New onset of isolated adrenocorticotropin deficiency associated with encephalopathy following coronavirus disease 2019 in a healthy elderly man

Abstract

Coronavirus disease 2019 (COVID-19) due to a severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can include various systemic organ disorders including endocrinopathies and neurological manifestations. We report the case of a 65-year-old Japanese man who developed isolated adrenocorticotropic hormone (ACTH) deficiency and encephalopathy following SARS-CoV-2 infection. Two weeks after his COVID-19 diagnosis, he was emergently admitted to our hospital because of subacute-onset delirium. On admission, he presented hyponatremia (128 mEq/L) and secondary adrenal insufficiency (ACTH <1.5 pg/mL, cortisol 0.53 μg/dL). Brain imaging and laboratory examinations including SARS-CoV-2 polymerase chain reaction testing in the cerebrospinal fluid revealed no abnormalities. His consciousness level worsened despite the amelioration of hyponatremia by intravenous hydrocortisone (100 mg/day), but his neurological presentations completely resolved after three consecutive days of high-dose (400 mg/day) hydrocortisone. His encephalopathy did not deteriorate during hydrocortisone tapering. He continued 15 mg/day hydrocortisone after discharge. His encephalopathy might have developed via a disturbance of the autoimmune system, or a metabolic effect associated with adrenal insufficiency, although the time lag between the hyponatremia’s improvement and the patient’s neurological response to the steroid was incompatible with common cases of delirium concurrent with adrenal insufficiency. At 13 months after his hospitalization, the patient’s neurological symptoms have not recurred and he has no endocrinological dysfunctions other than the remaining ACTH deficiency. A thorough consideration of the immunological and metabolic characteristics of SARS-CoV-2 is advisable when clinicians treat patients during and even after their COVID-19 disease period.

SINCE THE 2020 start of the worldwide pandemic of coronavirus disease 2019 (COVID-19), systemic organ disorders including endocrinopathies and neurological manifestations associated with severe acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV-2) infection have been reported [1-5]. SARS coronaviruses are known to be able to invade the pneumocytes interacting with the host angiotensin-converting enzyme 2 (ACE2). The spike protein presented on the surface of SARS-CoV-2 can bind well to the human cell ACE2 as a receptor to allow the virus to fuse with the cells and release the viral ribonucleic acid (RNA) into the cells [6]. ACE2 is located not only in the respiratory tract epithelium cells but also in cells of various organs, such as the intestines, heart, kidney, brain, and endocrine glands. This implies that the virus is freely available to interact with ACE2 expressed in the organs apart from pneumocytes. As possible mechanisms of extra-respiratory manifestations of COVID-19, not only direct damage of organs via ACE2 expressed on the cells but also indirect effects mediated by cytokine storm [7] or autoimmunity [8] have been considered.

We present a rare case of new-onset adrenocorticotropic hormone (ACTH) deficiency associated with subacute-onset encephalopathy at 2 weeks after the patient’s COVID-19 infection. Autoimmune or metabolic mechanisms are suspected as the etiology since successive high-dose steroid administrations achieved a complete remission of the patient’s encephalopathy following an immediate rescue from adrenal insufficiency.

Case

The patient was a 65-year-old Japanese man with no remarkable medical history and no medication use. He had been vaccinated against SARS-CoV-2 three times. Five months after the last vaccination, he developed a high fever and dysgeusia. At a local clinic, he was diagnosed with being a SARS-CoV-2 infection based on a positive polymerase chain reaction (PCR) result. He did not receive anti-COVID-19 medications, including steroids. Ten days after having the confirmed COVID-19 infection, he revisited the clinic because his anorexia and fatigue had not improved even after the fever’s alleviation. A laboratory examination revealed hyponatremia (sodium 125 mEq/L), hypoglycemia (glucose 68 mg/dL), increased C-reactive protein (17.2 mg/dL), and leukocytosis (11,800/μL) with a 72% neutrophil ratio, 14% lymphocyte ratio, and 3.2% eosinophil ratio. He was treated with a fluid infusion and an oral antibiotic medicine. Four days after that treatment, his family observed that he was not able to eat or speak appropriately and had developed delirium. He was emergently admitted to our hospital.

On admission (Day 1 on Fig. 1), the patient’s body temperature was 36.9°C, his blood pressure was 158/96 mmHg, his pulse rate was 86/min, and his oxygen saturation was 96% in room air. A negative result on a SARS-CoV-2 PCR test by nasopharyngeal swabs and a positive result for antibodies against SARS-CoV-2 in the serum were obtained (Table 1). The patient’s neurological presentations included delirium symptoms, such as rambling and incoherent speech, delusion, and hallucination, but neither signs of meningeal irritation nor neurological involvement in cranial and peripheral nerves were confirmed by neurologists.

Fig. 1

Clinical course of the patient, a 65-year-old Japanese male. GCS: Glasgow Coma Scale, JCS: Japan Coma Scale.

Table 1

Laboratory examinations at admission

	Case	Reference		Case	Reference
Blood examinations			SS-B antibody (U/mL)	<1.0	<10.0
White blood cell (/μL)	4,700	3,300–8,600	MPO-ANCA (U/mL)	<1.0	<3.5
Red blood cell (×104/μL)	380	386–492	PR3-ANCA (U/mL)	<1.0	<3.5
Hemoglobin (g/dL)	12.6	11.6–14.8	Free thyroxine (ng/mL)	1.10	0.9–1.7
Platelet (×104/μL)	31.5	15.8–34.8	Cortisol (μg/dL)	0.53	2.96–19.6
Sodium (mEq/L)	128	138–145	Adrenocorticotropic hormone (pg/mL)	<1.5	7.0–56
Potassium (mEq/L)	3.8	3.6–4.8	Thyroid stimulating hormone (μIU/mL)	3.09	0.5–5.0
Chloride (mEq/L)	94	101–108	Luteinizing hormone (mIU/mL)	7.68	2.2–8.4
Blood urea nitrogen (mg/dL)	6.0	8.0–20	Follicle-stimulating hormone (mIU/mL)	13.3	1.8–12
Creatinine (mg/dL)	0.74	0.46–0.79	Prolactin (ng/mL)	21.9	4.3–13.7
Aspartate aminotransferase (IU/L)	24	13–30	Growth hormone (ng/mL)	2.40	0.13–9.88
Alanine aminotransferase (IU/L)	16	7.0–23	Total testosterone	899	225–1,039
γ-glutamyltransferase (IU/L)	13	<48	Thyroglobulin antibody (IU/mL)	<10.0	<19.3
Glucose (mg/dL)	120	73–109	Thyroid peroxidase antibody (IU/mL)	2.0	<3.3
Glycated hemoglobin (%)	5.9	4.9–6.0	NH2-terminal of α-enolase antibody	(–)	(–)
C-reactive protein (mg/dL)	3.32	<0.14	Vitamin B1 (ng/mL)	41.1	21.3–81.9
Ammonia (μg/dL)	30	12–66	SARS-CoV-2 antibody (U/mL)	61,278	<0.8
IgA (mg/dL)	60	90–400	SARS-CoV-2 PCR (nasopharyngeal swab)	(–)	(–)
IgG (mg/dL)	766	820–1,740
IgG4 (mg/dL)	28.9	5.0–117	Cerebrospinal fluid (CSF) examinations
IgM (mg/dL)	85.8	52–270	White blood cell (/μL)	1
Herpes simplex virus-IgM (U/mL)	<2.0	<2.0	Glucose (mg/dL)	71
Herpes simplex virus-IgG (U/mL)	0.27	<2.0	Protein (mg/dL)	51
Varicella zoster virus-IgM (U/mL)	0.33	<0.80	Lactate dehydrogenase (IU/L)	26
Varicella zoster virus-IgG (U/mL)	13.2	<2.0	Oligoclonal band (ng/mL)	(–)
Cytomegalovirus-IgM (U/mL)	<0.10	<0.85	Cryptococcus	(–)
Cytomegalovirus-IgG (U/mL)	141	<6.0	Herpes simplex virus DNA (/mL)	<100	<100
HRP-C7 (/50,000 cell)	(–)	(–)	Varicella zoster virus DNA (/mL)	<100	<100
T-SPOT.TB	(–)	(–)	SARS-CoV-2 PCR	(–)	(–)
RPR test for Treponema pallidum	(–)	(–)	SARS-CoV-2 antibody (U/mL)	241	<0.8
TPHA	(–)	(–)	IgG index*	0.40	<0.73
Antinuclear antibodies	×80 (speckled)	<40	CSF/serum albumin quotient (QAlb)	0.010
SS-A antibody (U/mL)	<1.0	<10.0

ANCA, antineutrophil cytoplasmic antibody; DNA, deoxyribonucleic acid; HRP-C7, horseradish peroxidase-conjugated Fab’ fragment of human monoclonal antibody; Ig, immunoglobulin; MPO, myeloperoxidase; PR3, proteinase 3; RNA, ribonucleic acid; RPR, rapid plasma regain; SS-A, Sjögren’s-syndrome-related antigen A; SS-B, Sjögren’s-syndrome-related antigen B; T-SPOT.TB, type of ELISpot assay used for tuberculosis diagnosis; TPHA, Treponema pallidum hemagglutination.

* The IgG index is calculated by the following formula: (CSF-IgG/CSF-Albumin)/(Serum-IgG/Serum-Albumin) (15)

As summarized in Table 1, hyponatremia and secondary adrenal insufficiency were observed in the patient. His thyroid function and hypothalamus-pituitary axis excluding ACTH were considered intact based on the baseline concentrations of hormones. A newly developed isolated ACTH deficiency was confirmed as a cause of his hyponatremia and adrenal insufficiency. A magnetic resonance imaging (MRI) examination revealed no findings of brain tumors, cerebral infarction, or encephalitis (Fig. 2A) and no abnormality in the hypothalamus or pituitary gland (Fig. 2B).

Fig. 2

The MRI examination on Day 1 of the patient’s admission. A: The T2-weighted fluid attenuated inversion recovery imaging. No abnormal findings in intracranial parenchyma or cerebrospinal meninges were identified. B: The postcontrast T1-weighted imaging. No abnormalities in the hypothalamus or anterior- and posterior-pituitary gland were identified.

A systemic evaluation by computed tomography revealed no significant findings, including pneumonia. Electroencephalography (EEG) showed an 8- to 10-Hz basal α-wave associated with a generalized 5-Hz slow wave. An examination of the patient’s cerebrospinal fluid (CSF) on Day 2 revealed a slightly positive result for antibodies against SARS-CoV-2 but a negative result on a SARS-CoV-2 PCR test (Table 1). The CSF levels of SARS-CoV-2 antibodies might be explained by a nonspecific diffusion of immunoglobulin when considering the patient’s IgG index at 0.40 and the CSF/serum albumin quotient at 0.010. The absence of evidence of common viral encephalitis was confirmed by the serological findings. Hashimoto encephalopathy was unlikely since anti-thyroid autoantibodies and NH₂-terminal of α-enolase antibodies were not identified in the serum. Imaging and laboratory investigations could not identify the cause of the patient’s encephalopathy, suggesting a possible mechanism of metabolic etiology associated with adrenal insufficiency.

As depicted in Fig. 1, on hospitalization Day 2 the patient received hydrocortisone 100 mg intravenously for the treatment of his adrenal insufficiency. The serum sodium levels increased soon after the hydrocortisone replacement. However, on Day 4 the patient’s consciousness worsened (E4V2M6 on the Glasgow Coma Scale and II-10 on the Japan Coma Scale) although his serum sodium levels had improved to within the normal range. We increased the hydrocortisone dose to 400 mg on the same day, and the patient’s consciousness level and psychosis then improved and he became completely alert on Day 8. His neurological presentation did not deteriorate during the tapering of the hydrocortisone.

On Days 16–18 the patient’s anterior pituitary functions were evaluated by the stimulation tests, and these functions were confirmed as intact with the exception of the ACTH secretion (Fig. 3). He discharged on Day 18 and continued to take hydrocortisone 15 mg/day. As of this writing (13 months after discharge), the patient’s encephalopathy has never recurred and he has not developed pituitary hormonal disorders other than the remaining ACTH deficiency.

Fig. 3

Pituitary function tests on Days 16–18 of the admission. A: The insulin stress test with an intravenous injection of 5 units of regular insulin. B: The growth hormone releasing peptide-2 (GHRP-2) test with an intravenous injection of GHRP-2 100 μg. C: The thyrotropin-releasing hormone (TRH) test with an intravenous injection of TRH 200 μg. D: The gonadotropin-releasing hormone (GnRH) test with an intravenous injection of GnRH 100 μg. The serum levels of cortisol, thyroid-stimulating hormone (TSH), prolactin (PRL), growth hormone (GH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and plasma adrenocorticotropic hormone (ACTH) levels were determined by the Cobas e801 assay using the ECLusys kit (Roche, Basel, Switzerland).

Discussion

Several cases of delirium concurrent with adrenal insufficiency have been reported [9-11], and in all of those cases, hydrocortisone replacement immediately achieved a dramatic improvement in the patient’s consciousness. In our patient’s case, the intravenous administrations of hydrocortisone 100 mg/day immediately increased his serum sodium level from 128 mmol/L to the normal range on the following 2 days. However, his consciousness level gradually deteriorated during the hydrocortisone administration at the treatment dose for adrenal insufficiency (100 mg/day). The administration of high-dose (400 mg/day) hydrocortisone for three consecutive days ameliorated his consciousness level and he became completely alert. We suspected that our patient’s case involved metabolic encephalopathy associated with adrenal insufficiency, but the time lag between the improvement of his adrenal crisis and the response of his encephalopathy to the steroid was incompatible with the earlier cases [9-11]. It was reported that psychiatric symptoms tend to occur especially in chronic adrenal insufficiency, the psychosis rarely persist for several months although most of the symptoms disappear within a few days after glucocorticoid therapy is begun. It was also reported that psychiatric improvement does not correlate with correction of electrolyte imbalance except in patients with severe hyponatremia [12]. These suggest that delirium might have improved without a significant increase in the hydrocortisone dosage in our patient.

The PCR test did not detect SARS-CoV-2 RNA in our patient’s CSF. In a national cohort study in Spain, only 3% of the patients who underwent a lumbar puncture showed a positive result on a SARS-CoV-2 PCR test in a CSF examination conducted after they developed encephalopathy during acute COVID-19 infection [13]. Although a negative PCR result does not per se rule out a SARS-CoV-2 infection of the nervous system [14], neurological involvement may possibly be secondary to the inflammatory phase of the COVID-19 infection rather than its direct infection to the brain parenchyma. In our patient, the slightly positive result for SARS-CoV-2 antibodies in his CSF might be explained by a nonspecific diffusion of immunoglobulin, considering his not-significantly high IgG index value [15] and the CSF/serum albumin quotient [16].

A retrospective cohort study from Mayo Clinic showed that 0.05% of patients who suffered from COVID-19 developed possible autoimmune encephalopathy [8]. These patients presented with the subacute-onset phenotype of encephalopathy after a COVID-19 infection and had epileptiform discharges on EEG but no viral particle or neuronal IgG [8]. A possible case of autoimmune encephalitis following infection of the SARS-CoV-2 omicron variant was reported from Japan [17]. Our patient’s CSF findings and his acute response to high-dose steroid therapy were similar to the clinical course of the reported patients who developed putative autoimmune encephalitis after recovery from COVID-19 infection (Table 2) [8, 17-22]. Since we could not perfectly diagnose the cause of encephalopathy as either autoimmune or metabolic mechanisms when treated the patient, we continued using hydrocortisone instead of methylprednisolone that has a more immunosuppressive effect. However, some reported cases recovered from encephalopathy without corticosteroid therapy [8], and we cannot exclude the possibility that encephalopathy in our patient was a spontaneous recovery process. Considering these, our present patient’s case might not be inconsistent with post-COVID-19 immune-mediated encephalopathy.

Table 2

Overview of reported cases of putative autoimmune encephalitis or encephalopathy with absence of underlying identifiable causes after recovery from COVID-19 infection

References	Age/Sex	Onset from identifying COVID-19 (days)	Neurological presentation	MRI	CSF	Therapy	Outcome
Our patient	65/M	14	Delirium	Normal	Protein 51 mg/dL, OCB(–), PCR(–), IgG index 0.40, QAlb 0.010	Hydrocortisone 100–400 mg/day for 10 days	Improved 7 days after initiating hydrocortisone administration
Kato 2022 [17]	55/F	10	Delirium, myoclonus, gait disturbance	Normal	Protein 59 mg/dL, PCR(–), QAlb 0.010	High-dose mPSL pulse therapy	Improved 2 days after the successive 3 days of mPSL therapy
Valencia Sanchez 2021 [8]	61/F	13	Delirium, seizures	T2-high in mesial temporal lobes	WBC 30/μL, PCR(–), IgG(–)	Corticosteroid, plasma exchange	Improved seizure but remained mild amnestic cognitive impairment and mood disturbance
Valencia Sanchez 2021 [8]	62/M	23	Delirium, seizures	Normal	Protein 61 mg/dL, PCR(–), IgG(–)	None	Improved
Chakraborty 2022 [18]	61/M	5	Delirium, aphasia, drowsiness	T2-high in left temporal lobe and left thalamus	Protein 66 mg/dL, PCR(–), NMDA Ab(–)	mPSL plus Immunoglobulin for 5 days	Improved
Hilado 2022 [19]	6/M	12	Gait ataxia, seizures	T2-high in bilateral parietal lobes	SARS-CoV-2 Ab(–), NMDA Ab(–)	mPSL 1 g for 3 days	Improved
Dono 2021 [20]	81/M	14	Delirium, myoclonus, gait disturbance	T2-high in bilateral parietal cortex, left temporal cortex and right cingulate cortex	Protein 47 mg/dL, WBC 26/μL, glucose 78 mg/dL, PCR(-)	mPSL 1 g for 5 days followed by PSL 60mg for 10 days plus Immunoglobulin for 5 days	Not ameliorated even after the immunotherapy and died 37 days after the onset of encephalopathy because of sepsis
Dahshan 2022 [21]	67/M	8	Delirium, agitation	Normal	Normal	High-dose corticosteroid for 5 days	Regained full consciousness 2 days after steroid administration, and improved completely afterwards
Grimaldi 2020 [22]	72/M	17	Tremor, ataxia, dysarthria	Not performed	Protein 49 mg/dL, PCR(–), OCB(–)	Immunoglobulin for 5 days followed by mPSL 1g for 5 days	Improved after mPSL administration

The previous cases reported as autoimmune encephalitis or encephalopathy with absence of underlying identifiable causes after recovery from COVID-19 infection are listed in the table. The cases of antibodies-mediated encephalitis such as anti-N-Methyl-D-aspartate encephalitis were excluded.

Ab, antibodies; CSF, cerebrospinal fluid; IgG, neuronal immunoglobulin G; mPSL, methylprednisolone; MRI, magnetic resonance imaging; OCB, oligo clonal band; PCR, SARS-CoV-2 polynucleotide chain reaction test; PSL, prednisolone; Q_Alb, the CSF/serum albumin ratio; WBC, white blood cell.

As similar to our patient, there have been several reports on developing ACTH deficiency with absence of underlying identifiable causes after COVID-19 infection (Table 3) [23-26]. One of the possible mechanisms of endocrine dysfunctions associated with SARS-CoV-2 infection is a direct destruction of glands that express ACE2 [1, 7, 27]. It was confirmed that ACE2 messenger RNA is expressed in hypothalamus and pituitary gland cells [28]. In autopsy studies, neuronal degeneration along with the SARS genome were identified in the pituitary gland of patients who died due to a SARS-CoV-2 infection [29] as well as patients who had died from SARS coronavirus-1 [30].

Table 3

Overview of reported cases of ACTH deficiency with absence of underlying identifiable causes after COVID-19 infection

References	Age/Sex	Onset from identifying COVID-19	Severity of COVID-19	Hormonal defects	Clinical presentations at the onset	Hypothalamus-pituitary MRI	Details of outcome
Our patient	65/M	14 days	Mild	ACTH	Hyponatremia, fatigue, anorexia	Normal	Isolated ACTH deficiency was developed 14 days after COVID-19 infection. Secretion of other pituitary hormones had been intact until 13 months after the onset of ACTH deficiency.
Yoshimura 2022 [23]	65/M	36 days	Moderate	ACTH, GH, Testosterone	Suddenly drop in blood pressure	Normal	Relative adrenal insufficiency was developed 1 month after improving respiratory condition of COVID-19 pneumonia. ACTH and GH responses recovered until 12 months later, although hypogonadism persisted.
Hamazaki 2022 [24]	23/F	1 month	Mild	ACTH	Weight loss, anorexia, low-grade fever	Normal	Isolated ACTH deficiency was developed a month after COVID-19. The responsiveness of other pituitary hormones was intact.
Gorbova 2022 [25]	35/F	2 months	Mild	ACTH, TSH, LH, FSH	Weight loss, fatigue, armpit/pubic hair loss	Hypophysitis with swelled anterior lobe and stalk of pituitary	Hypopituitarism was developed 2 months after COVID-19 infection and was alleviated 4 months later. The hormonal defects had completely improved 10 months after the onset of hypopituitarism.
Chua 2021 [26]	47/M	1 week	Mild	ACTH, TSH	Dyspepsia, eosinophilia	Normal	Absolute ACTH deficiency with partial TSH deficiency developed a week after COVID-19. TSH secretion was normalized 3 weeks after the diagnosis of pituitary dysfunction, but ACTH deficiency had not been improved.

The previous cases reported as ACTH deficiency with absence of underlying identifiable causes after COVID-19 infection are listed in the table. The cases identified any lesions in hypothalamus or/and pituitary, such as pituitary apoplexy, were excluded.

Another possible effect of COVID-19 infection on the hypothalamic-pituitary axis may be mediated by the immune system. SARS coronaviruses may deflect the host immune responses by expressing a certain amino-acid sequence that acts as a molecular mimic of the mammalian ACTH [2]. Antibodies produced by the host to counteract SARS-CoV-2 may attenuate the suitable adrenal response to the inflammatory stress [31, 32]. On the other hand, the homology in the amino-acid sequence of SARS-CoV-2 may prime the immune system to destroy the host ACTH and pituitary adrenocorticotrophs. In fact, a case of new-onset isolated ACTH deficiency following immunization with a SARS-CoV-2 vaccine was reported [33]. Our patient developed ACTH deficiency but the secretions of other pituitary hormones were completely intact, and MRI showed no abnormalities. The autoimmune system could be considered a primary cause in the development of our patient’s isolated ACTH deficiency.

Conclusion

We presented an intriguing case of new-onset isolated ACTH deficiency associated with encephalopathy following a COVID-19 infection. We should assume a possibility of SARS-CoV-2-associated encephalopathy when we encounter a case of adrenal insufficiency that does not improve with corticosteroid replacement. Clinicians should carefully treat patients during and even after their COVID-19 infection while carefully considering the immunological and metabolic characteristics of SARS-CoV-2.

Disclosure

The authors have no conflicts of interest to declare.

References

• 1   Bellastella  G,  Cirillo  P,  Carbone  C,  Scappaticcio  L,  Maio  A, et al. (2022) Neuroimmunoendocrinology of SARS-CoV 2 Infection. Biomedicines 10: 2855.
• 2   Pal  R (2020) COVID-19, hypothalamo-pituitary-adrenal axis and clinical implications. Endocrine 68: 251–252.
• 3   Cho  SM,  White  N,  Premraj  L,  Battaglini  D,  Fanning  J, et al. (2023) Neurological manifestations of COVID-19 in adults and children. Brain 146: 1648–1661.
• 4   Chang  S,  Schecht  M,  Jain  R,  Belani  P (2023) Acute neurological complications of coronavirus disease. Neuroimaging Clin N Am 33: 57–68.
• 5   Pal  R,  Banerjee  M (2020) COVID-19 and the endocrine system: exploring the unexplored. J Endocrinol Invest 43: 1027–1031.
• 6   Medina-Enriquez  MM,  Lopez-Leon  S,  Carlos-Escalante  JA,  Aponte-Torres  Z,  Cuapio  A, et al. (2020) ACE2: the molecular doorway to SARS-CoV-2. Cell Biosci 10: 148.
• 7   Puig-Domingo  M,  Marazuela  M,  Yildiz  BO,  Giustina  A (2021) COVID-19 and endocrine and metabolic diseases. An updated statement from the European Society of Endocrinology. Endocrine 72: 301–316.
• 8   Valencia Sanchez  C,  Theel  E,  Binnicker  M,  Toledano  M,  McKeon  A (2021) Autoimmune encephalitis after SARS-CoV-2 infection: case frequency, findings, and outcomes. Neurology 97: e2262–e2268.
• 9   Murakami  M,  Matsushita  N,  Arai  R,  Takahashi  N,  Kawamura  R, et al. (2012) Isolated adrenocorticotropin deficiency associated with delirium and takotsubo cardiomyopathy. Case Rep Endocrinol 2012: 580481.
• 10   Nwokolo  M,  Fletcher  J (2013) A rare case of hypopituitarism with psychosis. Endocrinol Diabetes Metab Case Rep 2013: 130007.
• 11   Imai  H,  Matsuishi  K,  Kitamura  N,  Matsui  Y,  Tamiya  S, et al. (2009) Isolated adrenocorticotropic hormone deficiency accompanied with delirium. Psychiatry Clin Neurosci 63: 426–427.
• 12   Nieman  LK (2022) Clinical manifestations of adrenal insufficiency in adults. UpToDate https://www.uptodate.com/contents/clinical-manifestations-of-adrenal-insufficiency-in-adults accessed on Nov 10, 2023.
• 13   Abenza Abildua  MJ,  Atienza  S,  Carvalho Monteiro  G,  Erro Aguirre  ME,  Imaz Aguayo  L, et al. (2021) Encephalopathy and encephalitis during acute SARS-CoV-2 infection. Spanish society of neurology COVID-19 registry. Neurologia (Engl Ed) 36: 127–134.
• 14   Jarius  S,  Pache  F,  Kortvelyessy  P,  Jelcic  I,  Stettner  M, et al. (2022) Cerebrospinal fluid findings in COVID-19: a multicenter study of 150 lumbar punctures in 127 patients. J Neuroinflammation 19: 19.
• 15   Tibbling  G,  Link  H,  Ohman  S (1977) Principles of albumin and IgG analyses in neurological disorders. I. Establishment of reference values. Scand J Clin Lab Invest 37: 385–390.
• 16   Reiber  H,  Peter  JB (2001) Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs. J Neurol Sci 184: 101–122.
• 17   Kato  S,  Yoshikura  N,  Kimura  A,  Shimohata  T (2022) Possible autoimmune encephalitis associated with the severe acute respiratory syndrome coronavirus 2 omicron variant successfully treated with steroids: a case report. Intern Med 61: 3739–3741.
• 18   Chakraborty  AP,  Pandit  A,  Dutta  A,  Das  S,  Ganguly  G, et al. (2022) Transcortical sensory aphasia heralding SARS-Cov-2-induced autoimmune encephalitis with gyral restricted diffusion hyperintensities: a novel case report. Egypt J Neurol Psychiatr Neurosurg 58: 167.
• 19   Hilado  M,  Banh  M,  Homans  J,  Partikian  A (2022) Pediatric autoimmune encephalitis following COVID-19 infection. J Child Neurol 37: 268–272.
• 20   Dono  F,  Carrarini  C,  Russo  M,  De Angelis  MV,  Anzellotti  F, et al. (2021) New-onset refractory status epilepticus (NORSE) in post SARS-CoV-2 autoimmune encephalitis: a case report. Neurol Sci 42: 35–38.
• 21   Dahshan  A,  Abdellatef  AA (2022) Autoimmune encephalitis as a complication of COVID-19 infection: a case report. Egypt J Intern Med 34: 32.
• 22   Grimaldi  S,  Lagarde  S,  Harle  JR,  Boucraut  J,  Guedj  E (2020) Autoimmune encephalitis concomitant with SARS-CoV-2 infection: insight from (18)F-FDG PET imaging and neuronal autoantibodies. J Nucl Med 61: 1726–1729.
• 23   Yoshimura  K,  Yamamoto  M,  Inoue  T,  Fukuoka  H,  Iida  K, et al. (2022) Coexistence of growth hormone, adrenocorticotropic hormone, and testosterone deficiency associated with coronavirus disease 2019: a case followed up for 15 months. Endocr J 69: 1335–1342.
• 24   Hamazaki  K,  Nishigaki  T,  Kuramoto  N,  Oh  K,  Konishi  H (2022) Secondary adrenal insufficiency after COVID-19 diagnosed by insulin tolerance test and corticotropin-releasing hormone test. Cureus 14: e23021.
• 25   Gorbova  NY,  Vladimirova  VP,  Rozhinskaya  LY,  Belaya  ZY (2022) [Hypophysitis and reversible hypopituitarism developed after COVID-19 infection—a clinical case report]. Probl Endokrinol (Mosk) 68: 50–56.
• 26   Chua  MWJ,  Chua  MPW (2021) Delayed onset of central hypocortisolism in a patient recovering from COVID-19. AACE Clin Case Rep 7: 2–5.
• 27   Muller  JA,  Gross  R,  Conzelmann  C,  Kruger  J,  Merle  U, et al. (2021) SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas. Nat Metab 3: 149–165.
• 28   Frara  S,  Loli  P,  Allora  A,  Santini  C,  di Filippo  L, et al. (2022) COVID-19 and hypopituitarism. Rev Endocr Metab Disord 23: 215–231.
• 29   Poma  AM,  Proietti  A,  Macerola  E,  Bonuccelli  D,  Conti  M, et al. (2022) Suppression of pituitary hormone genes in subjects who died from COVID-19 independently of virus detection in the gland. J Clin Endocrinol Metab 107: 2243–2253.
• 30   Leow  MK,  Kwek  DS,  Ng  AW,  Ong  KC,  Kaw  GJ, et al. (2005) Hypocortisolism in survivors of severe acute respiratory syndrome (SARS). Clin Endocrinol (Oxf) 63: 197–202.
• 31   Gonen  MS,  De Bellis  A,  Durcan  E,  Bellastella  G,  Cirillo  P, et al. (2022) Assessment of neuroendocrine changes and hypothalamo-pituitary autoimmunity in patients with COVID-19. Horm Metab Res 54: 153–161.
• 32   Das  L,  Dutta  P,  Walia  R,  Mukherjee  S,  Suri  V, et al. (2021) Spectrum of endocrine dysfunction and association with disease severity in patients with COVID-19: insights from a cross-sectional, observational study. Front Endocrinol (Lausanne) 12: 645787.
• 33   Morita  S,  Tsuji  T,  Kishimoto  S,  Uraki  S,  Takeshima  K, et al. (2022) Isolated ACTH deficiency following immunization with the BNT162b2 SARS-CoV-2 vaccine: a case report. BMC Endocr Disord 22: 185.