Cerebrospinal fluid (CSF) analysis showed a normal cell count and a moderate increase of protein level in the up to 80 mg/L in two cases. RT-PCR and IgM for SARS-CoV-2 in the CSF were negative in all patients. On EEG, non-rhythmic frontal slow waves were observed in two patients. Three patients had electrophysiological features of acute motor demyelinating polyradiculoneuropathy with delayed distal latencies and F-waves, slowed conduction velocities and conduction blocks (Supplementary Table). The remaining patient had lower motor neuron features in both the upper and lower limbs. Two patients had an additional decrease of sensorimotor potential amplitude compatible with a critical illness neuropathy. Swallowing and eye movement improved within the first week. Given the persistent muscle weakness and electromyographic features suggesting a post-infectious mechanism, an immunoglobulin therapy was introduced for 5 days. Psychiatric symptoms, cognitive impairment and dysautonomia improved thereafter, but myoclonus and motor weakness of the upper limbs persisted 3 weeks after discharge. Three patients required prolonged rehabilitation in a specialized center.

Fig. 1
figure 1

Timelines showing general and neurological symptoms onset, timing of hospital admission and discharge, timing of ICU admission and discharge, and paraclinical examinations and treatments. EEG, electroencephalogram; EMG electromyogram; ICU intensive care unit; IVIg intravenous immunoglobulin; MRI magnetic resonance imagery. P1: Patient 1 (M, 62 y.o), P2: Patient 2 (M, 72 y.o), P3: Patient 3 (M, 50 y.o), P4: Patient 4 (M, 66 y.o). For P2, cerebral and spinal MRI were performed at two different dates (days 49 and 62, respectively)

Full size image
Table 1 Characteristics and management of severe COVID-19 patients presenting with mixed central and peripheral neurological manifestations
Full size table

We describe here delayed mixed central and peripheral disorders as a complication of severe COVID-19. It combines acute encephalopathy and motor demyelinating polyradiculoneuropathy or diffuse lower motor neuron involvement. Persistent cognitive and motor deficit might result from a critical illness, but neurological features differ from critical illness-related encephalopathy and neuropathy. Critical illness-related neuropathy is characterized by a bilateral, symmetric, axonal sensorimotor polyneuropathy resulting in an areflexic tetraplegia, without dysautonomia or cranial nerves palsy. In our patients, clinical and neurophysiological features of peripheral nervous system involvement could partly reflect critical illness neuropathy but most of them are not expected in this context and are thus more likely linked to COVID-19. Abnormal eye movement, swallowing dysfunction and action myoclonus are unusual in critical illness-related encephalopathy and might rather result from COVID19-related brainstem dysfunction in our patients.

Our study suggests a wider spectrum than previously reported of neurological manifestations associated with COVID-19 and further suggests that patients with severe forms of COVID-19 should be systematically screened for neurological complications.