1. Introduction
The encephalopathies associated with Hashimoto’s thyroiditis were initially described by Brain et al. in 1966. Their prevalence is 2.1/100.000 [1]. However, it is rare in the pediatric population [2]. Hashimoto encephalopathy (HE) is a rare autoimmune disorder that is particularly corticosteroid-sensitive. It associates encephalopathy, autoimmune thyroiditis and high levels of anti-thyroid antibodies in plasma or in cerebrospinal fluid (CSF). The clinical presentation is often misleading, possibly associating cognitive and behavioral disorders such as seizures, abnormal movements, as well as vascular episodes.
Frequent changes in nomenclature and pathophysiology and the lack of uniform diagnostic criteria make diagnosis more difficult [3] [4].
We report the observation of a 7-year-old girl who presented convulsive seizures revealing Hashimoto’s encephalopathy.
2. Observation
This is a 7-year-old girl followed up in Neurology Unit for tonic-clonic epileptic seizures for 1 year and under Sodium Valproate 500 mg daily. Analysis of her thyroid function revealed hsTSH at 0.005 mUI/L [0.027 - 4.22 mUI/L] and free T4 level at 20.6 pg/mL (N: 9 - 19 pg/mL). The patient consulted at our Endocrinlogy unit for the first time six months later. Upon examination, she presented with tachycardia, difficulties to concentrate and psychomotor agitation. There was no goiter and the rest of the clinical examination was unremarkable.
Her new biological work up revealed hsTSH at 12 mUI/L (0.027 - 4.22 mUI/L), free T4 level at 15.58 pg/mL (N: 9 - 19 pg/mL) and anti-TPO antibodies positive at 30 IU/mL [N < 13 IU/mL]. The thyroid ultrasound showed a thyroid in place with a normal volume and echostructure. There was no nodule as well as no hypervascularization on Doppler. The vascular axes were permeable as shown in Figure 1.
The brain MRI did not find any abnormality. The cerebrospinal fluid was clear in color, pressure was normal during puncture and there was no cell on cytology. On the sleep-wake electroencephalogram (EEG), the waves were well organized with paroxysmal discharges in the left parietotemporal region as shown in Figure 2.
The diagnosis for Hashimoto’s encephalopathy in our patient was made based on the neurological and electroencephalographic disorders, positive antiTPO antibodies, good response to corticosteroids and exclusion of other diagnosis.
Hashimoto’s encephalopathy is a rare and controversial disease, whose pathophysiology is still poorly understood, and can be presented in several forms. Symptoms can relate to neurological and psychiatric signs associated with an
increase of antithyroid antibodies, anti-thyroperoxidase antibodies (antiTPO) and antithyroglobulin, in the serum and sometimes in the cerebrospinal fluid of affected patients. Also found protein increase in the cerebrospinal fluid, some abnormalities on electroencephalography in the cerebral magnetic resonance imaging. It often and not always responds to corticosteroids and can start suddenly or progressively in the form of relapse and remission. It is a diagnosis of exclusion.
A substitution with 12.5 µg of levothyroxine was instituted and the patient was put on corticosteroid therapy with prednisone 1 mg/kg for 6 weeks with a decrease of 5 mg every two weeks associated with adjuvant therapy. After two months of levothyroxine, the hsTSH level normalized within limits at 3.280 mIU/L. After 10 months of 5 mg of prednisone daily, anti TPO antibodies were negative. The evolution remained favorable with an improvement in cognitive and behavioral disorders. The patient did not have any relapse of epileptic seizures again. She maintained clinical and biological euthyroidism with hsTSH at 3.280 mIU/L (0.027 - 4.22 mIU/L). Since she had been on corticosteroid for ten months, a Synacthen test was performed at the end of corticosteroid therapy to confirm that her adrenal glands were still responding; allowing us to definitely stop corticosteroid.
3. Discussion
Hashimoto’s encephalopathy is a rare, possibly underdiagnosed autoimmune condition first described in 1966 [2]. The prevalence is estimated at 2.1/100.000, but this number is probably largely underestimated [1]. The average age of onset is 45 years (12 - 84 years). The sex ratio is 4 women to 1 man. It is relatively rare in the pediatric population, with around 60 cases described to date and an unknown prevalence. The majority of pediatric cases are adolescents, with a median age of 14 years at diagnosis [4].
The pathophysiology of HE is still inconclusive. Three major mechanisms have been suspected in the pathogenesis: the vascular mechanism, the autoimmune mechanism (which can combine anti-thyroid autoantibodies, but also extra-thyroid antigens), the toxic mechanism - deregulation of certain hormones, excessively produced in response to hypothyroidism [5] [6].
The pathogenesis of HE remains unexplained. The epileptogenic effect of TRH on suprahypothalamic TRHergic receptors has been mentioned. An increase in their receptivity is also discussed. However, the autoimmune origin seems much more likely and had already been discussed by Brain et al. [2] and Mauriac et al. either in the form of acute encephalomyelitis or an autoimmune cerebral vasculitis with deposits of immune complexes. A thyroid - central nervous system antigen community was considered. Activated T lymphocytes are thought to cross the blood-brain barrier and cause vasculitis. Brain dysfunction linked to hypoperfusion was found during a SPECT scan [6].
In the greatest series of literature [7] [8], the most frequently reported clinical symptoms are: tremors (80% - 84%), transient aphasia (73% - 80%), headache (50% - 90%) and seizures (60% - 67%). We also find: sleep disorders (55%), myoclonus (38% to 65%), cognitive decline (33% to 100%), psychosis and hallucinations (25% to 50%), ataxia (16% to 65%).
The epileptic seizures present in our patient are found in only 12% of cases.
Always neurological or psychiatric, these signs are not specific and sometimes even frequent in the general population. Thus, their presence alone is necessary but insufficient for the diagnosis of HE.
As for the thyroid status, patients with Hashimoto’s encephalopathy are most often moderately hypothyroid, but can also be euthyroid [8], exceptionally hyperthyroidism has been reported. Our patient went through a phase of subclinical hyperthyroidism and then to subclinical hypothyroidism. Neurological explorations do little to help but eliminate other possible causes of encephalopathy (infectious, metabolic, toxic, vascular, neoplastic and paraneoplastic causes). The electroencephalogram often shows a diffuse slowing. Cerebrospinal fluid study found hyperproteinorachia in 75% of cases without pleocytosis. The absence of pleocytosis was also found in this case. Anti-TPO antibodies are sometimes found in cerebrospinal fluid. This assay is not performed systematically in the majority of cases described in the literature [2].
Brain computed tomography is most often normal but can show areas of hypodensity. Magnetic resonance imaging is normal or shows diffuse hyperintensity of white matter in T1 and T2 not enhanced by gadolinium. These abnormalities may disappear after corticosteroid therapy. During Hashimoto’s encephalopathy, the plasma level of anti-TPO antibodies is always high and a sign of the disorder. These rates are not correlated with clinical status [4] [9].
HE is a diagnosis of exclusion. It is suspected in patients with neurological and neuropsychiatric conditions highly variable with normal or non-specific MRI results and detection of a high concentration of circulating serum anti TPO antibodies. Clinical response to corticosteroid therapy supports diagnosis [9].
The current standard treatment for HE is the use of corticosteroids in addition to the treatment of any concomitant dysthyroidism. Symptomatic treatment, either with anticonvulsants or neuroleptics, may be indicated depending on the clinical picture.
Usually symptoms improve or go away completely within a few months. The majority of cases, currently over 90% of them, are subject to glucocorticoid therapy with a high initial dose (500 - 1000 mg of methylprednisolone per day for adults or 30 mg/kg of body weight for children) given for 3 - 7 days, followed by an oral relay with prednisone (1 - 2 mg/kg/day, max 60 mg/day) for 6 to 8 weeks. The dose should be gradually reduced. Initially, doses of prednisone ranging from 50 mg to 150 mg per day were also used. No greater benefit of one treatment over another has been demonstrated.
Like our patient, the improvement is singular and often obtained within 72 hours, especially when there are disturbances in vigilance. In general, all the manifestations improve after a few weeks on corticosteroid therapy [2]. Corticosensitivity has been proposed as a diagnostic criterion for Hashimoto encephalopathy and the acronym “SREAT” (Steroid-responsive encephalopathy associated with autoimmune thyroiditis) recommended to replace this entity [4].
In cases resistant to corticosteroid therapy, immunosuppressive treatments may be used including plasma exchange, intravenous polyclonal immunoglobulins, methotrexate, azathioprine, cyclophosphamide and mycophenolate mofetil [10]. The first report of intravenous polyclonal immunoglobulin therapy in EH children was described by Berger and al. with a significant advantage. Some authors have reported achieving a lasting remission of 7 years after IVIG treatment in a patient with glucocorticoid resistant HE. Plasmapheresis has been used successfully in steroid non-responders and in case of worsening after corticosteroids, possibly due to the elimination of certain autoantibodies or inflammatory mediators from the blood [10] [11].
4. Conclusions
Hashimoto’s encephalopathy is a rare, but probably unrecognized entity.
This clinical case reminds us of the various often misleading clinical presentations, current hypotheses regarding its pathophysiology, but also its particular corticosensitivity is insufficient. The latter is a major diagnostic argument. Recognition of Hashimoto’s encephalopathy and early initiation of high dose corticosteroid therapy may dramatically improve its clinical course.
Over the past decades, knowledge about thyroid, brain and immunity interactions has increased, which indicates the importance of the multidisciplinary approach associating endocrinologists, neurologists, psychiatrists and pediatricians for early treatment.