Division of Neurology, Medical Department, Sungai Buloh Hospital, Ministry of Health, Selangor, Malaysia
Corresponding author: Tien Lee Ong, MBBS (IMU), MRCP (UK) Division of Neurology, Medical Department, Sungai Buloh Hospital, Ministry of Health, 47000 Sungai Buloh, Selangor, Malaysia / Tel: +603-61454333 / Fax: +603-61454222 / E-mail: ongtienlee@gmail.com
• Received: November 26, 2021 • Revised: January 17, 2022 • Accepted: January 25, 2022
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Catatonia is an underrecognized fatal syndrome, with patients presenting with prominent motor and behavioral abnormalities due to underlying psychiatric or medical illnesses. Catatonia can occur in critically ill patients and has been reported in novel coronavirus disease (COVID-19) infection [1,2]. Herein, we report 4 cases of COVID-19-associated catatonia. We were given written consent to disclose the information reported.
Case 1 is a 25-year-old male patient with no prior medical illness. He was admitted with a seven-day history of fever, restlessness, disorientation, persecutory delusion, and insomnia. He tested positive for COVID-19 by reverse-transcriptase polymerase chain reaction (PCR) from a nasopharyngeal swab. Oral risperidone at 0.5 mg twice daily was prescribed to control his abnormal behavior. His mental status gradually worsened, and he was referred to neurology department two days later. Upon review, he was disorientated and had significant bilateral upper limb postural tremor. The following day, he deteriorated and became stuporous and immobile, with staring, mutism, and limb rigidity (Supplementary Video 1, segment 1 in the online-only Data Supplement). He was afebrile with no other features of autonomic dysfunction. Cerebrospinal fluid (CSF) analysis was normal, but he had rapidly declining renal function and elevated serum creatine kinase (> 7,800 U/L), suggesting malignant catatonia progressing to neuroleptic malignant syndrome (Table 1). Risperidone was withheld, and he was intubated and sedated with immediate dialysis support. Plasma exchange was initiated due to concern of immune-related encephalitis, but a limbic encephalitis antibody panel was not available. However, he developed sepsis with Acinetobacter pneumonia hindering further plasma exchange and, despite antibiotics, he succumbed to the infection.
Case 2 is a 51-year-old prisoner with schizophrenia and a history of marijuana abuse, who was admitted for COVID-19 infection. He had progressive bilateral lower limb stiffness one week prior to admission and was sent in from a local jail due to altered consciousness. He was treated with intravenous dexamethasone for his COVID-19 pulmonary infection, but his mental status did not improve. He was referred to neurology department on day eight of admission. Upon assessment, he was stuporous, immobile, not responding to painful stimuli, and had a pillow sign with rigidity of the upper and lower extremities (Supplementary Video 1, segment 2 in the online-only Data Supplement). A diagnosis of catatonia was made, and he was given oral clonazepam. Immunotherapy was not offered due to concern of superimposed bacterial lung infection on his chest CT scan. His brain MRI and CSF studies were normal (Table 1). Four days after clonazepam was titrated to 2 mg three times daily, he showed marked improvement in alertness and rigidity. He remained inpatient for an additional 14 days for rehabilitation. Clonazepam was tapered down and discontinued prior to discharge back to prison, with complete resolution of catatonia and recommencement of his antipsychotics for schizophrenia.
Case 3 is a 40-year-old female patient with no prior medical or psychiatric illness, who was admitted with an eight-day history of fever and cough. Her COVID-19 PCR from a nasopharyngeal swab was positive. She had difficulty sleeping for two days prior to admission and was brought in for abnormal behavior with agitation, food refusal, persecutory delusion, and self-harm. She was given olanzapine 5 mg nightly from the start of her admission. Her CSF findings, brain MRI and autoimmune encephalitis panel were normal (Table 1). On day nine of admission, she became withdrawn with mutism, staring, pillow sign, limb rigidity, and waxy flexibility (Supplementary Video 1, segment 3 in the online-only Data Supplement). Antipsychotic treatment was immediately withheld; she was given clonazepam 2 mg twice daily with gradual recovery five days later. Her condition improved further with rehabilitation, and clonazepam was tapered off before she was sent home, with no recollection on the events that occurred during admission and the week prior.
Case 4 is a 67-year-old male patient with diabetes, hypertension, and chronic renal disease, who was admitted for COVID-19 infection presenting with a three-day history of cough, fever, and shortness of breath. He was intubated for acute respiratory distress syndrome and was mechanically ventilated for two weeks. He had minimal features of organizing pneumonia on chest CT; his prolonged ventilation was due to delayed recovery of mental status. Following extubation, he refused food and was noncommunicative. Although he had spontaneous voluntary limb movements, there was significant variable resistance during passive limb mobility, consistent with the gegenhalten sign (Supplementary Video 1, segment 4 in the online-only Data Supplement). He responded with clonazepam at 1 mg three times daily and had complete recovery two weeks later.
Catatonia is a psychomotor syndrome involving both motor and behavioral disturbances associated with many medical conditions, such as metabolic, autoimmune, and infectious conditions, as well as with numerous substances, and has been reported in COVID-19 infection [1-4]. The above four patients presented with catatonic symptoms of different severities (Supplementary Video 1 in the online-only Data Supplement). In the published literature, many of the patients had underlying psychiatric disorders, urging clinicians to have a high index of suspicion in these groups of patients (Supplementary Table 1 in the online-only Data Supplement). All patients had mild to moderate lung injury due to COVID-19. Two of the cases tested negative for anti-N-methyl-D-aspartate receptor receptor autoimmune encephalitis, a frequent cause of organic catatonia [4], but inflammatory markers such as serum ferritin and C-reactive proteins were elevated (Table 1). CSF analysis, electroencephalography, and brain MRI imaging did not reveal any other potential etiologies of catatonia.
Various infections have been reported to cause catatonia and are postulated to be due to activation of the innate immune system [4] or alterations in gamma-Aminobutyric acid-ergic (GABAergic) and dopaminergic modulation of the cortico-basal ganglia-thalamo-cortical circuit [1]. Exposure to proinflammatory cytokines during the acute phase response has been associated with altered GABAergic transmission in the basal ganglia [1,5]. The use of antipsychotics may precipitate malignant catatonia, as illustrated in case 1; hence, a high index of suspicion should prompt immediate withdrawal of the dopaminergic blocking agent to avoid catastrophic outcomes. The first-line treatment is a benzodiazepine, which is a GABA agonist [4], and our subsequent three patients had complete recovery after clonazepam without immunotherapy, suggesting that COVID-19-associated catatonia may be a transient syndrome precipitated by systemic proinflammatory cytokines. Intravenous methylprednisolone was used in several case reports in the treatment of catatonia (Supplementary Table 1 in the online-only Data Supplement) [3,6]. It is important to differentiate this condition from akinetic mutism, which is a neurologic state of alertness without speech or movement resulting from irreversible medial prefrontal or midbrain injury [7].
In conclusion, catatonia should be considered in patients with COVID-19-associated encephalopathy, as early detection can avoid iatrogenic sequelae of prescribing dopamine antagonists that will inadvertently provoke the malignant form of catatonia.
Segment 1: Case 1 was a 25-year-old man with COVID-19 infection who presented with stupor, immobility, staring, mutism, upper and lower extremity rigidity, and tremor. Segment 2: Case 2 was a 51-year-old prisoner infected with COVID-19 who developed mutism, rigidity, unresponsiveness to painful stimuli, abnormal limb posturing, and pillow signs. Segment 3: Case 3 was a 40-year-old woman who presented with rigidity, pillow sign, and waxy flexibility following COVID-19 infection. Segment 4: Case 4 was a 67-year-old gentleman with spontaneous limb movements but had significant variable resistance during passive limb mobility consistent with the gegenhalten sign.
Notes
Ethics Statement
Written consent was obtained from patients for the publication of the information and videos shown in the manuscript. The manuscript has received approval for publication by the National Medical Research Register (NMRR) (RSCH ID-21-01312-RPD, NMRR ID-21-02414-MBT).
Conflicts of Interest
The authors have no financial conflicts of interest.
Funding Statement
None
Author Contributions
Conceptualization: Tien Lee Ong. Data curation: Tien Lee Ong. Writing—original draft: Tien Lee Ong. Writing—review & editing: Tien Lee Ong, Sapiah
Sapuan.
Acknowledgments
We would like to thank the Director General of Health Malaysia, Datuk Dr Noor Hisham Abdullah for his permission to publish this article.
Table 1.
Summary of demographics and investigation findings of patients presenting with catatonia in COVID-19 infection
Case 1
Case 2
Case 3
Case 4
Age/sex
26/male
52/male
40/female
67/male
Premorbid
No med problem
Smoker, marijuana, and amphetamine
None
Diabetes, hypertension, chronic kidney disease
Underlying schizophrenia, on antipsychotics
COVID-19 nasopharyngeal swab PCR
Positive
Positive
Positive
Positive
Clinical presentation
Persecutory delusion, disorientation paranoia, restlessness, disorganized behavior (peed and sat on the floor)
Progressive stiffness, walking difficulty one week prior to admission, progressed to stupor, mutism, food and drink refusal, severe rigidity, and pillow sign
Disorientated, food and drink refusal, shouting, and screaming with self-harm. Need physical restraint. Progressed to mutism, catalepsy, waxy flexibility, gegenhalten in the lower limbs
Mutism, negativism, food and drink refusal, gegenhalten sign involving upper and lower limbs
Rapidly progressed to stupor, staring, mutism, immobility, and limb rigidity
BFCRS
17
26
20
12
Day of COVID illness at onset of catatonia
8
17
17
19
Severity of COVID-19
Minimal lung involvement in CXR
Moderate lung involvement in CTPA
Minimal lung involvement in CXR
Minimal Lung organising pneumonia in CTPA
On nasal prong
On room air
Inflammatory markers
CRP 1.1 mg/L, LDH > 4,500 U/L, D dimer 3,437 ng/mL, ferritin 3,963 μg/L, CK > 7,800 U/L
CRP 9.4 mg/L, LDH 228 U/L, D dimer 3,344 ng/mL, ferritin 518 μg/L, CK 342 U/L
CRP 4.4 mg/L, LDH 514 U/L, D dimer 761 ng/mL, ferritin 397 μg/L, CK 396 U/L
CRP 9.4 mg/L, LDH 324 U/L, D dimer 569 ng/mL, CK 45 U/L
EEG
Not done
Diffuse slowing theta
Diffuse slowing theta to delta
Not done
CSF finding
Protein 0.27 g/L, glucose 6.6 mmol/L, acellular, culture neg, oligoclonal band neg, viral panel neg
Protein 0.27 g/L, glucose 4.0 mmol/L, acellular, culture neg, oligoclonal band neg, viral panel neg
Protein 0.25 g/L, glucose 5.2 mmol/L, acellular, oligoclonal band neg, viral panel neg
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Catatonia in Hospitalized Patients With COVID-19: An Important Clinical Finding That Should Not be Missed
Catatonia in Hospitalized Patients With COVID-19: An Important Clinical Finding That Should Not be Missed
Case 1
Case 2
Case 3
Case 4
Age/sex
26/male
52/male
40/female
67/male
Premorbid
No med problem
Smoker, marijuana, and amphetamine
None
Diabetes, hypertension, chronic kidney disease
Underlying schizophrenia, on antipsychotics
COVID-19 nasopharyngeal swab PCR
Positive
Positive
Positive
Positive
Clinical presentation
Persecutory delusion, disorientation paranoia, restlessness, disorganized behavior (peed and sat on the floor)
Progressive stiffness, walking difficulty one week prior to admission, progressed to stupor, mutism, food and drink refusal, severe rigidity, and pillow sign
Disorientated, food and drink refusal, shouting, and screaming with self-harm. Need physical restraint. Progressed to mutism, catalepsy, waxy flexibility, gegenhalten in the lower limbs
Mutism, negativism, food and drink refusal, gegenhalten sign involving upper and lower limbs
Rapidly progressed to stupor, staring, mutism, immobility, and limb rigidity
BFCRS
17
26
20
12
Day of COVID illness at onset of catatonia
8
17
17
19
Severity of COVID-19
Minimal lung involvement in CXR
Moderate lung involvement in CTPA
Minimal lung involvement in CXR
Minimal Lung organising pneumonia in CTPA
On nasal prong
On room air
Inflammatory markers
CRP 1.1 mg/L, LDH > 4,500 U/L, D dimer 3,437 ng/mL, ferritin 3,963 μg/L, CK > 7,800 U/L
CRP 9.4 mg/L, LDH 228 U/L, D dimer 3,344 ng/mL, ferritin 518 μg/L, CK 342 U/L
CRP 4.4 mg/L, LDH 514 U/L, D dimer 761 ng/mL, ferritin 397 μg/L, CK 396 U/L
CRP 9.4 mg/L, LDH 324 U/L, D dimer 569 ng/mL, CK 45 U/L
EEG
Not done
Diffuse slowing theta
Diffuse slowing theta to delta
Not done
CSF finding
Protein 0.27 g/L, glucose 6.6 mmol/L, acellular, culture neg, oligoclonal band neg, viral panel neg
Protein 0.27 g/L, glucose 4.0 mmol/L, acellular, culture neg, oligoclonal band neg, viral panel neg
Protein 0.25 g/L, glucose 5.2 mmol/L, acellular, oligoclonal band neg, viral panel neg