Neuropsychiatric manifestations of hospitalized patients with coronavirus disease 2019 during the second wave in Egypt

Since the end of 2019, pneumonia of unknown cause was diagnosed among a group of patients in Wuhan, China. A new coronavirus was isolated from respiratory system cells among them which was named 2019-nCoV [1]. Egyptian government announced the 1st case in the country on 14th February and declared partial lockdown on March 25th [2].

Corona viruses contain a positive-sense single-stranded RNA which is enclosed in an envelope-like capsid with spikes, which resemble solar corona and COVID-19 is the 7th member of the family of coronaviruses that infect humans [1]. It can be transmitted between humans directly via aerosols, tears, saliva, feco-oral secretions, semen, and mother-to-child or indirectly via fomites [3].

COVID-19 mainly affects respiratory system causing fever, cough, dyspnea but also can affect other systems including nervous system through neuroinvasion directly by the virus via peripheral nerves, olfactory bulb or systemic circulation, or indirectly via immune response precipitating neuroinflammation causing neurological and psychiatric disorders [4] (Orsini and colleagues, 2020).

Previous studies showed that COVID-19 infection and vaccine are associated with higher prevalence rates of psychiatric and neurological manifestations. Previous studies reported prevalence of neurological manifestations among COVID-19 patients varies from 36.4%: 82.3% [5, 6] and those of psychiatric manifestations vary from 18.1%: 55.7% [7, 8].

COVID-19 infection-associated neurological manifestations include ischemic strokes, transient ischemic attacks, intracranial hemorrhage [9], cerebral venous sinus thrombosis, headache, seizures [10], olfactory and gustatory dysfunction [6], Guillain–Barré syndrome and encephalitis [11].

A study investigated neurological problems in the context of COVID-19 infection in Egypt and found out that most manifestations were optic neuritis, seizures, and ataxia, while in rare cases, acute ischemic stroke, and cerebral venous sinus thrombosis developed [12].

Another study conducted et al.-Azhar University Hospitals reported that neurological manifestations included headache (78.0%) taste and smell impairment (74.0%), myalgia (62.0%) and dizziness (58.0%). It was also shown that 30 patients (60.0%) died among patients with neurological affection while in patients without neurological affection only 13 patients (26.0%) died (p = 0.001) suggesting that neurological manifestations are independent predictor of mortality [OR (95% CI): 0.35 (0.14–0.88), p = 0.025] [13].

On the other hand, psychiatric manifestations associated with COVID-19 infection include delirium [14], mood, psychotic and anxiety disorders [15], and stress, adjustment and sleep disorders [16].

According to [15], hospitalized COVID-19 patients showed intracranial hemorrhage in 1.3%, ischemic stroke 4.38%, Guillain–Barré syndrome (GBS) 0.22%, encephalitis 0.24%, mood disorder 14.7%, anxiety disorder 16.4%, and psychotic disorder 2.9%.

An observational cross-sectional study was conducted on 203 COVID-19 patients who attended the COVID-19 outpatient clinic in Kasr Al-Ainy hospital, Egypt, and reported that most of the patients had extremely severe depression, anxiety, and stress (65%, 77.8% and 48.3%, respectively), while insomnia was moderate to severe in 36% of the sample. Anxiety, stress, and depression were positively correlated with insomnia severity index score [17].

There are currently not enough data regarding prevalence of neurological and psychiatric manifestations among Egyptian hospitalized COVID-19 patients.

We aimed in this study to determine neuropsychiatric manifestations in COVID-19 hospitalized patients and to find out possible sociodemographic and clinical risk factors.

A cross-sectional observational study conducted at Ain Shams university isolation hospitals during the period from June 2021 to August 2021 and included 110 hospitalized COVID-19 patients. The study was approved by the Ethical Committee of faculty of medicine, Ain Shams University, Egypt. The research was completed in accordance with Helsinki Declaration. We included hospitalized Egyptian patients who were positive COVID-19 RT-PCR. Patients who were COVID-19 RT-PCR test negative during examination or those who refused to sign the informed consent were excluded.

The researcher had interviewed patients presented with COVID-19 infection and admitted at Ain Shams university isolation hospitals (ICU, intermediate care unit or ward). ICU admission criteria include oxygen requirements equal or superior to 6–8 l/min to reach a peripheral oxygen saturation ≥ 90–92%, respiratory failure, shock, acute organ dysfunction, and patients at high risk for clinical deterioration [18]. Then the researcher applied the following: careful history taking from patients or from their doctors, full neurological examination, COVID-19 severity criteria scoring system, MMSE (Mini-Mental State Examination), SCID1 (Structured Clinical Interview for DSM-IV) questionnaire and recording neuroimaging and laboratory tests results (including creatinine, AST, ALT, bilirubin, D-dimer, LDH, CRP, serum ferritin) done to the patient if available to confirm diagnoses.

A short-predesigned sheet including age, gender, education, residency, occupation (health care worker or not), past and current general medical history, past and current psychiatric history, clinical symptomatology of COVID infection, place of admission (ICU, intermediate care unit or ward), duration since admission.

COVID-19 severity criteria scoring system [19, 20]: It classifies COVID-19 patients into 4 categories; asymptomatic to mild, moderate, severe and critical: (1) asymptomatic to mild patients may be asymptomatic or have common cold-like symptoms; (2) moderate patients have a cough and fever (≥ 37.5 °C); (3) severe patients have suspected severe pneumonia, that is, a cough and ≥ 38 °C fever lasting over 3 days; and (4) critical patients have suspected critical pneumonia if they have had shortness of breath for over 1 day and a respiratory rate of 30/min or over.

Structured neurological examination sheet designed by Ain Shams University hospital neuropsychiatry department. We defined neurological problems in the context of COVID-19 as the following: Stroke: we considered stroke in patients with acute onset of a vascular insult. This insult can be diagnosed using CT or MRI. Encephalitis: we defined encephalitis as an altered mental status of more than 24 h. The presence of compatible acute lesions on brain MRI and CSF findings is also diagnostic. Seizures and/or focal neurological signs in the absence of encephalitis are diagnostic. Guillain–Barré syndrome: we defined Guillain–Barré syndrome (GBS) according to the established diagnostic criteria. We defined headache according to The International Classification of Headache Disorders 3rd Edition (ICHD-3).

Mini-Mental State Examination: [21], the Arabic version [22]. A short, standardized form was devised for the serial testing of the cognitive mental state in patients on a neurogeriatric ward, as well as for consecutive admission to a hospital. It was found to be quick, easy to use, and acceptable to patients and testers. The used Arabic version was translated by [22]. Furthermore, according to [23], using the Mini-Mental State Examination to screen for delirium showed an acceptable sensitivity of 88% with a specificity of 54%.

The Structured Clinical Interview for DSM-IV Axis-I Disorders (SCID-I) [24]: the Structured Clinical Interview for DSM-IV Axis-I Disorders (SCID-I) is a clinician-administered, semi-structured interview for use with psychiatric patients or with non-patient community subject, who are undergoing evaluation for psychopathology. The SCID-I was developed to provide broad coverage of psychiatric diagnosis according to DSM-IV. It was designed to be more efficient and simpler to use than other existing instruments and, consequently, to require less time for administration. It was done to demonstrate past co-morbidities of these disorders and to exclude current co-morbidities [24]. It took 30 min in average to be applied.

All data were recorded, and statistical analyses were carried out using the statistical package for the social sciences (SPSS, 25th version). The results were tabulated, grouped, and statistically analyzed using the suitable statistical parameters. For description analysis, data were expressed as mean values and SD for parametric numerical data, while median and interquartile range (IQR) for non-parametric numerical data, and frequency and percentage of non-numerical data. We also used the student T test to assess the statistical significance of the difference between two study group means. Mann–Whitney test (U test) was used to assess the statistical significance of the difference of a non-parametric variable between two study groups. Chi-square test was used to examine the relationship between two qualitative variables. Fisher’s exact test was used to examine the relationship between two qualitative variables when the expected count is less than 5 in more than 20% of cells. For all tests, a significance level of P less than 0.05 was predetermined. P value was used to indicate the level of significance (P40.05: insignificant; P 0.05: significant).

A total of 158 patients hospitalized in Ain Shams university isolation hospitals were examined by the researcher, 48 of them were excluded due to having negative RT-PCR on time of examination. The remaining 110 participants had mean age of 56 ± 18 years old, most of the study sample was illiterate, unemployed, tobacco smokers and living in urban areas. 61% of the sample had past medical history of chronic illnesses, with the most common being hypertension followed by diabetes mellitus. Most of the study sample was of severe to moderate infection severity. With regard to place of admission, most of the study sample was admitted at intermediate care unit (IMCU), followed by ward group then intensive care unit (ICU). The rest of clinical characteristics of the sample are shown in Table 1.

Moving to the prevalence of neurological manifestations, 75.5% of the study participants had neurological manifestations, central nervous system manifestations seen in 62.7% while peripheral nervous system manifestations seen in 45.5% of the sample. The most common neurological manifestations seen were headache (50.9%), hypogeusia (24.5%), hyposmia, paresthesia (23.6% each) and coma (15.5%), as shown in Fig. 1. After exclusion of 17 patients who could not be examined by MMSE due to being aphasic or in coma, psychiatric manifestations were seen in (61.5%) out of the remaining 91 patients. The most prevalent psychiatric disorders were delirium (30.8%), depression (19%), and adjustment disorder (17.5%), as shown in Fig. 2.

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Upon assessing the characteristics of headache, tension headache was the most common type (62.5%), followed by migraine (30.4%), then headache of increased intracranial tension (5.4%) and sinus headache (1.8%). Moving to types of seizures seen, the most common type was generalized tonic clonic seizures (77.8%) followed by focal seizures (22.2%).

The current study showed that factors affecting occurrence of neurological manifestations include hypertension (P-value = 0.011), COVID-19 severity (p-value = 0.022), place of admission (p-value = 0.002), having myalgia, dyspnea or fever on presentation (p-value = 0.006, 0.016 and 0.036, respectively), and having high levels of LDH and ALT (p-value = 0.014 and 0.01, respectively), while other clinical and sociodemographic factors are not statistically significant as shown in Table 2.

In regard to factors affecting occurrence of psychiatric manifestations, the current study showed that leukocytosis is associated with higher occurrence of psychiatric manifestations (p-value = 0.039). No significant statistical correlation was seen with other sociodemographic and clinical characteristics screened for among the study sample, despite higher percentage of psychiatric disorders among female patients (p-value = 0.569), living in urban areas (p-value = 0.577) with comorbid ischemic heart disease (p-value = 0.093), who were admitted in ward (p-value = 0.197), as shown in Table 2.

Regarding factors affecting COVID-19 severity include patient’s age (p-value = 0.019), having fever, dyspnea (p-value =  < 0.001, each), cough and diarrhea (p-value = 0.002 and 0.008, respectively), having high body temperature, tachypnea, tachycardia, hypoxia (p-value =  < 0.001, each), lower diastolic blood pressure (p-value = 0.014), as shown in Table 2.

It was found that COVID-19 severity is a significant risk factor for developing neurological manifestations among our sample of COVID-19 patients (p-value = 0.002). Thus, patients with severe and critical COVID-19 infection and patients admitted to IMCU and ICU have higher risk to develop neurological manifestations, as shown in Table 3. However, developing psychiatric manifestations is statistically not significantly related to COVID-19 infection severity with (p-value = 0.1743).

According to previous studies, COVID-19 infection is associated with higher neurological and psychiatric manifestations through neuroinvasion directly by the virus via peripheral nerves, olfactory bulb or systemic circulation, or indirectly via immune response precipitating neuroinflammation as well as psychological effects of unpredicted social and health measures such as quarantine, self-isolation and disruption of personal and social healthcare and lifestyle [19, 25, 26].

The current study showed higher prevalence rates of neurological manifestations (75.5%) versus 36.4%and 46% in [5] and [27] studies, respectively. In comparison to previous studies done during the first wave of the pandemic, the current study showed almost equal or higher prevalence of altered mental status 40.9% versus 31.8% in [6], stroke 4.5% versus 4.6% in [28], intracranial hemorrhage 0.9% versus 0.5% in [28], cerebral venous sinus thrombosis (CVST) 3.6% versus 3.5% in [12], encephalitis 4.5% versus 3.3% in [27], seizure 8.2% versus 2% in [5], CNS fungal infection 4 cases in 2 months (3.6%) versus 15 cases during 6 months as described by [29], and Guillain–Barré syndrome 2.7% versus 0.1% in [30]. This may be because of the different viral variants between the two waves or because of the preformed immunity toward the virus in the second wave causing more severe cytokines storm and higher immune reaction causing more neurological manifestations [4].

The definite mechanisms for these disorders are still under research, but previous studies reported that COVID-19 patients have exaggerated vascular risk factors, proinflammatory, a prothrombotic state, electrolyte disturbance, multiple drugs use, and immune suppressive drugs [31, 32].

Our study reported headache in 50.9% of the participants versus 37.7% and 13.1% reported by [6]and [5], respectively. [33] study and our study showed that tension headache was the commonest type of headache followed by migraine like headache. Studies suggested fever, hypoxia, and dehydration as causes of headache, in addition to trigemino-vascular system invasion by the virus [34].

Encephalitis resembled 4.5% of our study participants. According to [11], CSF analysis of these patients may be normal or shows pleiocytosis. Moreover, CSF PCR for SARS-CoV-2 is found negative for most of the cases.

COVID-19 causes intracranial hemorrhage in different sites as in addition to [35] and [36] reporting lobar intraparenchymal hemorrhages, subdural hemorrhage and subarachnoid hemorrhage, we reported intraventricular hemorrhage. Compatible with our findings [37] reported that cerebrovascular disorders were more prevalent in the COVID-19 pandemic. Surprisingly, compared to prior times, individuals with autoimmune-mediated neurological diseases had higher hospitalization rates than those with other neurological disorders.

The current study showed that neurological manifestations are more common in elder patients with medical co-morbidities such as hypertension, severely and critically infected patients, patients with fever and dyspnea on presentation, and those admitted to IMCU or ICU which is compatible with [30] and [15] studies. This can be attributed to the presence of high viral loads in already immunologically exhausted victims, and they are at risk for infections, electrolyte disturbances, and hypercoagulable state due to immobilization [6]; [27]. Also, this comes in agreement with an Egyptian study which showed that patients with neurological affection are significantly older (54.7 ± 12.8 versus 44.2 ± 18.8 years, p = 0.002) with significantly higher BMI (32.4 ± 7.8 versus 26.3 ± 6.5 kg/m^2, p < 0.001) [13].

The current study showed higher prevalence rates of psychiatric manifestations (61.5%) versus 22.5% and 55.7% in [38] and [7] studies, respectively.

Our study showed higher or almost equal prevalence of delirium 30.8% versus 24.3% in [39], depression 19% versus 14.7% in [15], psychotic disorder 1.6% versus 1.4% in [15] and panic disorder 9.5%versus 4.3% in [40], as our study was done on hospitalized patients who are more prone to suffer from psychiatric disorders especially patients in ICU with severe infection [8].

However, it showed lower prevalence of adjustment disorder17.5% versus 27% in [16], generalized anxiety disorder 1.6% versus 4.5% in [40] and post-traumatic stress disorder 1.6% versus 7% in [41]. This may be because our study was done during the acute infection phase and the criteria of diagnosis of some of these disorders are affected by time [24].

However, a study carried out by [42] where a total of 382 participants with mean age of 41.5 ± 15.0 years old, of whom 72.5% were males were included in the study. 91.6% of participants had all the three studied psychological disorders; depression, anxiety, and stress with most of participants had either severe or extremely severe conditions (13.9 and 75.7 for anxiety, 22.8 and 46.3% for depression, 38.5 and % 19.6 for stress, respectively).

Also a study held in Kasr-Al-Ainy outpatient clinic found that the majority of the sample had extremely severe depression, anxiety and stress (65%, 77.8% and 48.3%, respectively) while insomnia was moderate to severe in 36% of the sample.

This wide range of prevalence can be explained by many factors, starting with the assessment tools, where many studies had different cutoff points for their tools. In addition, COVID-19 related factors should be considered, like the time of assessment (first wave was associated with more stress), the severity of the illness, and the restrictive measures (more measures in winter are associated with more insomnia). Another aspect is the healthcare system in each country, where better systems can detect milder or earlier cases and have better outcomes [43].

In contrast to neurological manifestations, psychiatric manifestations in our study showed no statistical correlation with sociodemographic and clinical data of the patients except leukocytosis (p-value = 0.039) which is partially compatible with previous studies [44]. This shows that psychological and social factors such as fear of death, loneliness, uncertainty about the treatment and coronaphobia play a great role in developing psychiatric manifestations in these patients [45].

However, although both our study and [16] showed similar mean age among patients with psychiatric diagnoses and patient without (55.5 and 54.9 years, respectively), the latter showed that delirium was associated with older age (73.8 ± 15 years). Moreover, [46] reported that COVID-19 patients with depressive or adjustment disorders shows higher IL-6 and CRP levels which means that inflammation associated with COVID-19 infection plays a major role in developing depressive or adjustment disorders. Also, ICU survivors and patients receiving mechanical ventilation show high rates of anxiety, depression, and PTSD [47].

Our study shows that COVID-19 infection is more severe in elder patients, patients presenting with fever, cough or dyspnea and those with tachypnea, tachycardia or hypoxia. However, previous studies reported other factors such as gender, medical co-morbidities as hypertension, leukocytosis, impaired kidney and liver functions [5, 48].

Reliable estimates of neurological and psychiatric prevalence during COVID-19 patients’ hospitalization are important for informing efforts to prevent, treat, and identify causes of these disorders especially in light of recent work revealing a high prevalence of neurological and psychiatric disorders among them.

Although adverse events are not necessarily predictable or preventable, strategies to change or decrease their impact on the COVID-19 patients are available. So, screening for neurological and psychiatric disorders during hospitalization of COVID-19 patients is mandatory for shortening the duration of hospital stay along with improving the outcome and post-infection quality of life. Intervention studies are needed, as screening tools, virtual support groups, family visits through video calls, and treatment protocols adjustment.

The limitation of this study was that it took a snap-shot view of the studied outcomes; therefore, it is difficult to be generalized as there might be other factors affecting the results. Second, including only a small sample size of hospitalized patients in a tertiary health care center to decrease risk of spread of the infection to investigator and others, limits generalization of its findings. Third, high percentage of patients had altered mental status on time of examination (40.9%), hindering further psychiatric assessment of them.

We did not consider medications used in management of COVID-19 patients as a confounding factor for the underlying neurological and psychiatric manifestations due to the over crowdedness of the isolation hospitals and the burn out of health care workers at that time which hindered comprehensive data collection.

Finally, studying patients during isolation where they are still infectious along with the affordability of the hospital hindered the performance of some needed investigations to confirm some of the diagnoses such as electroencephalogram (EEG), nerve conduction velocity (NCV), MRI brain and CSF analysis.

There is high evidence that prevalence of neurological and psychiatric manifestations is high in COVID-19 hospitalized patients. Multiple sociodemographic and medical factors affect their prevalence. Second wave of the pandemic is associated with higher prevalence of neurological and psychiatric disorders. So, early detection and treatment of such disorders improve the quality of life of COVID-19 survivors. It is crucial to increase awareness of the problem of psychiatric and neurological consequences of COVID-19 infection and to screen for COVID-19 infection in patients with neurological or psychiatric disorders even without its common respiratory symptoms.