On February 24, 2020 a 42-year-old male patient presented in emergency room for persisting dyspnea, diarrhea, and fever (38–39 °C) in the previous 6 days. He had a past mild allergic asthma history, with sporadic salbutamol use, a recent tight contact with a Chinese asymptomatic woman, and a recent travel by train to Milan (the week before the symptoms started). From February 16, 2020, he had cough without mucus production, described as dry and snappy: general practitioner started amoxicillin 2 days after the cough onset. On February 21, he started suffering from dyspnea and went to hospital.
In the emergency room, he underwent a blood sample (emergency checklist) showing increasing PCR without increasing of procalcitonin and normal white blood cell count. Arterial gas analysis showed an oxygen desaturation with mild hypoxemia; chest radiography was negative. D-Dimer, creatine phosphokinase, blood glucose, and hepatic and renal function were normal. After 3 h, he had been tested positive for SARS CoV-2 RNA on polymerase chain reaction (RT-PCR) with a nasopharyngeal swab. The day after repletion test confirmed positivity. General examination showed harsh vesicular murmur with bilateral basal crackles, high respiratory frequency, and no other signs. Neurological examination was negative. Chest CT scan showed patchy ground glass opacities, which tend to be predominantly peripheral and basal widespread areas, with initial consolidation aspects, recognizable to both lungs, especially in the cranial sectors of the upper and lower lobes, with preserved patency of the trachea and its bronchial branches. Patient was transferred to infectious disease department and started azithromycin and chlorochin therapy. He initially underwent not invasive ventilation with 60% inspired fraction (FiO2), with normal blood oxygenation. After 24 h, he had an important decreased saturation (O2 saturation 89–90%, low blood oxygen pressure pO2 = 57 mmHg at gas analysis) and was transferred to intensive care unit (ICU) after oral tracheal intubation. In the early days, he was pronated and had a strong sedation with propofol, midazolam, remifentanil, and a neuromuscular block with curare. From the beginning, he was treated with remdesivir without side effects. On March 11, blood oxygenation improved and anesthetics were reduced gradually; he was extubated and transferred to pneumology department on March 20. He was gradually mobilized, started eating independently with semiliquid food, and started physiotherapy.
On March 30 and April 2, he had been tested negative for SARS CoV-2 RNA (nasopharyngeal swab). Since the first days after extubation, he developed dysarthria with slowness of articulation and low speech speed, with no sure swallowing difficulties (he complained of difficulty in bringing the food bolus down), and tongue movements difficulty, especially in sticking it out of the mouth. A neurological examination showed normal cognitive performance, normal language, and no symbolic function involvement. The cranial nerve examination showed miosis, ptosis, and enophthalmia limited to the right eye (Claude Bernard Horner syndrome); his pupils reacted briskly to light; ocular movements had no limitation nor was diplopia present; there were normal and symmetric mandibular and facial movements and normal cranic sensibility. The lower cranial nerves were normally functioning (no velum palatinum deviation, nor swallowing problems) except for global tongue hypotrophy with sporadic bilateral fasciculation, slow and incomplete extrusion movement both outwards and sideways, slow speech rate with impaired pitch control (Fig. 1). He had diffuse muscle hypotrophy, but strength and muscle tone were normal in all extremities, and no sensory deficits were detected for all modalities. There was no dysmetria on finger-to-nose and heel-to-shin tests. Muscle stretch was normal, but he had hyporeflexia in the upper and in the lower limbs. The plantar responses were flexor bilaterally.
A complete neurophysiological examination showed normal blink reflex and masseteric reflex study, normal electromyography (EMG) findings in masseter, orbicularis oris and oculi, and sternocleidomastoideus and trapezius muscles. In the genioglossus muscle, we found bilateral abundant spontaneous activity (fibrillation potentials, positive sharp waves); after tongue activation, we bilaterally registered a few motor unit action potentials (MUAPs) with low recruitment activity polyphasic morphology, normal amplitude, and mild increase of duration.
Electrophysiology study of the limb nerves showed low amplitude sensitive and motor action potentials with normal morphology and conduction velocity with disto-proximal distribution and F waves with normal latency, indicating a mild axonal polyneuropathy. EMG of proximal and distal limb muscles was normal. Motor and somatosensorial evoked potentials ruled out central pathway injuries showed. Brain magnetic resonance imaging was negative.
The blood workup revealed G-immunoglobulin with mild M-immunoglobulin positivity for CoV-2 virus (IgG anti-SARS CoV-2 15.06 AU/ml, IgM anti-SARS CoV-2 1.21 AU/ml). Anti-gangliosides (GM1, GM2, GM3, GD1a, GD1b, GD3, GT1a, GT1b, GQ1b) and anti-sulfatide antibodies in the serum were examined without any positivity. The cerebrospinal fluid (CSF) examination revealed a normal opening pressure, white blood cell count in the normal range (3 cells/mmc), normal CSF proteins (34 mg/dl), glucose (50 mg/dl, with 82 mg/dl blood level), with normal cytology, sterile cultures, and negative serologies, including RT-PCR for COVID-19 in CSF.
He then was treated with intravenously human immunoglobulin (2 g/kg in 5 days) starting 7 days after his neurological symptom’s onset. The cranial neuropathies improved significantly over the succeeding days, since after the third administration, and he started moving the tongue with more agility, reporting less sialorrhea and less dysarthria.
The control EMG, after 15 days since the last immunoglobulin infusion, showed a reduction of denervation in the tongue with ameliorated inference recruitment pattern, and abundant reinnervation. Patient was discharged at home: he had no swallowing nor salivation problems but only residual mild speech articulation problems (slow speech rate and modestly impaired pitch control).
The second patient, a 67-year-old male patient was admitted to hospital on March 17, 2020, with dry cough since the previous week and rest dyspnea. There was no smoking history nor significant disease in remote anamnesis. In emergency room, chest X-ray showed accentuation of the lung interstitial space at lung bases with ground glass aspects in the lower peri-hilar zone; SARS CoV-2 RNA (through nasopharyngeal swab) was detected. He was hospitalized in the infectious diseases department for an attempt of non-invasive ventilation with continue positive pressure (cPAP) but after 24 h was transferred to intensive care unit for acute respiratory failure (ARDS) after orotracheal intubation. He was treated with Ceftazidime and Avibactam, and he also developed a Klebsiella pneumoniae sepsis. During ICU staying, especially in the pronation phases during ventilation, he was treated with anesthetics (Propofol, Remifentanil, Midazolam, Ketamine) and noradrenalin for hemodynamic sustain. After tracheostomy, on April 14, he was extubated and transferred to pneumology department: he had weakness, especially in superior limbs, and he was scarcely reactive to the surrounding ambient. He had dysphagia for liquid without inhalation and difficulty moving the food bolus in the mouth, slow word articulation. The neurological examination showed hypotrophic tongue in the left side, with right deviation at rest and left deviation during protrusion. No other signs were present at cranic examination (normal pupils, ocular movement, other motor and sensitive function of cranic nerves). At segmentary level, there were mild hyposthenia, greater in proximal superior limbs, without sensibility involvement. Tendon reflexes were everywhere hypo-valid but not absent. Indifferent cutaneo-planctar response was detected bilaterally. A complete neurophysiological examination showed denervation in the left hypoglossus nerve, without other nerves involvement (Fig. 2). Electroneuromyography at 4 limbs showed mild amplitude reduction of sensitive and motor action potentials in all examined nerves (symmetrical and disto-proximal distribution) with mild denervation EMG pattern in arm proximal muscles. CSF analysis showed albumin-cytologic dissociation (52 mg/dl CSF protein, with 2 cells/mmc, normal glucose and cytology): negative was rRT-PCR for COVID-19 in CSF such as serum anti-ganglioside antibodies. Cerebral and cervical MRI was negative.
At the time of beginning of these neurological symptoms, SARS CoV-2 test through nasopharyngeal swab was negative (April 26). Intravenous human immunoglobulin treatment (2 g/kg in 5 days) was started, and since the beginning, there was a significative improvement, confirmed also with neurophysiological examination. The patient was subsequently transferred to rehabilitation hospital.