Hashimoto's encephalopathy – presenting with epilepsia partialis continua and a frontal lobe lesion

Key Clinical Message We report a case of Hashimoto's encephalopathy (HE), who presented with epilepsia partialis continua (EPC) and a frontal lobe lesion. The diagnosis of HE remained elusive until the serum thyroid antibodies became positive 7 months after the onset of EPC. The histopathology of this frontal lesion showed nonvasculitic inflammation.

EPC in HE is rarely reported in the literature [2,3] nor are tumor-like lesions [2,3,11]. Here, we report a patient of HE who presented with EPC and a contralateral frontal nodular lesion. This case is similar to the two patients reported earlier in the literature [2,3]. The cases differ in that total lesionectomy was performed and serum TPOAb and TgAb remained negative in the first 7 months of onset of EPC in this case.

Case Report
We present a 49-year-old woman with a history of thyroidectomy 5 years prior to the onset of EPC. She was on thyroid replacement therapy. The pathological report was consistent with benign lymphoepithelial cysts of thyroid which could be associated with chronic thyroiditis occurring in a background of Hashimoto's or chronic lymphocytic thyroiditis [14].
She presented with a new onset of constant semirhythmic clonic twitching, weakness, and clumsiness in the left foot. The left foot clonic twitching persisted throughout the day (around once every 5 to 30 sec). At times, the clonic twitching spread to her left hand, leading to the contraction of her left fingers, wrist, and elbow; these episodes lasted around 30 sec. She had one witnessed generalized tonic-clonic seizure (GTCS) 1 week after the onset of her left foot clonic twitching. The patient also had spells of grunting and posturing of the left limbs during sleep.
The initial MRI of the brain was negative. The follow-up MRI of the brain 2 weeks after the onset showed a nonenhancing lesion in the right mesial frontal gyrus. The lesion stayed stable in the subsequent 4 months (Fig. 1). Routine scalp EEG was unremarkable. Clonic twitching of the left foot decreased after trials of anti-epileptic medicines, which included levetiracetam, oxcarbazepine, sodium valproate, and clonazepam. The video EEG monitoring revealed repetitive blunted sharp waves over the right central region (on the reference montage), which became prominent after the withdrawal of seizure medication. The video EEG evolved into one generalized tonic-clonic seizure, which was triggered by standing on the floor (reflex seizure) (Fig. 2). The aura (sensation of falling) preceding the GTCS was a horrible experience for the patient so antiseizure medication was put back immediately after the first recorded GTCS. The repetitive blunted sharp waves over the right central region subsided after reinstitution of antiseizure medication. These blunted sharp waves could have been easily missed on the bipolar montage. Similarly, the epileptic clonic twitching could have been mistakenly classified as a spasm, tremor, or myoclonus. During this time, the patient remained awake and oriented.
The initial laboratory studies were not conclusive. The antinuclear antibody was 1:40 with a speckled pattern. The serum TPOAb and TgAb remained in the normal range during the first 7 months of EPC onset (Fig. 3). CBC, basic metabolic chemistry, thyroid functions (Free T3, Free T4, and Total T3) were within normal range. The CSF performed at the beginning had WBC 1 cells/uL RBC 164 cells/uL, Glucose 78 mg/dL, total protein 28 mg/dL, IgG CSF 15 mg/dL (reference range 0-6 mg/ dL), IgG synthesis 30 mg/d (reference less than 8.0 mg/ d), IgG index 0.1 (reference range 0.28-0.66), and myelin basic protein 5.98 mcg/L (reference range 0-4.0 mcg/L).
MRI of the entire spinal cord did not show any lesions, and the whole-body computed tomography scan did not reveal any occult tumors.
Four months after the onset of EPC, focal clonic seizures remained intractable. Repeated MRI of the brain showed the same frontal lobe lesion. Consciousness and cognition remained intact. The patient underwent a total resection of the lesion with the goal of controlling EPC. The lesion was found to be gliotic with marked perivascular and parenchymal inflammation (Fig. 4). This histopathology result did not support true vasculitis. Instead, it was consistent with nonvasculitic autoimmune inflammatory meningoencephalitis.
After the lesionectomy, the left foot clonic twitching decreased temporarily. Six months after the onset of EPC, the clonic twitching of the left limbs worsened and spread to the ipsilateral face. At times, speech became unintelligible due to the ipsilateral tongue and facial clonic twitching. Consciousness and cognition remained intact. Although the EPC worsened after the lesionectomy, a follow-up MRI of the brain 7 months after the onset did not show any new changes (Fig. 5). Under the working diagnosis of probable autoimmune encephalitis, the patient was started on monthly intravenous immunoglobulins (IVIG 2 g/kg) 9 months after the onset. There was a partial improvement of symptoms after monthly IVIG but the benefits were temporary. Low-dose steroidsprednisone (10 mg-20 mg daily) were added but they failed to halt the EPC progression (Fig. 3). Rasmussen encephalitis or mild forms of HE were probable diagnoses.
Twelve months after the onset of EPC and 3 months after the IVIG treatment, the patient developed poor appetite, disorientation, and confusion. The patient was admitted to the hospital. MRI of the brain showed stable postsurgical changes (Fig. 5) but serum TPOAb and TgAb were elevated further to 70 IU/mL and 172 IU/mL (Fig. 3), respectively. Therefore, the patient was administered high-dose IV methylprednisolone 1000 mg daily for 3 days. Consciousness and appetite improved dramatically, and the patient was prescribed oral 60 mg prednisone daily after discharge.
Fourteen months after the onset of EPC, the patient's mental status normalized, left limb twitching decreased, and speech became intelligible. With steroid treatment,  improvement was accompanied by a parallel decrease in the serum TPOAb and TgAb levels (Fig. 3).

Discussion
This case of HE presented with EPC and contralateral frontal lobe lesion. It took 1 year for this patient to develop steroid-responsive encephalopathy. Finally, the case met the traditional diagnostic criteria of HE despite serum thyroid antibodies that remained negative in the first 7 months. Lesionectomy was performed, and histopathology showed nonvasculitic inflammation. The progressive clinical course of this case suggests that HE is an autoimmune spectrum disorder.
This patient is unique in the following three aspects. First, the patient was not encephalopathic, and serum thyroid antibodies remained negative during the first 7 months of EPC. Our team did not start immunotherapy immediately. The authors hypothesize that the traditional diagnostic criterion of HEsteroid-responsive encephalopathy manifesting as cognitive impairmentonly represents the severe forms of the HE spectrum disorder.
Lastly, this case presented with constant semirhythmic left foot twitching (a focal motor seizure affecting the left foot associated with a contralateral frontal cortex lesion). Could HE have its preference regarding the areas of the brain it affects?
Based on the published case series [13,24], the protean clinical manifestations of HE include seizures, multiple stroke-like episodes, tremor, and myoclonus. The strokelike episodes, tremor, and myoclonus in HE could represent occult seizure originating from the motor/sensory cortex.
Nonspecific EEG abnormalities such as diffuse slowing were well documented in HE [2,25]. Because scalp EEG is not sensitive in detecting frontal lobe seizures, nonspecific EEG abnormality suggests that HE may have a preference in affecting the motor/sensory cortex close to the frontal lobe.
As the prevalence of thyroid antibodies is high in the general population, the link between thyroid antibodies and the neurological syndrome was regarded to be spurious in the asymptomatic population [26]. On the other hand, it is also possible that mild forms of HE are underdiagnosed because its clinical manifestations such as  tremor, tingling, twitching, psychosis, or stroke-like symptoms are transient, vague, and at times hard to differentiate from psychogenic disorders. Better objective tests would be necessary to clarify this issue. In the last decade, autoimmune epilepsy has become increasingly recognized to be one of the major causes of seizures of unknown etiology (more than 20%) [27]. In one study, thyroid antibodies were observed more commonly in females with late-onset focal epilepsy with unknown etiology (7.8%) [28].
HE, as our case illustrates, can present as progressive EPC with a focal cortical lesion. It is important to consider this diagnosis in any patient with intractable EPC and/or progressive encephalopathy. Initial normal thyroid antibody levels do not completely exclude the diagnosis of HE. HE could be underdiagnosed as the currently accepted diagnostic criteria of HE represent only the severe cases of HE spectrum disorder.