Encephalopathy and central nervous system symptoms of coronavirus disease 2019: a case series from northern India

Abstract

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results in multi-organ involvement, with increasing evidence of neurological manifestations such as encephalopathy, encephalitis, stroke, and Guillain-Barré syndrome. This case series reports nine patients admitted between November 2020 and May 2021 with COVID-19–related encephalitis, primarily presenting with altered sensorium and other neurological symptoms. Clinical, laboratory, and cerebrospinal fluid (CSF) analysis as well as neuroimaging findings were reviewed. The patients, aged 30 to 88 years (mean age, 64 years), presented with fever, cough, shortness of breath, and altered sensorium. Neurological examination revealed abnormalities such as altered muscle tone, upgoing plantars, and neck rigidity. Laboratory results showed elevated levels of D-dimer, lactate dehydrogenase, and interleukin-6, indicating systemic inflammation and hypercoagulability. CSF was acellular with normal protein and glucose levels, and SARS-CoV-2 reverse transcription polymerase chain reaction was negative. Neuroimaging varied, with some patients showing normal computed tomography and others demonstrating mild meningeal enhancement or lacunar infarcts. The patients received supportive care, including oxygen therapy, remdesivir, dexamethasone, and ceftriaxone. Outcomes ranged from complete recovery to death, with those over 60 years of age or with significant comorbidities facing a higher mortality risk. Neurological manifestations, particularly encephalopathy, are common in COVID-19, with potential mechanisms involving systemic inflammation and microvascular damage rather than direct viral invasion of the central nervous system. Early recognition and management are crucial, especially in older patients or those with comorbidities, in order to reduce the risk of severe complications and mortality.

Introduction

Despite the passage of several years, the coronavirus disease 2019 (COVID-19) pandemic continues to affect people globally. The rapid acquisition of mutations by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has contributed to the ongoing nature of this pandemic, leaving health professionals struggling to manage it effectively [1]. While the virus predominantly presents with pneumotropic symptoms, gastrointestinal, cardiac, and dermatological manifestations are also well documented [2]. Additionally, SARS-CoV-2 has neuroinvasive potential. The presence of angiotensin-converting enzyme 2 receptors in nearly all human tissues, to which the virus attaches itself, explains the multi-organ and neurological involvement observed in COVID-19 [3].

There is growing evidence supporting the manifestation of central nervous system (CNS) symptoms in COVID-19 patients. Mild neurological symptoms such as headache, myalgia, anosmia, and ageusia are common. However, more severe symptoms, including encephalopathy, encephalitis, stroke, and Guillain-Barré syndrome (GBS), though rare, have been described [4,5]. In this report, we present a series of nine cases in which the primary presentation was encephalopathy, and the patients were diagnosed with COVID-19 encephalitis.

Case Report

All enrolled cases had laboratory-confirmed COVID-19, as determined by reverse-transcription polymerase chain reaction (RT-PCR) testing of nasopharyngeal swab specimens, and were admitted to the hospital’s designated COVID-19 care unit.

Case 1

A 70-year-old male was admitted on November 14, 2020 with fever and shortness of breath (SOB), presenting with altered sensorium. His neurological examination revealed a Glasgow Coma Scale (GCS) of E3M4V4, positive Babinski sign, and brisk deep tendon reflexes (DTRs). He had no significant comorbidities. The patient was treated with remdesivir, dexamethasone, ceftriaxone, and oxygen via a non-rebreather mask (NRBM). Laboratory findings showed a white blood cell (WBC) count of 9,220/µL with a predominance of polymorphs (91%) and a platelet count of 88,600/µL. His electrolytes were within normal limits, with sodium 131 mEq/L and potassium 5.8 mEq/L. His blood urea was 45 mg/dL and dextrose was 128 mg/dL. D-dimer was elevated at 458 ng/mL, lactate dehydrogenase (LDH) at 23 U/L, and interleukin-6 (IL-6) at 4,100 pg/mL. His serum ferritin level was 128 ng/mL. Cerebrospinal fluid (CSF) analysis was acellular with normal protein and glucose levels. CSF RT-PCR for SARS-CoV-2 was negative, and computed tomography (CT) of the head was normal. The patient recovered after 2 weeks.

Case 2

A 72-year-old male presented on November 17, 2020 with fever and mild cough associated with altered sensorium. His neurological examination revealed a GCS of E3M3V2, muscle tone abnormalities, positive Babinski, and brisk DTRs. He had no significant comorbidities. The patient was treated with remdesivir, methylprednisolone (MPS), ceftriaxone, oxygen, and required pressure support ventilation (PSV) on day 3. Laboratory findings revealed a WBC count of 11,760/µL with a predominance of lymphocytes (66%) and a platelet count of 130,000/µL. Sodium was 146 mEq/L and potassium was 4.1 mEq/L. Blood urea was 56 mg/dL and dextrose was 110 mg/dL. D-dimer was elevated at 892 ng/mL, LDH at 288 U/L, and IL-6 at 23 pg/mL. Serum ferritin was 4,100 ng/mL. CSF analysis was acellular with normal protein and glucose levels. CSF RT-PCR for SARS-CoV-2 was negative. Neuroimaging was not done, and the patient expired on the 4th day of admission.

Case 3

A 55-year-old male was admitted on October 17, 2020 with fever, cough, and SOB, along with altered sensorium. He had neck rigidity and increased muscle tone, with positive Babinski and normal DTRs. The patient had no comorbidities. He received remdesivir, dexamethasone, and ceftriaxone, along with oxygen via NRBM. Laboratory findings showed a WBC count of 12,810/µL with 86% polymorphs and a platelet count of 229,000/µL. Sodium was 140 mEq/L and potassium was 3.6 mEq/L. Blood urea was 38 mg/dL and dextrose was 124 mg/dL. D-dimer was elevated at 328 ng/mL, LDH at 12.6 U/L, and IL-6 at 116 pg/mL. Serum ferritin was 82 ng/mL. CSF analysis was acellular with normal protein and glucose levels. CSF RT-PCR for SARS-CoV-2 was negative. CT of the head was normal. Unfortunately, the patient expired on the 2nd day of admission.

Case 4

An 88-year-old male was admitted on November 9, 2020 with a fever and mild cough, accompanied by poor sensorium. He had increased muscle tone, with positive Babinski and hyperactive DTRs. There were no significant comorbidities. He was treated with remdesivir, dexamethasone, ceftriaxone, and oxygen via NRBM. Laboratory findings showed a WBC count of 8,700/µL with 76% polymorphs and a platelet count of 180,000/µL. Sodium was 136 mEq/L and potassium was 3.8 mEq/L. Blood urea was 34 mg/dL and dextrose was 98 mg/dL. D-dimer was elevated at 424 ng/mL, LDH at 22 U/L, and IL-6 at 98 pg/mL. Serum ferritin was 74 ng/mL. CSF analysis was acellular with normal protein and glucose levels. CSF RT-PCR for SARS-CoV-2 was negative. CT of the head was normal, and the patient recovered after 2 weeks.

Case 5

A 64-year-old male was admitted on May 7, 2021 with fever, cough, and SOB, along with altered sensorium. On examination, he had normal muscle tone and DTRs, but a positive Babinski sign. The patient had hypertension and diabetes mellitus (DM) as comorbidities. He received remdesivir, dexamethasone, ceftriaxone, oxygen via NRBM, and PSV support later. Laboratory findings revealed a WBC count of 11,600/µL with 78% polymorphs and a platelet count of 240,000/µL. Sodium was 140 mEq/L and potassium was 3.7 mEq/L. Blood urea was 46 mg/dL and dextrose was 122 mg/dL. D-dimer was elevated at 1,280 ng/mL, LDH at 154 U/L, and IL-6 at 120 pg/mL. Serum ferritin was 1,280 ng/mL. CSF analysis was acellular with normal protein and glucose levels. CSF RT-PCR for SARS-CoV-2 was negative. Non-contrast CT of the head was normal, but the patient expired within 48 hours.

Case 6

A 65-year-old male presented on May 14, 2021 with a fever and altered sensorium. His neurological examination revealed normal muscle tone, DTRs, and plantar response. The patient had hypertension and DM. He was treated with remdesivir, dexamethasone, ceftriaxone, and oxygen via NRBM; PSV support was required later. Laboratory findings showed a WBC count of 14,640/µL with 95% polymorphs and a platelet count of 228,000/µL. Sodium was 139 mEq/L and potassium was 4.1 mEq/L. Blood urea was 80 mg/dL and dextrose was 220 mg/dL. D-dimer was elevated at 328 ng/mL, LDH at 28 U/L, and IL-6 at 444 pg/mL. Serum ferritin was 120 ng/mL. CSF analysis was acellular with normal protein and glucose levels. CSF RT-PCR for SARS-CoV-2 was negative. Neuroimaging was not done, and the patient expired after 72 hours.

Case 7

A 35-year-old female was admitted on November 8, 2020 with fever, cough, and altered sensorium, along with seizures. She had a history of Sjögren syndrome and celiac disease. For Sjögren syndrome, she had last received steroids 14 months prior, and was compliant with a gluten-free diet. On examination, she had normal tone, hyperactive DTRs, positive Babinski, and neck rigidity. She was treated with MPS, ceftriaxone, and oxygen via NRBM with PSV support. Laboratory findings revealed a WBC count of 8,600/µL with 82% polymorphs and a platelet count of 140,000/µL. Sodium was 141 mEq/L and potassium was 3.8 mEq/L. Blood urea was 34 mg/dL and dextrose was 108 mg/dL. D-dimer was elevated at 562 ng/mL, LDH at 12.8 U/L, and IL-6 at 2,800 pg/mL. Serum ferritin was 130 ng/mL. CSF analysis was acellular with normal protein and glucose levels. CSF RT-PCR for SARS-CoV-2 was negative. CT showed mild meningeal enhancement, but the patient expired on the 5th day of admission.

Case 8

A 30-year-old female was admitted on May 2, 2021 with fever, SOB, and altered sensorium, along with seizures. She had DM as a comorbidity. On examination, she had increased muscle tone, brisk DTRs, and a positive Babinski sign. She was treated with MPS, ceftriaxone, and oxygen via NRBM with PSV support. Laboratory findings showed a WBC count of 16,300/µL with 85% polymorphs and a platelet count of 266,000/µL. Sodium was 139 mEq/L and potassium was 3.2 mEq/L. Blood urea was 28 mg/dL and dextrose was 98 mg/dL. D-dimer was elevated at 5,000 ng/mL, LDH at 36 U/L, and IL-6 at 725 pg/mL. Serum ferritin was 120 ng/mL. CSF analysis was acellular with normal protein and glucose levels. CSF RT-PCR for SARS-CoV-2 was negative. CT of the head was normal, and the patient’s sensorium improved.

Case 9

A 58-year-old male was admitted on July 6, 2021 with fever, SOB, and altered sensorium. On examination, he had normal muscle tone, normal DTRs, and a positive Babinski sign. He had a history of hypertension. He was treated with remdesivir, dexamethasone, ceftriaxone, and oxygen via NRBM with PSV support. Laboratory findings showed a WBC count of 18,600/µL with 93% polymorphs and a platelet count of 153,000/µL. Sodium was 138 mEq/L and potassium was 4.1 mEq/L. Blood urea was 42 mg/dL and dextrose was 130 mg/dL. D-dimer was elevated at 120 ng/mL, LDH at 725 U/L, and IL-6 at 150 pg/mL. Serum ferritin was 72 ng/mL. CSF analysis was acellular with normal protein and glucose levels. CSF RT-PCR for SARS-CoV-2 was negative. Neuroimaging revealed a lacunar infarct. The patient recovered after 2 weeks.

The clinical presentations of all nine patients are described in Table 1, and laboratory data are compiled in Table 2.

Table 1.

Clinical details of patients

Variable	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6	Case 7	Case 8	Case 9
Age (yr)/sex	70/male	72/male	55/male	88/male	64/male	65/male	35/female	30/female	58/male
Date of admission	November 14, 2020	November 17, 2020	October 17, 2020	November 9, 2020	May 7, 2021	May 14, 2021	November 8, 2020	May 2, 2021	July 6, 2021
Symptoms	Fever/SOB	Fever/mild cough	Fever/cough/SOB	Fever/mild cough	Fever/cough/SOB	Fever	Fever/cough	Fever/SOB	Fever/SOB
Neurological	Altered senses	Altered senses	Altered senses	Poor senses	Altered senses	Altered senses	Altered senses+seizures	Altered senses+seizures	Altered senses
Anosmia/aguesia	None	None	None	None	None	None	None	None	None
Headache	None	None	None	None	None	None	None	None	None
Comorbidities	None	None	None	Hypothyroidism	None	Hypertension, diabetes mellitus	Sjögren syndrome, celiac disease	Diabetes mellitus	Hypertension
CNS examination findings	GCS, E3M4V4	GCS, E3M3V2	Tone, normal	Tone++	Tone, normal	Tone, normal	Tone, normal	Tone, normal	Tone, normal
	Tone++	Tone++	Brisk DTRs	Brisk DTRs	DTRs, normal	DTRs, normal	DTRs, normal	Brisk DTRs	DTRs, normal
	Brisk DTRs	Brisk DTRs	Neck rigidity	Babinski+	Babinski+		Babinski+	Plantars, normal	Babinski+
	Babinski+	Babinski+	Babinski+				Neck rigidity
Treatment received	Rem/Dex/Cef	Rem/MPS/Cef	Rem/Dex/Cef	Rem/Dex/Cef	Rem/Dex/Cef	Rem/Dex/Cef	Rem/MPS/Cef	Rem/MPS/Cef	Rem/Dex/Cef
	O2 by NRBM	Off O2	O2 by NRBM	O2 by NRBM	O2 by NRBM, PSV	O2 by NRBM	O2 by NRBM, PSV	O2 by NRBM, PSV	O2 by NRBM, PSV
		Day 3 PSV
Outcome	Recovered after 2 wk	Expired on the 4th day of admission	Expired on the 2nd day	Recovered after 2 wk	Expired in 48 hr	Expired in 72 hr	Expired on the 5th day of admission	Sensorium improved	Recovered after 2 wk

SOB, shortness of breath; DM, diabetes mellitus; CNS, central nervous system; GCS, glasgow coma scale; DTRs, deep tendon reflexes; Rem, remdesivir; Dex, dexamethasone; Cef, ceftriaxone; O₂, oxygen; MPS, methylprednisolone; PSV, pressure support ventilation; NRBM, non-rebreather mask.

Table 2.

Laboratory findings of patients

Variable	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6	Case 7	Case 8	Case 9
WBC (/µL)	9,220	11,760	12,810	8,700	11,600	14,640	8,600	16,300	18,600
Neutrophils/lymphocytes (%)	91/8	66/23	86/11	76/24	78/24	95/3	82/14	85/13	93/1
Platelet (×10/µL)	88.6	130.0	229.0	180.0	240.0	228.0	140.0	266.0	153.0
Sodium/potassium(mEq/L)	131/5.8	146/4.1	140/3.6	136/3.8	140/3.7	139/4.1	141/3.8	139/3.2	138/4.1
Blood urea (mg/dL)	45	56	38	34	46	80	34	28	42/1.3
Dextrose (mg/dL)	128	110	124	98	122	220	108	98	98
D-dimer (ng/mL)	458	892	328	424	NA	328	562	5,000	NA
Interleukin 6 (pg/mL)	23	288	12.6	22	12	28	12.8	36	120
Serum ferritin(ng/mL)	4,100	NA	NA	NA	1,280	444	2,800	NA	725
CSF analysis
Appearance	Clear	Clear	Clear	Clear	Clear	Clear	Clear	Clear	Clear
Protein(mg/dL)	128	146	116	98	154	124	130	129	150
Glucose(mg/dL)	90	72	82	74	120	98	90	68	72
Cell counts	Acellular	Acellular	Acellular	Acellular	Acellular	Acellular	Acellular	Acellular	Acellular
CSF RT-PCR for SARS-CoV-2	Negative	Negative	Negative	Negative	Negative	Negative	Negative	Negative	Negative
Neuroimaginga)	Normal	Not done	Normal	Normal	Normal	Not done	Mild meningeal enhancement	Normal	Chronic lacunar infarct

WBC, white blood cell; NA, not available; CSF, cerebrospinal fluid; RT-PCR, reverse transcriptase polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

^a)All findings are based on brain computed tomography imaging.

Status of ethical clearance for the study

During the COVID-19 crisis (2022), our institutional ethics committee prioritized original research/studies, and a waiver was given to publish case reports. The authors certify that they have obtained all appropriate patient consent forms.

Discussion

This case series reports nine patients who were diagnosed with COVID-19 and presented with encephalopathy and neurological manifestations. The spectrum of neurological symptoms in COVID-19 has attracted attention due to the increasing number of reports suggesting the virus’s neuroinvasive potential. While respiratory symptoms have been the hallmark of COVID-19, there is growing evidence of its involvement in multiple organ systems, including the CNS [6,7].

In this series, all nine patients exhibited altered sensorium as their primary neurological presentation. This highlights encephalopathy as a common manifestation in patients with COVID-19. Other notable symptoms included seizures, neck rigidity, and altered tone, which were observed in select cases. This is in line with existing literature, which has described encephalitis, encephalopathy, and other CNS complications in patients with COVID-19, including seizures, GBS, and stroke [8,9].

Most patients in our case series were elderly, with the majority >60 years of age (mean age, 64 years). This aligns with the general finding that COVID-19 severity increases with age and comorbidities [10]. Interestingly, although many of our patients had underlying comorbidities, such as hypertension, DM, and cardiovascular diseases, not all exhibited the same degree of neurological involvement, suggesting that other factors, such as viral load and host immunity, could play a role in the development of neurological complications.

The most common laboratory findings in our cases included elevated D-dimer, LDH, and IL-6 levels, which are indicative of systemic inflammation, endothelial damage, and hypercoagulability, all of which are associated with severe COVID-19. D-dimer in particular is often elevated in COVID-19 and has been linked to poor prognosis, especially in the presence of thromboembolic events [11]. Elevated IL-6 levels, a marker of inflammation, were also consistent with severe systemic involvement, including CNS damage.

CSF analysis in all patients was acellular, with normal protein and glucose levels, and CSF RT-PCR for SARS-CoV-2 was negative in all cases. These findings are not unusual in COVID-19–associated encephalopathy and suggest that the observed neurological manifestations may not always be due to direct viral invasion of the CNS. Instead, it is possible that neurological involvement could result from a combination of systemic inflammation, cytokine storm, and microvascular damage, which can lead to secondary damage in the brain [12]. The absence of direct viral RNA in CSF does not rule out neuroinvasion, as SARS-CoV-2 may also affect the CNS via other routes, such as hematogenous spread or through the olfactory bulb [13].

Neuroimaging findings varied, with some patients showing normal CT, while others exhibited mild meningeal enhancement or, in one case, a lacunar infarct. These imaging findings are indicative of mild or moderate CNS involvement, likely due to microvascular damage, an established complication of severe COVID-19 [14]. The patient who showed a lacunar infarct may have had a thromboembolic event, which is consistent with reports of stroke in COVID-19 patients, especially those with severe illness [15].

The outcomes in this case series were mixed. Some patients recovered after treatment with remdesivir, dexamethasone, ceftriaxone, and supportive care, including oxygen therapy, while others, particularly those with more severe comorbidities or delayed presentation, expired within a few days. Factors affecting outcomes have been tabulated in Table 3. These results are consistent with the findings in larger studies, which have shown that older patients and those with significant comorbidities face a higher mortality risk, particularly when they develop complications such as encephalopathy, respiratory failure, or multi-organ dysfunction [10,11].

Table 3.

Comparison of good (recovered) vs. poor outcome (death) factors

Variable	Good outcome (n=4)	Poor outcome (n=5)	p-value	Significance
Age (yr)	57.5 ± 16.4	62.6 ± 18.4	0.570	NS
Comorbidities	2 (50.0)	3 (60.0)a)	>0.999	NS
IL-6 levels (pg/mL)	27.5 (12–120)	144 (12–288)	0.080	Trend
D-dimer (ng/mL)	441 (328–562)	892 (424–5,000)	<0.040	Yes
Platelet count	Mostly normal	Variable	NA	NS
Ventilatory support	NRBM only	PSV required: 4 (80.0); NRBM only: 1 (20.0)	<0.048	Yes

Values are presented as mean ± standard deviation, number (%), or median (interquartile range).

NS, not significant; IL, interleukin; NRBM, non-rebreather mask; PSV, pressure support ventilation; NA, not applicable.

^a)Hypertension, diabetes mellitus, autoimmune diseases.

This case series contributes to the growing body of evidence that highlights the neuroinvasive potential of SARS-CoV-2 and its ability to cause neurological manifestations, particularly encephalopathy. Given the rising number of COVID-19 cases and the emerging evidence of neurological involvement, healthcare professionals need to remain vigilant and recognize these signs early. Further studies, including larger cohort analyses and autopsy studies, are needed to better understand the mechanisms behind CNS involvement and to develop targeted interventions for the neurological sequelae of COVID-19.