Hashimoto’s Encephalopathy with Use of Intravenous Immunoglobulin as First-Line Therapy

ABSTRACT

Hashimoto’s encephalopathy is an uncommon cause of altered mental status in hospitalized patients and is challenging to diagnose, particularly in the presence of other psychiatric comorbidities. Corticosteroids are the primary treatment. Here, we present a patient with history of post-traumatic stress disorder and prior substance abuse admitted with profound altered mental status and agitation requiring admission to the intensive care unit and mechanical ventilation. He was treated with intravenous immunoglobulin (IVIG) instead of the standard steroid course because of concerns for worsening agitation. The patient had improvement with IVIG infusions, returned to a functional state, and has remained on IVIG therapy monthly since the initial episode without any disease recurrence.

INTRODUCTION

Hashimoto’s encephalopathy (HE) is an uncommon cause of encephalopathy and largely a diagnosis of exclusion. It is characterized by neurologic and/or cognitive deficits, elevated anti-thyroid antibodies, and immunotherapy-responsiveness when other etiologies have been excluded.¹ Frequently, patients with HE have elevated anti-thyroperoxidase (anti-TPO) or anti-thyroglobulin (anti-Tg) antibodies, which can serve as biomarkers supporting the diagnosis.^1,2 There are two predominant clinical presentations: Stroke-like manifestations with focal and transient neurologic deficits or progressive cognitive decline with psychiatric features.^1,3,4 These manifestations are not mutually exclusive, and patients may present with an overlapping of symptoms at the time of diagnosis. A mainstay of treatment is high-dose steroids, although there are a growing number of published reports outlining treatment in patients who are steroid-resistant or have conditions where steroids may be contraindicated, posing a need for alternative therapy.^4–11 Azathioprine, cyclophosphamide, and intravenous immunoglobulin (IVIG) have been used, with IVIG having the most supportive literature.^5,6,8,10 Recently, Abboud et al. (2021) have outlined best practice recommendations supporting IVIG as an alternative therapy for autoimmune encephalitis when corticosteroids are contraindicated.¹¹

CASE REPORT

A 47-year-old male with history of chronic pain, opiate dependence managed with buprenorphine/naloxone, and recent diagnosis of hypothyroidism presented with 3 months of progressive symptoms of ataxia, poor sleep, aggression, slurred speech, cognitive decline, headaches, and low-grade temperature elevations not meeting fever criteria (99–100.2°F). One day before presentation, he had an acute onset of altered mental status and aphasia, prompting emergency department evaluation. On presentation, examination identified no motor deficits, appropriate response to pain, and spontaneous eye movements. The patient was combative and unable to follow commands, only repeating “yes, sir” and “I’m sorry” without appropriate context.

The patient’s physical examination showed a pulse of 74 beats per minute, a blood pressure of 148/91, a temperature of 98.2°F, a respiratory rate of 22, and a pulse oxygenation of 98% while on room air. His neurologic examination was significant for inability to follow commands for strength or sensory examination, although he retracted to painful stimuli and had spontaneous movement in all four limbs. He was speaking with a slight slurring of his speech and opened his eyes spontaneously and sometimes to command, and his pupils were reactive to light. He was resistant to examination often pushing the provider away but no defined movements to purposely harm providers. His Glasgow Coma Scale was 11.

Initial investigations noted slight leukocytosis (11.5 × 10/µL), elevated C-reactive protein (7.790 mg/dL), and erythrocyte sedimentation rate (66 mm/h). Free T4 and thyrotropin levels were within normal limits while on 50 mcg of levothyroxine daily. Urine drug screen was negative, as were serum ethanol and salicylate levels (Table I). Neuroimaging including both CT without contrast and MRI with and without gadolinium contrast of the head returned negative for intracranial pathology. CT of the chest with iodinated contrast noted an enlarged left hilar lymph node (2.3 × 2.6 cm), enlarged left para-aortic (2.3 × 1.2 cm), right paratracheal (1.0 × 1.6 cm), and subcarinal lymph nodes (1.0 × 2.5 cm). A follow-up PET/CT scan did not demonstrate increased 18-fluorodeoxyglucose avidity, inconsistent with an acute infectious process or lymphoma.

TABLE I.

Laboratory Evaluation

Laboratory Results	Result	Reference range
Serum
Ethanol	<10 mg/dL	0.0–10.0
Acetaminophen	<5 mcg/mL
Ammonia	23 mcmol/L	16–60
White blood cell count	11.5 × 103/mcL	3.6–10.6
Neutrophils	80%	40.7–76.4
C-reactive protein	7.790 mg/dL	0.0–0.5
Erythrocyte sedimentation rate	66 mm/h	2–28
Thyrotropin	2.11 mcIU/mL	0.27–4.20
Thyroxine free	1.31 ng/dL	0.93–1.7
Thyroglobulin Antibody (Ab)	<1	0.0–0.9
Thyroperoxidase Ab	272 IU/mL	0–34
Urine
Amphetamines	Negative
Barbiturates	Negative
Benzodiazepines	Negative
Cocaine	Negative
Opiates	Negative
Phencyclidine	Negative
Cannabinoids	Negative
Methadone	Negative
Oxycodone	Negative
CSF fluid
White blood cells	<1/mcL	0.0–5.0
Protein	21 mg/dL	15–45
Glucose	64 mg/dL	40–70
CSF fluid culture	No growth at 4 days
Glutamic acid decarboxylase Ab	<5.0 IU/mL	0.0–0.5
NMDA receptor Ab	<1:1	<1:1
Neuromyelitis optical/AQP4-IgG	<1:1	<1:1
AMPA receptor Ab IgG	<1:1	<1:1
GABA-B receptor Ab IgG	<1:1	<1:1
CASPR2 Ab IgG	<1:1	<1:1
LGl1 Ab IgG	<1:1	<1:1
Voltage-gated K+ channel Ab	<1:1	<1:1
Escherichia coli K1	Negative
Haemophilus influenza	Negative
Listeria monocytogenes	Negative
Neisseria meningitides	Negative
Streptococcus agalactiae	Negative
Cytomegalovirus	Negative
Human simplex virus 1/2	Negative
Human herpesvirus 6	Negative
Parechovirus	Negative
Varicella-zoster virus	Negative
Ccryptococcus neoformans	Negative
Enterovirus	Negative
Streptococcus pneumoniae	Negative

Abnormals are bolded.

Deep sedation and intubation were required for lumbar puncture as the patient was hyperactive and combative despite the use of haloperidol and a dexmedetomidine drip for sedation. Cerebrospinal fluid analysis showed normal glucose (63 mg/dL), protein (22.6 mg/dL), and no pleocytosis (Table I). Molecular testing for viral/bacterial causes of encephalitis was negative, as was an immune-mediated encephalitis panel (Table I). Electroencephalogram demonstrated only mild-moderate generalized slowing, with no epileptiform activity appreciated.

The patient was extubated, and on hospital day 4, he spontaneously regained mental status and signed out against medical advice. He continued to have ataxia, confusion, agitation, and inappropriate interactions after discharge. On posthospitalization follow-up, ∼2 weeks later, his anti-TPO antibodies returned elevated to 272 IU/mL (range 0–34) and additional workup was negative. The diagnosis of HE was made after ruling out other causes of encephalopathy, to include sarcoidosis, based on serologic studies, neuroimaging, and the lack of a CSF pleocytosis and a normal CSF protein level. Therapies other than corticosteroids were pursued because of concerns of exacerbating the patient’s ongoing agitation. After consultation with a multidisciplinary team to include neurology, hematology-oncology, and infectious disease, we started therapy with IVIG at 400 mg/kg for 5 days. The patient and wife noted clinical improvement after two doses of IVIG including improved cognition, gait, and sleep. The patient was discharged after the fifth dose with near complete resolution in symptoms, but continued to receive doses every 4 weeks because of mild symptom relapse noted by mental slowing and word-finding difficulties. Neuropsychiatric testing was performed after initiation of IVIG with normal results although neurocognitive testing was not performed pretreatment. At the time of this report, the patient is 16 months postdiagnosis and has remained clinically stable with monthly IVIG infusions. He has continued to receive IVIG infusions monthly because of a slight cognitive decline that occurs during longer intervals between therapy. He has had no further hospitalizations and has been able to return to his pre-illness level of activity including a full-time job. He has had a subsequent MRI brain, done for headaches, that was negative. A follow-up CT of chest, abdomen, and pelvis showed resolution of lymphadenopathy.

DISCUSSION

Here, we presented a case of a 47-year-old male with a history of substance abuse and recently diagnosed hypothyroidism admitted to the Intensive Care Unit (ICU) for acute agitated delirium, who was subsequently diagnosed with HE. HE is an uncommon cause of encephalopathy often warranting ICU admission because of profound agitation, stroke symptoms, psychosis, or seizures. HE is a diagnosis of exclusion, with all other identifiable causes of encephalitis including bacterial or viral infection, autoimmune causes, or toxic metabolites being ruled out. The patient had an elevated erythrocyte sedimentation rate and C-reactive protein, which have been reported in HE.¹²

The diagnosis of HE is commonly debated. The consensus definition includes neurologic manifestations at presentation in the presence of elevated anti-TPO or anti-Tg antibodies and must be responsive to immune suppressive treatments.¹ The presence of anti-TPO antibodies alone cannot be used to diagnose HE, since these can occur in 5–20% of the general population, including in 11% of those with similar demographics to our patient.¹³ Thus, excluding other potential etiologies of encephalopathy is central to the evaluation of patients suspected of having HE.

Many different treatment modalities for HE have been attempted, although glucocorticoids remain the first-line treatment option because of the high rate of clinical response. Castilla et al. report using a steroid therapy protocol of intravenous methylprednisolone 1 g per day for 5 days.² Chong et al., in their review, showed a 98% success with glucocorticoid treatment in the 45 patients who received glucocorticoids.¹ There is a subset of patients with relative contraindications to steroid therapy, or steroid-resistant HE, where alternative therapies must be considered. IVIG has been documented in case reports as a suitable alternative to steroid therapy, often used in second line after steroids have failed to produce long-term remission.^5,6,8,10

IVIG is pooled immunoglobulin that is infused intravenously or injected subcutaneously and acts to mediate the hosts’ immunoglobulin G (IgG) production leading to the suppression of the autoantibody production as well as blocking the autoantibodies to the target. The half-life of IVIG is ∼4 weeks.¹⁴ At this time, there are limited case reports outlining the use of IVIG as a first-line therapy.^9,11 However, given the patient’s profound agitation, endangering both the patient and the team, it was felt that alternative therapies should be pursued first.

This case demonstrates the potential to utilize IVIG as first-line therapy for HE patients with significant agitation thought to be a relative contraindications to high-dose corticosteroids. This is the first identified case requiring continued monthly IVIG infusions to obtain long-term symptom control; however, chronic steroid use has been documented in the literature and is consistent with the need for continual suppression of antibody production. Approximately 60% of patients required additional steroids after the initial 5-day course used most commonly in the literature.² Since the patient has required recurrent infusions approximately every 4 weeks, this is consistent with both the half-life and treatment course for other autoimmune diseases, including myasthenia gravis and chronic inflammatory demyelinating polyradiculoneuropathy. This case adds to the body of growing literature and highlights that IVIG can be considered as first-line treatment for HE in patients for whom high-dose corticosteroids are contraindicated.

ACKNOWLEDGMENT

None declared.

FUNDING

None declared.

CONFLICT OF INTEREST STATEMENT

None declared.

CLINICAL TRIAL REGISTRATION

Not applicable.

INSTITUTIONAL REVIEW BOARD (HUMAN SUBJECTS)

Not applicable.

INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE

Not applicable.

INDIVIDUAL AUTHOR CONTRIBUTION STATEMENT

L.D.B., E.E., and M.B. were all involved in the care of this patient. The draft was written by L.D.B. and reviewed and edited by E.E. and M.B. All authors read and approved the final case report.

DATA AVAILABILITY

Not applicable.

INSTITUTIONAL CLEARANCE

Institutional clearance–approved.

Author notes

Oral presentation: Walter Reed National Military Medical Center Research and Innovation Month, May 4, 2022, Bethesda, MD, USA.

The views expressed in this material are those of the authors and do not reflect the official policy or position of the U.S. Government, the Department of Defense, or the Departments of the Army, Navy, or Air Force.