Steroid-Responsive Encephalopathy Associated With Hashimoto’s Thyroiditis in an Adolescent With Chronic Hallucinations and Depression: Case Report and Review

We describe the case of a 14-year-old girl who presented with a 5-year history of hallucinations and depression. She had significantly elevated thyroperoxidase (TPO) antibody titers consistent with the diagnosis of Hashimoto’s thyroiditis. A magnetic resonance imaging (MRI) scan of the brain showed white matter changes affecting the frontal lobe, and cerebral hypoperfusion deficits were observed on serial single-photon emission computed tomography (SPECT) scans. The patient had significant clinical improvement and showed resolution on neuroimaging after corticosteroid treatment. Steroid responsive encephalopathy associated with Hashimoto’s thyroiditis (SREHT) is a more accurate description of the previously named “Hashimoto’s encephalopathy.” This is a condition with neuropsychiatric symptoms associated with high anti-thyroid antibody titers which shows marked improvement following corticosteroid treatment.The medical evaluation of adolescents who present with psychiatric symptoms requires a full clinical assessment to exclude organic disease. The list of potential etiologies in these patients can be long, particularly if presenting symptoms do not fall into recognized patterns. We present the case of an adolescent with recent disclosure of long-standing hallucinations and depression who was found to have elevated thyroid-stimulating hormone (TSH) and anti-thyroid antibody titers. This case reinforces the importance of evaluating thyroid function in pediatric patients who present with ill-defined neuropsychiatric symptoms.The patient is a 14-year-old girl with no significant past medical history who described visual and auditory hallucinations beginning at age 9. Her visual hallucinations comprised seeing animals and unknown people on walls often engaged in violent acts and she began hearing commanding and denigrating voices. Her symptoms caused significant distress associated with decreased mood and energy.After normal electroencephalogram background activity (EEG), the patient was treated with numerous psychotropic medications over a 6-month period by her psychiatrist including valproic acid, sertraline, and quetiapine fumarate. These medications reduced the intensity, but not the frequency, of her hallucinations and resulted in intolerable adverse effects including marked weight gain and hypersomnolence.The patient had menarche at 11 years. The patient’s father suffers from epilepsy, her mother has rheumatoid arthritis, and her twin sister has also been diagnosed with Hashimoto’s thyroiditis. She was an above-average eighth grade student whose school performance had recently declined.On evaluation, the patient had an intact mental status examination with a score of 38/38 on the Kokman scale. Temperature was 37.4°C, heart rate 90 beats per minute, respiratory rate 19 breaths per minute, blood pressure 110/78 mm Hg. Height 168.3 cm (25%), weight 129 kg (≫97%), and body mass index 45.5 kg/m2. Her formal neurologic examination did not reveal any focal findings. Thyroid examination was normal. Aside from flesh-colored striae on the abdomen, the remainder of the examination was unremarkable.A thorough laboratory and multidisciplinary evaluation was undertaken. Initial results revealed a TSH of 77.4 mIU/mL (0.3–5.0 mIU/mL), free thyroxine of 0.5 ng/dL (0.8–1.8), and TPO antibody titer of 6320 (normal <20 IU/mL). Hemoglobin was 10.7 g/dL, MCV 79 fL, with iron studies and peripheral blood smear indicative of a hypochromic, microcytic anemia. Other laboratory studies including white blood cells, platelets, erythrocyte sedimentation rate (3 mm/hour), electrolytes, liver and renal function, ceruloplasmin, lactate, AM cortisol, corticotropin, C-reactive protein, complement, glutamic acid decarboxylase, antinuclear antibody, anti-endomysial antibody, muscle acetylcholine receptor antibody, heavy metal screen, urine-free cortisol, angiotensin-converting enzyme, and syphilis serology were normal. A chest film, electrocardiograph, and echocardiogram were also normal. Cerebrospinal fluid (CSF) analysis revealed normal cell count, protein, glucose, and was negative for oligoclonal banding. MRI of the head showed scattered foci of T2 hyperintensity in the white matter of the frontal lobe. A brain perfusion scan (SPECT) was also abnormal with patchy decreased perfusion most notable in the left temporal lobe, inferior aspect of the frontal lobes as well as decreased perfusion to the right basal ganglia. Short and prolonged video electroencephalography (24-hour) did not reveal epileptiform activity despite hallucinatory episodes.The patient was started on 100 μg of l-thyroxine daily in addition to iron supplementation and her previous psychiatric medications. Because the patient was having some gradual improvement in symptoms and CSF analysis did not reveal elevated protein suggestive of an inflammatory process, steroids were held pending the patient returning for repeat thyroid function testing and SPECT imaging.On follow-up visit to the clinic 1 month after her initial assessment, the patient noted mild improvements in concentration and memory but remained hallucinatory, fatigued, and dysthymic. Her l-thyroxine dose was increased after repeat thyroid testing showed an elevated TSH, and her TPO antibodies remained elevated. A second SPECT scan remained abnormal. Cortical uptake was decreased in both frontal and fronto-parietal regions, worse on the right. Improvement was noted in temporal lobe and right basal ganglia perfusion. In light of the minimal improvement in symptoms of the patient on thyroid replacement, steroid therapy was initiated with methylprednisolone 1 g intravenously per day for 3 days, followed by prednisone at a dose of 60 mg orally per day.At the outset, the patient had a partial response to prednisone treatment with resolution of visual hallucinations, but persistence of auditory hallucinations. In an effort to lose weight, the patient stopped taking her prednisone 3 months into her steroid course. She immediately noticed an increase in frequency and intensity of her hallucinations and depressed mood, which were eliminated on resumption of corticosteroids. The patient returned for evaluation at 6 months after prednisone was initiated. She denied any hallucinations and described improved mood. Her school performance improved significantly and her weight stabilized on resumption of a regular exercise routine. At her latest visit, she had normal thyroid function tests (TSH = 2.1 mIU/L, free thyroxine = 1.2 ng/dL) and a decreased TPO antibody titer (2300 IU/mL). A repeat SPECT scan showed complete resolution of her prior perfusion deficits affecting the temporal lobe with continued decreased uptake in the frontal and parietal lobes. The steroid was decreased and the patient was advised to taper her dose monthly.Hashimoto’s thyroiditis is the most common cause of acquired hypothyroidism in children and adolescents.1 It is a chronic autoimmune thyroiditis characterized by diffuse lymphocytic infiltration, which may result in firm goiter with a high titer of circulating anti-thyroid antibodies. Although a minority of cases present with thyrotoxicosis, most children are euthyroid or hypothyroid at diagnosis. Clinical manifestations in hypothyroid patients may include impaired growth, myxedema, cold intolerance, and lethargy as well as behavioral changes. Psychiatric symptoms include impaired short-term memory and other cognitive dysfunction in 66% to 90% and depression in 40%.2 The term “myxedema madness,” coined in 1949, described a florid psychotic illness associated with profound hypothyroidism.3,4 This condition has become rare with the advent of sensitive thyroid screening tests and effective treatment.5 The first description of neuropsychiatric disease associated with autoimmune thyroid dysfunction was by Brain et al6 in 1966. He described the case of a 40-year-old coachbuilder with known thyroid-antibody positive Hashimoto’s disease who subsequently developed focal neurologic deficits and coma successfully treated with steroids and thyroxine replacement. This patient was noted to have elevated CSF protein as well as slowing on EEG. Shaw and colleagues7 further reported 5 cases with subacute onset of encephalopathy with elevated titers of anti-thyroid antibodies and proposed the term “Hashimoto’s encephalopathy” as a distinct clinical entity.SREHT is a clinical condition encompassing persistent or relapsing seizures, myoclonus, focal neurologic deficits, and delusions or hallucinations along with elevated thyroid antibody titers.8,9 A workup must exclude other etiologies and the neuropsychiatric deficits show significant clinical improvement with corticosteroid treatment. The patient, typically female, may be euthyroid or hypothyroid and anti-thyroid antibody titers do not correlate to the degree of encephalopathy.7–9 Although heterogeneous in presentation, 2 subtypes have been described. The vasculitic type is characterized by acute stoke-like episodes associated with focal neurologic features and seizures. The diffuse progressive type is associated with insidious onset with progressive impairment of mental status with confusion, somnolence, and psychosis.8 Neither presentation is exclusive and significant overlap may occur. Furthermore, EEG, computerized tomography, MRI, and CSF analysis cannot distinguish between the 2 types.Although numerous reports have been described in adults, few cases are described in children. In our review of the literature (see Table 1), we found a total of 16 cases (including our own) aged 9 to 17 years. All but 2 were female with a mean age of 13.7 years. Thirteen cases presented with seizures, and all of the cases had an intense initial workup to rule out traumatic and infectious etiologies. Only 2 primarily behavioral presentations are described: ours and a 10-year-old patient with longstanding attentional difficulties which improved with steroid treatment.9 Our case is unique because of the long (5-year) history of hallucinations and depressed mood.The MRI findings observed in our patient, with small T2 weighted white matter changes, has been described in other pediatric patients.10,11 Nevertheless, cranial imaging performed in most pediatric cases reported normal computerized tomography or MRI scans of the head. This differs from the adult literature, as a recent review of patients with SREHT followed at the Mayo Clinic revealed abnormal MRI scans in 57% of patients, a minority (45%) of which resolve with treatment.12An interesting aspect of our case relates to the changes seen in serial SPECT imaging studies over the course of the patient’s illness. When treated with thyroid hormone alone, the SPECT showed improved temporal lobe perfusion mirroring clinical improvement in her memory and cognition. These deficits completely resolved on initiation of steroids, although decreased perfusion in the frontal and parietal lobes persisted. Hypothyroid patients with “Hashimoto’s encephalitis” with abnormal SPECT scans at diagnosis have been described with full resolution of symptoms on treatment with thyroid hormone alone.13–15Although formal treatment studies are absent, most reports have shown that glucocorticoids are effective. We recommend use of high-dose steroids, initially with intravenous methylprednisolone, followed by a prednisone (1–2 mg/kg/days, max 60 mg/days) for 6 to 8 weeks. The dose should be gradually reduced with expected improvement in symptoms over 3 to 6 months. Despite treatment, patients may experience relapses, and adolescents with this condition may experience residual cognitive deficits.7,15–17Etiologically, SREHT is a controversial diagnosis, as it lacks a precise pathophysiologic basis. We are not aware of any evidence indicative of a causative link between thyroid autoimmunity and encephalitis. CSF analysis has not shown the presence of TPO antibodies or thyroglobulin antibodies in symptomatic adolescent and adult cases.11,18,19 This condition best describes an association that is postulated to include aspects of endocrine dysfunction, cerebral vasculitis, and impaired autoimmunity.8,9,17,20,21 In the case of our patient, subclinical hypothyroidism and abnormalities on SPECT scanning, indicative of altered cerebral microvascular perfusion, were found. Thus far, our patient has not shown any evidence of other autoimmune disease, which has been reported in a significant proportion of patients with Hashimoto’s thyroiditis.22Despite the speculative origin of SREHT, it remains a treatable encephalopathy. Pediatricians must be aware that younger patients may present with a diverse clinical picture, including seizures, myoclonus, focal neurologic deficits, delusions, and hallucinations. This case is unique as it illustrates that the neuropsychiatric component of this condition may be chronic. SREHT requires a high index of suspicion, and our case stresses the importance of evaluating thyroid function and thyroid antibody titers in adolescent patients with psychiatric presentations.