Mixed central and peripheral nervous system disorders in severe SARS-CoV-2 infection.

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 [6-8], 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

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)

Table 1

Characteristics and management of severe COVID-19 patients presenting with mixed central and peripheral neurological manifestations

ID age sex	Comorbidities	Delay between inaugural symptoms and admission to:	Inaugural symptoms	Neurologic features at evaluationa	MRI	EEG	EMG (main features)	SARS-CoV-2 RT-PCR Serologya	CSFb WCC/Protein mg/L SARS-CoV-2 tests	Severity of ARDSc and medical care
1, 62, M	Hypertension, diabetes mellitus	Hospital: 10 days, ICU: 12 days	Fever, cough, ageusia, dyspnea	Confusion, dysexecutive syndrome, memory deficit, swallowing disorders, left facial palsy, right UL weakness (2/5) with bilateral atrophy of the first palmar interosseous, left UL and LL strength 4/5, ataxia, postural and action myoclonus, lower limb areflexia, upper limb hyperreflexia, dysautonomiad, GSC 15, mRS 5 (aday 21)	Recent ischemic stroke in right middle cerebral artery territory (Brain MRI) Normal spinal cord MRI	Global slowing (5–6 Hz) Bilateral and frontal, disphasic, non-periodic slow activity (2 Hz)	Demyelinating asymmetric motor polyradiculo neuropathy and moderate axonal sensorimotor neuropathy of the four limbs	Positive RT-PCR in nasopharyngeal swab, + IgM, + IgG in plasma (aday 13)	0 / 45 negative RT-PCR,- IgM, + IgG, No intrathecal synthesis	Mild ARDSe Hydroxychloroquine sulfate 600 mg Azithromycin 250 mg, ICU, V, no PP, IVIg 0.4 g/kg, Rehabilitation center after 36 days, mRS 2
2, 72, M	Hypertension, Diabetes mellitus, Obesity, (BMI = 31.5), Urothelial carcinoma in remission	Hospital:15 days, ICU: 17 days	Fever, cough, dyspnea	Confusion, paranoid delusion, visual and auditory hallucinations, frontal syndrome, memory deficit, swallowing disorders, tetraparesis (UL and LL strength 2/5), ataxia, UL rest, postural and action myoclonus, slowing of eye movement saccades, four limbs hyperreflexia and neurogenic pain, dysautonomiad, GSC 14, mRS 5 (aday 44)	Normal brain and spinal cord MRI	Global slowing (5–6 Hz)	Demyelinating motor polyradiculoneuropathy and moderate to severe axonal sensorimotor neuropathy of the four limbs	Positive RT-PCR in nasopharyngeal swab, + IgM,—IgG in plasma, (aday 18)	0 / 74, negative RT-PCR,—IgM, + IgG, No intrathecal synthesis	Mild to moderate ARDSe Hydroxychloroquine sulfate 600 mg, Azithromycin 250 mg QT prolongation, Pregabalin 300 mg per day, ICU, V, no PP IVIg 0.4 g/kg, Rehabilitation center after 50 days, mRS 4
3, 50, M	Diabetes mellitus	Hospital: 18 days, ICU:20 days	Cough, dyspnea	Confusion, paranoid delusion, frontal syndrome, memory deficit, swallowing disorders, tetraparesis, (UL strength 2/5 and LL strength 3/5), bilateral atrophy of the first palmar interosseous, ataxia, UL rest, postural and action myoclonus, slowing of eye movement saccades, four limbs hyperreflexia, bilateral ankle clonus, dysautonomiad, GSC 14, mRS 5 (aday 54)	Normal brain and spinal cord MRI	Posterior and metric global slowing (6 Hz) bilateral frontal paroxysmal slow, delta waves	Lower motor neuron involvement with denervation of the four limbs, normal motor evoked potential amplitude	Positive RT-PCR in nasopharyngeal swab + IgM, + IgG in plasma (aday 19)	5 / 81 negative RT-PCR—IgM, + IgG, No intrathecal synthesis	Moderate to severe ARDSe, Hydroxychloroquine sulfate 600 mg, Azithromycin 250 mg Methylprednisolone 1 g, ICU, ECMO, V, PP (× 1), IVIg 0.4 g/kg, Rehabilitation center after 76 days, mRS 4
4, 66, M	Obstructive sleep apnea syndrome	Hospital: 10 days, ICU: 12 days	Cough, Dyspnea, Anosmia, Diarrhea	Confusion, paranoid delusion, visual hallucinations, frontal syndrome, memory deficit, tetraparesis (UL and LL strength 3/5), ataxia, UL postural and action myoclonus, UL hyperreflexia, LL areflexia, dysautonomiad, GSC 15, mRS 4 (aday 42)	Normal brain and spinal cord MRI	Normal	Demyelinating motor polyradiculo neuropathy of the four limbs	Positive RT-PCR in nasopharyngeal swab,—IgM, + IgG in plasma (aday 10)	1 / 22, negative RT-PCR,- IgM, + IgG, No intrathecal synthesis	Mild to severe ARDSe, Hydroxychloroquine sulfate 600 mg, Azithromycin 250 mg (day 11–18) Methylprednisolone 1 g (day 20 to 26) ICU, V, PP (× 6) IVIg 0.4 g/kg, Discharged at home after 40 days mRS 2

BMI body mass index; CSF cerebrospinal fluid; ECMO extracorporeal membrane oxygenation; EEG electroencephalogram; EMG electromyogram; GSC Glasgow scale; ICU intensive care unit; IgM immunoglobulin M; IgG immunoglobulin G; IVIg intravenous immunoglobulin; LL lower limb; UL upper limb; MRI magnetic resonance imaging; mRS, modified Rankin Scale; NA not applicable; PP prone position; RT-PCR real-time polymerase chain reaction; V mechanical ventilation; WCC white cell count (µL)

aTime after inaugural symptoms

bCerebrospinal fluid analysis was performed at the time of neurological examination

cSevere Acute Respiratory Distress Syndrome (ARDS): PaO2/FiO2 < 100; moderate ARDS: PaO2/FiO2 < 200; mild, ARDS: PaO2/FiO2 < 300; PaO2/FiO2 ratio was calculated using the arterial Pressure of oxygen (PaO2) and the fraction of inspired oxygen (FiO2) in mechanical ventilated patients

dDysautonomia: orthostatic hypotension, constipation

ePatient 1 (PaO2/FiO2): day 1: 208, day 2: 280, day 3: 240, day 7: 218; Patient 2 (PaO2/FiO2): day 1: 224, day 2: 220, day 3: 204, day 7: 174; Patient 3 (PaO2/FiO2): day 1: 140, day 2: 203, day 3: 78, day 7: 44; Patient 4 (PaO2/FiO2): day 1: 75, day 2: 234, day 3: 162, day 7: 69

mRS was defined as: 0: No symptoms at all; 1:No significant disability despite symptoms; able to carry out all usual duties and activities; 2:Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance; 3:Moderate disability; requiring some help, but able to walk without assistance; 4:Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance; 5:Severe disability; bedridden, incontinent and requiring constant nursing care and attention

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.

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 23 kb)