The study was initiated on April 7, 2020 when the clinical characteristics of the first hospitalized participant were assessed. The follow-up of survived cases lasted until November 18, 2020. Primary screening was performed on 1269 inpatients and 873 cases were included in the study (Fig. 1). Of eligible participants, 122 individuals died during hospitalization (case fatality rate: 13.97%) and 751 cases were discharged in 11.41 ± 6.20 (mean ± SD) days. There were 62 participants who were lost to follow-up and 689 individuals completed the study.
3.2. Non-neurological characteristics
The demographic clinical features of included cases during hospitalization were presented in Table 1. There were 551 males (63.7%) and 317 females (36.3%). The mean ± SD age of participants was 60.71 ± 18.14 years and 459 individuals (52.6%) aged over 60 years. The most common non-neurological manifestations were fever (708/873, 81.1%), cough (664/873, 76.1%), fatigue (315/873, 36.1%), and shortness of breath (241/873, 27.6%). Our analysis showed that aging (severity: OR: 1.020, 95%CI: 1.012 to 1.028; death: OR: 1.08, 95%CI: 1.06 to 1.99), male gender (severity: OR: 1.38, 95%CI: 1.03 to 1.86), presence of co-morbidity (OR: 1.43, 95%CI: 1.11 to 1.98; death: OR: 2.81, 95%CI: 1.79 to 4.42), smoking (severity: OR: 1.62, 95%CI: 1.11 to 2.34; death: 2.69, 95%CI: 1.73 to 4.18), hemoptysis (severity: OR: 3.55, 95%CI: 2.01 to 6.28; death: OR: 2.30, 95%CI: 1.21 to 4.36), chest tightness (severity: OR: 3.23, 95%CI: 2.09 to 5.00; death: OR: 2.63, 95%CI: 1.60 to 4.32), and shortness of breath (severity: OR: 2.51, 95%CI: 1.84 to 3.41; death: OR: 9.61, 95%CI: 6.25 to 14.92) were associated with increased odds of severity and/or death in participants.
The most common laboratory abnormalities were elevated CRP (542/873, 61.2%), lymphocytopenia (434/873, 49.7%), elevated LDH (316/873, 35.7%), and neutrophilia (291/873, 33.3%) (Table 2). The statistical analysis showed that the elevated procalcitonin (severity: OR: 2.26, 95%CI: 1.35 to 3.78; death: OR: 5.40; 95%CI: 3.12 to 9.34), elevated LDH (severity: OR: 1.99, 95%CI: 1.49 to 2.65; death: OR: 10.63; 95%CI: 6.53 to 17.24), neutrophilia (severity: OR: 1.68, 95%CI: 1.26 to 2.26; death: OR: 3.10; 95%CI: 2.09 to 4.58), elevated CRP (severity: OR: 1.46, 95%CI: 1.09 to 1.96; death: OR: 6.17; 95%CI: 3.40 to 11.11), leukocytosis (death: OR: 1.62, 95%CI: 1.04 to 2.53), and lymphocytopenia (severity: OR: 1.36, 95%CI: 1.03 to 1.81) were associated with increased odds of severity and/or death due to COVID-19.
3.3. Neurological manifestations
Smell and taste dysfunctions were reported in 561 (64.3%) included cases at the time of admission (hyposmia: 329/561 or 58.6%; anosmia: 232/561 or 41.4%; dysgeusia: 561/561 or 100%). They were more common among females (69.7%) than males (OR: 1.46, 95%CI: 1.08 to 1.96) and also more frequent among non-smokers (66.7%) than smokers (OR: 1.91, 95%CI: 1.32 to 2.77). Co-morbidities were more frequent among cases with normal smell and taste sensations (OR: 1.42, 95%CI: 1.07 to 1.89). There were 28 cases with rhinorrhea and 17 cases with nasal congestion who reported loss of smell sensation. Of 561 participants, 142 individuals (25.3%) reported these symptoms as the first clinical manifestation. Hyposmia/anosmia and dysgeusia were found to be associated with reduced odds of severe cases (OR: 0.69, 95%CI: 0.52 to 0.94) and death (OR: 0.63, 95%CI: 0.39 to 0.95) after adjustment for gender, age, smoking status, co-morbidity, rhinorrhea, and nasal congestion (Table 3).
Myalgia (217/873 or 24.9%), headaches (110/873 or 12.6%), and dizziness (104/873 or 11.9%) were other common neurological symptoms. The incidence rates of these conditions were not significantly different among genders. Headaches had negative correlation with severity (adjusted OR: 0.52, 95%CI: 0.32 to 0.85) and death due to COVID-19 (adjusted OR: 0.37, 95%CI: 0.92 to 0.75) but myalgia and dizziness were not associated (Table 3).
There were 10 cases (1.26%) with COVID-19 who presented cerebrovascular events (Table 4). The mean age was 63.40 years (SD: 20.55). Brain CT scans were performed in all cases and ischemic stroke was found in 7 patients (70%) and 3 cases (30%) were diagnosed with ICH. Of cases with ischemic stroke, mild impairment was observed in 1 case with NIHSS < 5. We found 3 cases with moderate (NIHSS: 5–15), 1 case with moderate to severe (NIHSS: 16–20), and 2 cases with severe (NIHSS > 21) neurological impairments. The ICH score of 4 was calculated in 2 cases and the score of 3 was calculated in 1 patient with ICH. Fever (n = 10), cough (n = 8), fatigue (n = 7), myalgia (n = 3), and headaches (n = 1) were reported in 10.7 ± 2.91 days prior to cerebrovascular events but none were severe COVID-19 cases. Six patients (60%) died in 4.15 ± 2.23 days after hospitalization.
One previously healthy 28 year-old-female was referred to Loghman hospital with status epilepticus as the sole clinical manifestation. No history of physical disorders, head trauma, drug use, or recent respiratory symptoms was reported from parents. Physical examination revealed bilateral mydriatic and non-reactive pupils with downward gaze. The EEG showed moderate to severe diffuse slowing and generalized rhythmic delta activity. She was intubated and received intravenous levetiracetam (3000 mg) and generalized tonic-clonic seizure occurred within 2 hours of drug administration. Intravenous midazolam was, then, added. No other convulsive seizures were developed during hospitalization. Bilateral ground glass opacities were observed in chest CT and the RT-PCR test for COVID-19 was positive. Cerebrospinal (CSF) analysis showed clear appearance with no cells, protein: 79 mg/dl (normal: 15–45), glucose: 135 mg/dl (normal: 45–80), and opening pressure: 22 cmH2O (normal: 6–25). The PCR panel of CSF was negative for herpes simplex and no bacterial or fungal organisms were detected. Other laboratory data showed thrombocytopenia (n = 43,000) at the time of admission but other tests were in normal limits (leukocytes: 5.1 x 103/µL, Na: 142, K: 4.4, Ca: 9.4, Albumin: 3.4, and Mg: 2.1). Urine toxicology analysis for methanol, methadone, benzodiazepines, cannabinoids, methamphetamine, tramadol, and opiates were negative. The primary brain CT scans showed no specific abnormalities but the top of basilar infarction was observed after ten days of hospitalization (Fig. 2A, B). The patient died 16 days after admission.
There were 442 individuals with hyposmia/anosmia and dysgeusia who survived from COVID-19 and completed the study. It was found that after four weeks of discharge, 209 cases (47.3%) fully recovered from these conditions; 181 cases (40.9%) had partial improvements; and 52 cases (11.8%) reported no changes in their smell and taste dysfunctions. The full recovery was reported in 302 individuals (68.3%) after eight weeks of discharge and partial improvements were found among 119 participants (26.9%). Twenty one cases (4.8%) with hyposmia (n = 15) and anosmia (n = 6) reported no changes (Fig. 3). Intermittent parosmia (distortion of odor perception when an odor is present) was reported in 42 cases (9.5%) after 4 weeks and 137 cases (30.9%) after 8 weeks of discharge. Intermittent phantosmia (odor perception in the absence of odor stimulus) was also reported in 11 cases (2.5%) after 4 weeks and 40 cases (9.0%) after 8 weeks of discharge (Fig. 3). These events occurred in 86 cases (48.6%) with recovered hyposmia/anosmia, 83 cases (46.9%) with partial improvements, and eight case (4.5%) with no smell and taste improvements.
Headaches were reported among 37 of 689 individuals after four weeks of discharge (5.3%) and 14 cases (2.0%) after eight weeks. These individuals had no prior history of headaches (e.g. migraine). The severity was mild to moderate and headaches were well-controlled with simple analgesics. No functional impairments were reported among affected individuals due to headaches. There were 21 participants (3.0%) after four weeks and 9 cases (1.3%) after eight weeks of discharge with myalgia. Dizziness was also reported among 9 individuals after 4 weeks that was recovered after 8 weeks of discharge (Fig. 3).
The follow-up was continued in participants with parosmia, phantosmia, no improvements in smell and taste, headaches, and myalgia (Fig. 3). The full recovery was reported in 9 cases (6.6%) with parosmia, 3 cases (5.0%) with phantosmia, 2 cases (9.5%) with no prior changes in smell and taste sensations, 9 cases (64.3%) with headaches, and 4 cases with myalgia (44.4%) after 8 further weeks of follow-up (16 weeks after discharge). Partial improvements were reported in 64 cases (46.7%) with parosmia, 12 cases with phantosmia (30.0%), and 7 cases (33.3%) with no prior changes in smell and taste sensations after 16 weeks of discharge.
Demyelinating myelitis: One 43-year-old-male visited Loghman hospital after 16 days of prior admission with weakness, paresthesia, and paresis of upper and lower limbs. The patient also developed low abdominal pain with urinary retention. No history of similar symptoms and neurological disorders were reported. The initial manifestations due to COVID-19 were fever, fatigue, myalgia, and headaches that were recovered after discharge. Neurological examinations showed reduced forces of upper (4 / 5) and lower limbs (2 / 5). The deep tendon reflexes of all extremities were normal (1+) and Babinski’s sign was present. The position, vibration, and light tough sensations were impaired in lower limbs. The laboratory data including leukocyte count, CRP, and LDH were normal. The CSF analysis showed clear appearance with no cells, protein: 60 mg/dl, glucose: 43 mg/dl, and opening pressure: 18 cmH2O. The PCR panel of CSF was negative for herpes simplex and no bacterial or fungal organisms were detected. The CSF was assessed to detect anti-N-methyl-D-aspartate (NMDA) antibody, oligoclonal band, aquaporin-4 receptor (AQP-4), and myelin oligodendrocyte glycoprotein (MOG) antibodies which were negative. Serological testing for the anti-nuclear antibody, anti-phospholipid antibodies, neuromyelitis optica, anti-NMDA, AQP-4, and MOG antibodies was also negative. The brain and spinal cord MRI showed bilateral thalamic hypersignal lesions (Fig. 2C) with longitudinally extensive transverse myelitis at cervical and thoracic cord levels (Fig. 2D, E). The patient was diagnosed with post-infectious demyelinating myelitis and managed with intravenous immunoglobulin (IVIG) for seven days. Our patient was discharged from hospital after 16 days with significant improvements in forces of upper (5 / 5) and lower limbs (4 / 5).
Guillain-Barré syndrome (GBS): A 46-year-old-female visited Imam Hossein hospital after 21 days of prior admission with weakness and paresthesia of upper and lower limbs as well as bilateral facial paralysis. The initial symptoms due to COVID-19 were fever and dry cough that were recovered after discharge. Neurological examination showed decreased forces of upper (4 / 5) and lower limbs (3 / 5) with mild bilateral peripheral facial nerve palsy. The deep tendon reflexes of all extremities were absent. The CSF analysis showed no cells, protein: 93 mg/dl, glucose: 15 mg/dl, and opening pressure: 18 cmH2O. The EMG-NCV was conducted and acute axonal motor neuropathy (AMAN) variant of GBS was diagnosed. The motor nerve conduction and F-wave response were measured on the median, ulnar, tibial, and peroneal nerves. The sensory nerve conduction was measured using median, ulnar, and sural nerves. The normal NCV without evidence of conduction block, and normal sensory nerve action potential (SNAP) amplitude along with reduced compound muscle action potential (CMAP) amplitude were found in both upper and lower extremities. The electromyographic findings were reduced voluntary recruitment and increased insertional activity. The patient was treated with five consequent days of IVIG but the disease progressed and she developed dyspnea and was intubated. Arrhythmia due to autonomic dysfunction was also developed and pacemaker was inserted. The IVIG was used for further seven days. The symptoms improved gradually and the patient was discharged after 42 days of hospitalizations with improvements in forces of lower limbs (4 / 5).