Steroid-responsive encephalopathy associated with autoimmune thyroiditis presenting with a postpartum psychosis

Abstract

Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) is a rare condition characterised by neuropsychiatric symptoms, presence of antithyroid antibodies and significant response to steroid therapy. Postpartum psychosis (PP), although having a low prevalence, is a psychiatrical emergency with potentially serious impact in the mother and children. PP has an atypical presentation when compared with affective or psychotic episodes unrelated to pregnancy. Autoimmune dysfunction is frequent in the postpartum period and is closely related to PP. We report a case of a primiparous woman in her 20s with PP who did not respond to initial treatment with antipsychotics. After reassessment, SREAT was considered in the differential diagnosis. Neuropsychiatric symptoms improved dramatically after 72 hours of treatment with high-dose steroids treatment and the patient was discharged after 16 days. In women with PP, an autoimmune cause must be ruled out before assuming a psychiatry aetiology.

Background

Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), also called Hashimoto’s encephalopathy, is a rare condition characterised by neuropsychiatric symptoms and antithyroid antibodies (antibodies antiperoxidase and/or antithyroglobulin).¹ SREAT is more frequent in women and can have an acute onset with a progressive course or full remission recurrent episodes.² The most striking feature of SREAT is the manifestation of non-specific encephalopathy with an altered mental status and awareness,² and a typical good response to immunotherapies such as steroids.³ SREAT can present with psychiatrical symptoms, including psychosis, tachypsychia, depression and dementia.²

Both SREAT and Hashimoto’s thyroiditis (HT) have positive antithyroid antibodies, but the relationship between the two is unclear, as is the pathogenesis of SREAT.² It is hypothesised that SREAT is an immune-mediated syndrome and that several antibodies, rather than antithyroid antibodies, are proposed as having a direct or indirect role in promoting brain dysfunction.⁴

During pregnancy, women undergo immune and endocrinological changes that result in immune suppression, so that the placenta and fetus are not rejected. At the end of pregnancy, a proinflammatory state develops, and labour and delivery are triggered. After delivery, loss of immunosuppressive state of pregnancy leads to exacerbation or onset of various autoimmune conditions, including autoimmune thyroid disorders.⁵

Dysregulation of the immune system has been implicated in the pathophysiology of postpartum psychosis (PP), as high rates of autoimmune thyroid dysfunction and pre-eclampsia have been reported in women with PP.⁶

PP is a rare condition, with an estimated prevalence of 1–2 per 1000 births.⁷ This clinical picture is not yet recognised as a discrete entity.⁸ Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 classifies PP within brief psychotic disorders with the specifier ‘postpartum onset’.⁹ ICD-10 includes PP in the category ‘mental and behavioural disorders associated with the puerperium, severe mental and behavioural disorders associated with the puerperium’, not elsewhere classified, forewarning that PP diagnosis is applicable only when the clinical picture does not fit into affective disorders, schizophrenia or other disorder.¹⁰

This disorder can have devastating consequences for the mother and children, as it can manifest with serious behavioural changes, including suicidal behaviour, infanticide and relational dysfunction.⁷

PP is characterised by the acute manifestation of fluctuating psychiatrical symptoms. Patients may have mood lability, confusion and marked cognitive impairment, similarly to delirium. Bizarre behaviour, insomnia, hallucinations and delusions are frequent.^{11 12} Delusions are often persecutory and referential, often involving the child.⁶ Thought abnormalities can lead to protective behaviours, neglect or abuse. Infanticide occurs in 1%–4.5% of PP, occurring at higher rates in episodes with depressive characteristics.⁶

We report a case of a women presenting with PP as a clinical manifestation of SREAT.

Case presentation

The patient was a woman in her 20s, primiparous, with no psychiatrical history. She had a prior diagnosis of HT and Scheuermann’s disease and was maintained on folic acid supplementation throughout her pregnancy. During the first trimester at 10 weeks’ gestation, the patient had a fasting glucose of 92 mg/dL and was diagnosed with gestational diabetes. The patient adopted non-pharmacological measures, including diet and exercise, sufficient to reach normal blood glucose levels. During the remainder of the pregnancy and post partum, patient’s fasting glucose levels and occasional blood glucose levels were maintained at normal levels.

Due to high thyroid-stimulating hormone (TSH) levels (4.7 mU/L) and borderline free T4 (0.7 ng/dL), the patient was started on levothyroxine 12.5 µg po id during the third trimester. Antithyroid antibodies titre was high (582 IU/mL) and antithyroglobulin normal (4.1 IU/mL). Other blood tests were normal (complete blood count, creatinine, blood urea nitrogen, hepatic enzymes, C reactive protein and lactate-dehydrogenase). No other complications were reported until delivery.

The patient underwent a caesarean section at 40 weeks due to non-reassuring fetal status. After delivery, free T4 levels were consistently normal, and levothyroxine was discontinued. The child was born healthy, with an Apgar score of 9 in the 1st minute, 10 in the 5th minute and 10 in the 10th minute. The patient was discharged from the maternity hospital on the 4th day post partum, with no record of complications or psychiatrical symptoms. In the first days, the patient complained of difficulties in breastfeeding and expressed some concern about the child health. On the 6th day post partum, she became progressively more anxious and tearful, with concern about the baby becoming infected with COVID-19. Over the ensuing days, the anxiety progressively worsened with restlessness and global insomnia. The patient became aggressive towards family members, accusing them of trying to infect the baby and preventing them from seeing the child. She also complained feeling overactive, with excess of energy and less needy for sleep. On the 13th day post partum, due to severe agitation and disorganised behaviour, the patient was admitted to the psychiatrical ward.

At the hospital a significant fluctuation of the mental state was observed. On some occasions, the patient had normal arousal, but manifesting psychomotor agitation, aggressiveness, irritability, tachypsychia and persecutory delusional thoughts. During this period, the patient claimed to be target of a scientific experiment in the maternity hospital and that number three was the most important. Within hours, the mental status dramatically changed to reduced arousal with inattention, disorientation, motor retardation and slurred speech. The patient had persistent memory impairment with anterograde amnesia. Physical examination was normal, although subtle neurological signs might have been overlooked due to poor patient compliance.

The patient was started on risperidone 1 mg orally two times per day and lorazepam 1 mg per os due to psychomotor agitation (with a maximum daily dose of 5 mg).

As the patient exhibited extrapyramidal signs during the following days, the dose of risperidone was decreased to 0.5 mg two times per day per os.

Investigations

Routine biochemical and haematological investigations after childbirth, including drug testing, were unremarkable, except for a high erythrocyte sedimentation rate (73 mm/hour).

In addition, after childbirth, the patient was tested for infectious diseases and systemic autoimmune diseases. The patient was tested for cytomegalovirus (CMV), Rubella, Herpes simplex, Treponema pallium, Borrelia, Toxoplasma gondii, HIV, Brucella, Rickettsia and Coxiella infection. The testing only revealed previous infection by CMV. For autoimmune systemic diseases (anti-double-stranded DNA (anti-ds-DNA) antibody, anti-SSA60, anti-Sjögren's syndrome type B (SSB) antibody, Anti-Smith antibody (anti-Sm), (anti-RNP) anti-rabies virus ribonucleoprotein antibody, (anti-Scl70) anti-topoisomerase I antibody, Anti-histidyl tRNA synthetase autoantibodies (anti-Jo1), diffuse cytoplasmic staining Antineutrophil cytoplasmic antibody (anti-C-ANCA), perinuclear/nuclear staining Antineutrophil cytoplasmic antibody (anti-P-ANCA), anti-Cardiolipin (ACA), anti-beta-2 glycoprotein I antibodies (anti-B2-GPI), lupus anticoagulant), all results were negative except for anti-thyroperoxidase antibodies (anti-TPO) antibodies (582 units/mL).

Cerebrospinal fluid (CSF) analysis was performed after childbirth. CSF biochemical, cytological and culture analysis were normal. CSF was screened for autoimmune encephalitis (anti-N-methyl-D-aspartate receptor (anti-NMDAR) antibody, Anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor 1/2 (anti-AMPAR 1/2) antibody, Anti-leucine-rich glioma-inactivated 1 (anti-LGI1) antibody, Anti-contactin-associated protein-like 2 (anti-Caspr2), Anti-dipeptidyl-peptidase-like protein 6 (anti-DPPX) antibody, Anti-gamma aminobutyric acid receptor (anti-GABABr) antibody) and no autoantibodies were identified.

Before pregnancy, a thyroid ultrasound showed a 11 mm isoechogenic nodule in the right lobe (with benign features in pathology examination). In the second trimester of pregnancy, the patient had a 581 units/mL anti-TPO antibodies titre and was hypothyroid. In the third trimester, the anti-TPO antibodies titre decreased to 391 units/mL and the patient became euthyroid. After delivery, on the 20th day post partum the anti-TPO antibodies titre was 171 units/mL and maintained euthyroid. On the 25th day post partum anti-TPO antibodies titre increased to 196 units/mL and the patient became marginally hyperthyroid (TSH 0.38 mU/L).

After delivery, brain CT and MRI were performed, as well as an electroencephalogram (EEG). The CT scan was normal. Brain MRI with diffusion-weighted images revealed unspecific long TR (Repetition Time) punctiform foci in subcortical frontoopercular level and incipient sings of accentuation of frontotemporal and cerebellum sulci. Due to lack of collaboration only 1 minute of EEG could be recorded; an apparently organised baseline rhythm was observed.

Differential diagnosis

The diagnostic hypotheses the authors put forward were bipolar I disorder, current or most recent episode manic with psychotic features, with peripartum onset; PP, classified on the DSM-5 as brief psychotic disorders with postpartum onset and delirium due to a medical condition.

A bipolar I disorder, current or most recent episode manic with psychotic features, with peripartum onset was hypothesised because the patient had irritability, excessive energy, decreased need for sleep, tachypsychia and psychomotor agitation. These symptoms lasted more than a week and were disabling. A recent meta-analysis estimates that one in five women with bipolar disorder is affected by psychotic or mood episodes in postnatal period. Longitudinal research suggests an association between psychosis in the postpartum period and onset of bipolar disorder, particularly if hospitalisation is required.¹²

However, acute onset with minimal prodrome, fluctuating mental state with periods of reduced alertness, attention deficit and disorientation, in addition to memory impairment, are contrary characteristics to this diagnosis.

The hypothesis of PP, referring to brief psychotic disorders with postpartum onset, was raised due to the onset of the clinical picture after childbirth. The clear temporal relationship with childbirth is the main feature of PP.⁸ In this case, the symptoms began 13 days after delivery. The presence of delusional thoughts, psychomotor agitation, and disorganised behaviour, associated with emotional instability and acute onset of symptoms, also favour the diagnostic hypothesis of PP. Intense fluctuations in symptoms and mental status are atypical features when considering psychosis, although they are frequently reported in PP. The delirium-like presentation of PP may make it difficult to distinguish from delirium.¹³

The fluctuating mental state with decreased level of consciousness (arousal and awareness), global cognitive impairment as well as marked thought and behaviour disorganisation, led us to consider the diagnosis of delirium. Other clinical features also compatible with this diagnosis was memory impairment. Normal physical examination and haemodynamic stability, as well as laboratory testing of blood glucose, liver and kidney function, ionogram, drugs, complete blood count and urine/blood cultures, allowed to exclude a metabolic, infectious and drug (intoxication/withdrawal) cause of delirium. No focal neurological signs suggestive of structural lesions and absence of suggestive lesions on CT and MRI brain imaging excluded pre-eclampsia/eclampsia, ischaemic stroke, cerebral venous thrombosis, posterior reversible encephalopathy syndrome, postpartum angiopathy/reversible cerebral vasoconstriction syndrome, intracranial haemorrhage, pituitary lesions, intracranial neoplasms and intracranial hypotension due to CSF leaks.

Wernicke’s encephalopathy was also excluded by absence of MRI lesions and normal levels of B₁ vitamin. Absence of seizures and globally normal EEG excluded epilepsy. Normal CSF excluded meningitis and autoimmune encephalitis associated with antibodies against neuron cell proteins.

Although postoperative delirium is a possibility, it usually starts earlier than observed in the patient, between second and fifth postoperative day. In addition, postoperative delirium is closely related to risk factors including dementia, advanced age, significant blood loss and depth of anaesthesia, that the patient did not have.¹⁴

Delirium due to SREAT was considered the most probable diagnostic hypothesis because, in addiction to encephalopathy symptoms that present as fluctuating mental state, global cognitive impairment, thought and behaviour disorganisation, and memory impairment, the patient had high anti-TPO antibodies and had significant remission with high-dose steroid treatment. Standard treatment for SREAT includes high-dose steroids, usually a 5-day course of intravenous methylprednisolone 500–1000 mg/day. According to recent literature, continuation of oral steroid treatment may not be considered if the patient experiences full remission. The patient was treated with 1000 mg/day for 5 days and clinical improvement with return to normal neurological baseline status allowed for steroid discontinuation. Significant clinical improvement after steroid treatment supports the diagnosis of SREAT.¹⁵

Treatment

The patient underwent a 5-day course of intravenous methylprednisolone 1 g/day and risperidone concomitantly. At first, the patient was treated with 1 mg two times per day, being reduced to 0.5 mg two times per day due to extrapyramidal signs. Lorazepam was administered when the patient was agitated or anxious.

Outcome and follow-up

Clinical improvement began at fourth day on methylprednisolone with a dramatic improvement of mental status. The patient became calm, with normal level of conscience and with no cognitive disturbances. The mood was sightly irritable and delusional thoughts were not present.

At 3 months follow-up, as the patient maintained mild mood instability and transient inconsistent paranoid ideas, risperidone 0.5 mg two times per day was maintained as the main treatment. The patient regained global functionality and was able to care for her child autonomously.

Discussion

Although the pathophysiology of SREAT is still unclear, research suggest the involvement of underlying autoimmune mechanisms.¹⁶ Based on the knowledge that the phenomenon of postpartum immune reconstitution leads to an exacerbation of immune activity,¹⁷ SREAT could have been triggered in this patient by these immunological changes, manifesting as PP picture. In a recent systematic review of SREAT with psychiatrical presentation, psychosis was the most frequent presentation among 46 cases followed by depressive disorders. Most of the patients were women (80.4%) and 39.1% had pre-existing hypothyroidism. EEG was normal in 19.6% of the patients.¹⁸ No PP presentation of SREAT was found in the literature at this date.

The literature describes PP as a heterogenous condition, characterised by an abrupt onset of psychotic symptoms (hallucinations and delusions), confusion and perplexity, with a fluctuating course. These characteristics are highly atypical when it comes to psychosis or mood disorders (mania/depression). On the other hand, due to the overlapping symptoms of PP with delirium/encephalopathy, it is difficult to differentiate between these entities. This can lead to frequent misdiagnoses and further increase the supposed heterogeneity of the clinical picture.

Recommended first-line treatment for SREAT is a course of oral prednisone (50–150 mg daily or 1–2 mg/kg/day) or 5-day course intravenous methylprednisolone (500–1000 mg/day). The initial course of corticosteroids can be followed by an oral course of corticosteroids or other immunomodulatory therapy if necessary to maintain remission.^{15 19} Half of the patients have a complete response to corticosteroids and up to 40% have complete remission after the first course.¹⁹ In this case, we observed a significant improvement with corticosteroids therapy. The patient was also medicated with low doses of risperidone as an adjunctive therapy to control psychotic symptoms and psychomotor agitation. In the absence of robust evidence regarding the management of psychiatrical symptoms in SREAT patients, risperidone is one of the medications of choice to reduce agitation cases of hyperactive delirum as has been used in a similar case of SREAT.^{20 21} Although the patient showed global cognitive recovery, she maintained mild mood instability and transient inconsistent paranoid ideas, and so was maintained on low doses risperidone (0.5 mg two times per day). The persistence of mild psychiatrical symptoms may be associated with sequelae, which are described in 25% of the patients.²

This case illustrates the importance of accessing autoimmune diseases in PP, including thyroid autoimmune disease. Atypical psychiatrical features, particularly in patients without psychiatrical history, should prompt clinicians to look behind the plethora of symptoms and investigate underlying possible medical causes. A high index of suspicion is crucial to achieve a correct diagnosis and to provide an adequate treatment in due time. This can possibly spare the patient from sequela or side effects from inadequate treatment.

Learning points.

• Postpartum psychosis (PP) has an atypical presentation which can lead to misdiagnosis.

• Women are vulnerable to immunological dysfunction during postpartum period, being highly recommended screening for autoimmune diseases in patients presenting with PP.

• In patients with no psychiatrical history and atypical psychiatrical symptoms, it is important to consider underlying organic causes.

Ethics statements

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Consent obtained directly from patient(s).