Refractory seizures with encephalopathy may be due to Hashimoto encephalopathy

Atraya Samanta; Agniva Deb; Indranil Karmakar; Santanu Roy

doi:10.4103/ipcares.ipcares_114_23

CASE REPORT

Year : 2023 | Volume : 3 | Issue : 3 | Page : 184-187

Refractory seizures with encephalopathy may be due to Hashimoto encephalopathy

Atraya Samanta, Agniva Deb, Indranil Karmakar, Santanu Roy
Department of Pediatrics, The Calcutta Medical Research Institute, Kolkata, West Bengal, India

Date of Submission	11-May-2023
Date of Decision	10-Jul-2023
Date of Acceptance	12-Jul-2023
Date of Web Publication	14-Aug-2023

Correspondence Address:
Dr. Atraya Samanta
24, Parcus Road, Bardhaman - 713 101, West Bengal
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_114_23

Abstract

Background: Hashimoto's encephalopathy, also known as steroid-responsive encephalopathy associated with autoimmune thyroiditis, is a relatively uncommon neurological disorder, mostly in adults, with an extremely rare occurrence in children. Clinical Description: A 9-year-old girl presented with unprovoked seizures and encephalopathy. She had been diagnosed with hypothyroidism, at around 6 ½ years of age, though was noncompliant to therapy with levothyroxine. Management: The child was managed with intravenous (IV) antiepileptics and other supportive care. Seizures were refractory and with worsening sensorium, she required mechanical ventilation. The magnetic resonance imaging of the brain was unremarkable, as also the cerebrospinal analysis. Autoimmune encephalitis panel was negative. The electroencephalogram showed background activity of 10–11 Hz and few areas with generalized slow waves. As she was a known case of hypothyroidism without taking thyroid supplements for the past few months, thyroid profile was sent. Reports showed FT3-1.1 pg/dL, FT4-0.515 ng/dL, and thyroid-stimulating hormone (TSH) - 107.3 μIU/mL. Thyroid antibody profile revealed antithyroid peroxidase antibody >500 IU/mL and antithyroglobulin antibody >1000 IU/mL. Following this, an ultrasound of the neck was done which showed features of thyroiditis. Considering the possibility that the underlying thyroiditis could explain the obtunded state and refractory seizures, the patient was started on levothyroxine and IV methylprednisolone. The sensorium of the child improved dramatically, and she got extubated. There were no further seizures and her TSH level reduced gradually and eventually, she was discharged. Conclusions: In a child with altered sensorium and refractory seizures, Hashimoto encephalopathy is a diagnosis of exclusion and may be considered when most of the common causes of encephalopathy and seizures have been ruled out, especially in the setting of some clinical clues of hypothyroidism. The condition is often reversible with good response to steroid therapy.

Keywords: Altered sensorium, autoimmune thyroiditis, hypothyroid, steroid-responsive encephalopathy

How to cite this article:
Samanta A, Deb A, Karmakar I, Roy S. Refractory seizures with encephalopathy may be due to Hashimoto encephalopathy. Indian Pediatr Case Rep 2023;3:184-7

How to cite this URL:
Samanta A, Deb A, Karmakar I, Roy S. Refractory seizures with encephalopathy may be due to Hashimoto encephalopathy. Indian Pediatr Case Rep [serial online] 2023 [cited 2023 Sep 26];3:184-7. Available from: http://www.ipcares.org/text.asp?2023/3/3/184/383615

Hashimoto encephalopathy (HE) is an infrequent neurological condition, associated with thyroiditis, mostly reported in adult females. It is extremely rare in the pediatric age group with hardly 60 cases being reported till 2020.^[1] As the name suggests, the presentation of HE consists of alterations in mental status and seizures, but in addition, this condition is known to manifest certain specific features such as neuropsychiatric disturbances, cognitive decline, ataxia, and others.^[2],[3]

Here, we discuss a young girl presenting with refractory seizures, who turned out to be a case of Hashimoto's encephalopathy.

Clinical Description

The parents of a 9-year-old girl brought their child in a drowsy state, with a history of abnormal movements of all four limbs, about 2 h ago, which had been aborted by some intravenous (IV) medication in a local hospital. There was a vague history of fever 3–4 days back, though not documented. There was no history of associated infections or flu-like symptoms, fever, headache, vomiting, trauma, any drug intake, blurring of vision, animal bite, or travel in the recent past.

In the past history, it was found that the child had habitual constipation and was diagnosed with hypothyroidism around the age of 6 ½ years and had been receiving regular levothyroxine for initial 18 months after diagnosis. Thereafter, she was on irregular medication, and for the last 3 months, the child was completely off medication.

The child was born at term, with a birth weight of 2.8 kg, vaginally delivered, to parents married in a nonconsanguineous setting. The antenatal, natal, and postnatal periods were uneventful. The girl had achieved her developmental milestones as per normal limits. She had an apparently normal cognitive development also, with average scholastic performance. The child was the first in birth order and the only child of her parents. There was no family history of neurological or affective disorders, except for the paternal grandmother who had hypothyroidism. The child had an average regular Indian diet and was immunized for age.

On examination, the baby was overweight for her age (39 kg), height was 117 cm (just below 3^rd centile), and body mass index 28.49. On general physical examination, the child was in altered sensorium, with a Glasgow Coma Scale (GCS) of 8/15 (E2V2M4), normal pulse volume, a heart rate of 102/min, blood pressure of 110/70, respiratory rate of 24/min, temperature of 97.9° F, capillary blood glucose 89 mg/dl, and oxygen saturation of 98% on room air.

Neurological examination revealed that cranial nerves were intact and pupils were bilaterally symmetrical, mid-dilated, and reacting sluggishly to light stimulus. There were no signs of meningeal irritation. Superficial and deep tendon reflexes were present. Power was 3/5 in proximal and distal muscles of lower extremities and 4/5 in upper extremities bilaterally, with normal tone and bulk. Sensory examination was normal. Both planters were flexors.

There were no skin rashes, hypo or hyperpigmented patches, or any discoloration or telangiectatic changes. The rest of the systemic examination was within normal limits.

Management and Outcome

The child was received in an unconscious state and was immediately provided supportive care with oxygen through mask. IV cannulation was done for collecting blood samples for investigations and IV maintenance fluids were started. Soon, the child had another generalized tonic–clonic seizure in the emergency room, for which IV lorazepam was administered, but the seizures were not aborted. IV phenytoin at a half-loading dose (10 mg/kg) was given, as the child had earlier received a loading dose at the local hospital. As the seizures continued, IV levetiracetam was next administered at a loading dose at 30 mg/kg, following which the seizures were finally terminated. However, the GCS had deteriorated to 7/15 (E1V2M4). The child was intubated and started on mechanical ventilation with pressure-regulated volume control support, FiO₂ 30%, peak inspiratory pressure of 18 cm H₂O, and positive end-expiratory pressure of 6 cm H₂O. There was no need for vasopressors. The patient was started on IV antibiotics (ceftriaxone and vancomycin), and IV acyclovir, to give the benefit of the doubt to the possible history of an infective etiology. Maintenance doses of levetiracetam (10 mg/kg/day) and phenytoin (5 mg/kg/day) were continued.

Routine laboratory tests revealed hemoglobin of 12.6 g/dL, total leukocyte counts of 11,000/mm³, with neutrophils 62.%, lymphocytes 33%, platelet count of 1.9 lakhs/mm³, and erythrocyte sedimentation rate of 14 mm/1^st h. Her kidney function tests were normal with urea of 23 mg/dL and creatinine of 0.31.mg/dL. Alanine aminotransferase and aspartate aminotransferase were 34 and 28. IU/dL, respectively, serum albumin was 4.24 mg/dL, and total bilirubin was 0.7 mg/dL. Further tests revealed serum lactate of 10.6 mg/dL (normal range 4.6–20.1 mg/dL) and serum ammonia of 49.2 μg/dL (normal range 13–78 μg/dL).

A lumbar puncture was done and the cerebrospinal fluid (CSF) analysis was within normal limits (cell count 5/mm³, lymphocyte 100%, protein 38 mg/dL, sugar 68 mg/dL, and no growth in Gram stain. The herpes simplex virus DNA polymerase chain reaction in CSF was negative. Investigations for autoimmune encephalitis panel were done, including antibodies against N-methyl-D-aspartate, alpha-amino-3-hydroxy-methyl-4-isoxazolepropionic acid 1 and 2, contactin-associated protein 2, leucine-rich glioma-inactivated protein 1, gamma-aminobutyric acid a and b, glutamic acid decarboxylase, and voltage-gated potassium channel, which were all negative.

A noncontrast computed tomography of the brain was done on an emergency basis, to rule out any acute hemorrhage/signs of raised intracranial pressure. It was normal and helped us in taking the decision of doing a lumbar puncture. Later, we did a magnetic resonance imaging (MRI), which also turned out to be normal. An electroencephalogram (EEG), done within 12 h of hospitalization, showed background activity of 10–11 Hz and few areas with generalized slow waves which was suggestive of an interictal pattern of seizure disorder.

Seizures were controlled on maintenance doses of the two anti-epileptics. The child was seizure-free since day 2 of admission. At this point, the history and clinical features were reviewed and the following points were highlighted: First, the child had a past history of hypothyroidism, but had stopped taking medications; Second, the child was obese, had a history of constipation, and had family history of hypothyroidism. With this background, in a child presenting with new-onset, unprovoked generalized seizures, a possibility of hypothyroidism with Hashimoto encephalitis was considered. Hence, a thyroid profile was sent on the 2^nd day of admission. The reports showed FT3-1.1 pg/mL (1.7–4.2 pg/mL), FT4-0.515 ng/dL (0.7–1.8 ng/dL), and thyroid-stimulating hormone (TSH) 107.3 μIU/mL (0.3–5.5 μIU/mL). Thyroid antibody profile revealed antithyroid peroxidase (TPO) antibody >500 IU/mL (0–34 IU/mL) and anti-thyroglobulin antibody >1000 IU/mL (<116 IU/mL). Subsequently, an ultrasound of the thyroid gland was done [Figure 1], which revealed that both lobes and isthmus of the thyroid gland were enlarged with multiple nodules scattered through the gland. These features were suggestive of thyroiditis. The CSF for antithyroid antibodies could not be done.

Figure 1: Ultrasound of thyroid gland showing an enlarged thyroid along with multiple nodules

Click here to view

Thus, considering the possibility that the underlying thyroiditis could contribute to the obtunded state and refractory seizures, the patient was started on levothyroxine 75 μg once daily along with IV methylprednisolone 500 mg once daily for 3 days. Vancomycin and acyclovir were stopped.

Gradually, the sensorium of the child started to improve and the child was extubated. We attributed the improvement in GCS of the child to be a combined effect of antiepileptics, methylprednisolone, and levothyroxine.

Thyroid profile was being monitored at regular intervals. The TSH level started to decline gradually [Table 1]. IV anticonvulsants and methylprednisolone were stopped and oral levetiracetam, phenytoin, and prednisolone (60 mg/day) were started on day 6. The child remained seizure-free thereafter. Repeat EEG done 5 days after hospitalization, still showed an interictal pattern of generalized seizure disorder. The child remained clinically and hemodynamically stable. There were no residual neurodeficits.

Table 1: Serial titres of TSH, fT3 and fT4 of the child

Click here to view

The child was thus diagnosed as a case of late-onset refractory seizures, due to either idiopathic epilepsy associated with thyroiditis or primarily contributed by thyroiditis (steroid-sensitive encephalopathy associated with autoimmune thyroiditis). The child was discharged on day 12 on oral levetiracetam (at 10 mg/kg/day), phenytoin (5 mg/kg/day), prednisolone 60 mg/day, and levothyroxine 75 μg/day. Oral prednisolone was tapered over 1 month and stopped, while levothyroxine and levetiracetam were continued.

At follow-up, nearly 30 days after discharge, the child was clinically stable with no episodes of convulsions after discharge. Repeat thyroid profile was within normal limits with a TSH level of 4.2 μIU/mL, FT3 level of 2.2 pg/mL, and FT4 level of 1.3 ng/dL on day 30 after discharge. Our plan is to do a serial neurological follow-up along with EEG and to gradually stop levetiracetam and also to titrate levothyroxine supplement as per subsequent thyroid profile.

The above-described child is an interesting case of refractory seizures, with EEG suggestive of generalized slow waves, in which, none of the commonly known causes could be detected by routine investigations. With a grain of suspicion, we went ahead with testing the thyroid functions, which revealed remarkably high levels of TSH and unusually high titers of antithyroid antibodies. As the clinical condition improved and seizures abated after the use of steroids, along with already continuing standard anti-epileptics, we concluded that the girl was possibly having a steroid-sensitive encephalopathy associated with autoimmune thyroiditis or Hashimoto's encephalopathy.

Hashimoto's encephalopathy is a steroid-responsive acute or subacute encephalopathy associated with raised titers of antithyroid antibodies. The phenomenon of HE is a rare, but important association with Hashimoto's thyroiditis, and has mainly been described mostly in adults, with a female preponderance with 4:1 ratio, an average age of onset being 40 years.^[1] This disorder has very rarely been described in children, mostly between 9 and 18 years of age.^[2],[3]

The risk factors and pathogenesis of this condition are largely unclear. The postulated mechanisms include vasculitis, autoantibodies (both thyroid and extra-thyroid), and hormonal dysregulation associated with hypothyroidism.^[4] The dramatic improvement with steroids and other immunosuppressives in this condition supports the possible autoimmune mechanism.

As expected from the name of the disorder, the most important presenting symptom of HE is altered mental status. Cognitive impairment and behavior changes are quite commonly reported.^[2],[3] Children may become acutely symptomatic with generalized tonic–clonic or complex partial seizures, hallucinations, or acute confusional state. Of the 25 cases reviewed by Alink and de Vries, 80% presented with generalized tonic–clonic convulsions, 52% had confusion, and 40% had headache.^[2] In a child with generalized seizures, associated features which may raise suspicion of HE include tremors, myoclonus, and ataxia, in the background of a rapidly progressive dementia and mood alteration, already setting in the patient.^[2] Our child presented with acute-onset generalized refractory seizures and encephalopathy, with only subtle nonspecific features of hypothyroidism such as obesity and constipation, and without any specific features suggestive of HE.

Routine laboratory and imaging tests for structural and systemic causes of seizures and encephalopathy in our patient, were noncontributory. Sometimes, the neuropsychiatric manifestations of systemic lupus erythematosus may be similar to the symptoms of HE.

The finding of elevated anti-TPO and antithyroglobulin (TgAb) antibody titers along with the exclusion of other causes of encephalopathy and supports the diagnosis of HE. As far as the diagnostic criteria^[5] is concerned, our child was fulfilling them [Box 1].

Due to infrastructural and logistical issues, we were unable to do the IgG4 levels. Although IgG 4-related encephalopathies have been reported, they showed structural involvements of the brain, which was absent in our case.

Diffuse slowing of the background is the most common EEG abnormality seen in both children and adults,^[6] which was also seen in our patient. Neuroimaging is usually normal. However, MRI may occasionally show bilateral subcortical high-signal lesions on the T2-weighted images. Computed tomography and angiography are typically normal. Brain single photon emission computed tomography may show global hypoperfusion.^[7]

The mainstay of treatment of HE consists of methylprednisolone, with an initial high dose followed by prednisone (1–2 mg/kg/days, max 60 mg/days), tapered over 6–8 weeks. In case of failure of the first line of treatment, IVIG can be used, as well as other immunosuppressive drugs such as cyclosporine, azathioprine, methotrexate, and rarely, even plasmapheresis may be required.^[8] Our child responded well to steroids and levetiracetam. The latter has been known to have an anti-inflammatory effect also.^[9]

The prognosis of HE is usually satisfactory, though half of the children may have sequelae such as persisting neuropsychological difficulties, seizures, and behavior problems.^[2]

To conclude, our aim of reporting this case is to create awareness among pediatricians, that refractory generalized seizures with encephalopathy may rarely be a manifestation of HE. Having a high degree of suspicion and enquiring about the specific associated features in history, may direct the physician to conduct relevant tests so as to diagnose this rare condition.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal patient identity, but anonymity cannot be guaranteed.

Acknowledgements

Parents of the child, Pathology Department of Calcutta Medical Research Institute, Radiology Department of Calcutta Medical Research Institute, Doctors of the Pediatric Department of Calcutta Medical Research Institute, Staff and nurses of the Pediatric Department of Calcutta Medical Research Institute.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Chiarello P, Talarico V, Nicoletti A, et al. Hashimoto encephalopathy: A case report and a short revision of current literature. Acta Biomed 2020;91:e2020087.
2.	Alink J, de Vries TW. Unexplained seizures, confusion or hallucinations: Think Hashimoto encephalopathy. Acta Paediatr 2008;97:451-3.
3.	Yu HJ, Lee J, Seo DW, et al. Clinical manifestations and treatment response of steroid in pediatric Hashimoto encephalopathy. J Child Neurol 2014;29:938-42.
4.	Watemberg N, Greenstein D, Levine A. Encephalopathy associated with Hashimoto thyroiditis: Pediatric perspective. J Child Neurol 2006;21:1-5.
5.	Adams AV, Mooneyham GC, Van Mater H, et al. Evaluation of diagnostic criteria for Hashimoto encephalopathy among children and adolescents. Pediatr Neurol 2020;107:41-7.
6.	Li J, Li F. Hashimoto's encephalopathy and seizure disorders. Front Neurol 2019;10:440.
7.	Kaulfers AD, Bhowmick SK. Hashimoto encephalopathy in pediatrics: Report of 3 cases. AACE Clin Case Rep 2021;7:40-2.
8.	Stienen MN, Haghikia A, Dambach H, et al. Anti-inflammatory effects of the anticonvulsant drug levetiracetam on electrophysiological properties of astroglia are mediated via TGFβ1 regulation. Br J Pharmacol 2011;162:491-507.
9.	Wong LC, Freeburg JD, Montouris GD, et al. Two patients with Hashimoto's encephalopathy and uncontrolled diabetes successfully treated with levetiracetam. J Neurol Sci 2015;348:251-2.