Two unusual movement disorders associated with Hashimoto's encephalopathy thyroiditis

Dear Sir, Hashimoto’s encephalopathy (HE), also known as steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), is a poorly understood disease with marked clinical heterogeneity, attributed to an underlying autoimmune etiology and characterized by steroid responsiveness. Since its first description by Lord Brain and colleagues in 1966,[1] many cases of HE have been reported, with varied neurological presentations, ranging from focal, stroke-like features to diffuse encephalopathy.[2] The current diagnostic criteria include subacute cognitive dysfunction, seizures, or neuropsychiatric symptoms; elevated serum levels of antithyroid antibodies with a euthyroid state or hypothyrodism; a good response to steroid therapy; and the exclusion of alternative etiologies, with no other well-characterized autoantibodies in serum or cerebrospinal fluid (CSF).[3] Heterogenity and nonspecificity make the recognition and treatment of SREAT challenging, often leading to misdiagnosis or underdiagnosis. Due to the lack of specific diagnostic investigations and unclear etiopathogenesis, SREAT remains primarily a diagnosis of exclusion.[2,3] Although the core clinical presentation of HE is encephalopathy, and myoclonus is a case-defining movement disorder associated with HE, isolated movement disorders without encephalopathy—such as chorea, dystonia, ataxia, and orthostatic myoclonus— have rarely been reported.[4,5] We aim to report two unusual movement disorders associated with HE. Case Reports A 39-year-old woman presented with cognitive impairment and episodic painful spasms of the lower limbs, involving both the axial muscles and lower limbs. These spasms lasted a few seconds and occurred up to 20–30 times a day, without any loss of consciousness or exaggeration by sound, touch, or other stimuli. She also experienced involuntary jerky movements of both upper and lower limbs for 1 month [Video 1]. She had no history of alcohol or drug abuse and no medical comorbidities, except for hypothyroidism, for which she was receiving levothyroxine 50 µg daily. Neurological examination demonstrated a Mini Mental Status Examination (MMSE) score of 12/30, with deficits in orientation, attention, copying, naming, and recall. She was not amenable to a detailed assessment of lobar functions. Cranial nerve examination, including assessment of eye movements, was normal. There was Grade 3 bilateral, symmetrical appendicular and axial rigidity in all four limbs, along with distally predominant, generalized myoclonus of all four limbs and abdominal muscles at rest. The myoclonus was also present on action with no stimulus sensitivity. The spasms recorded at home, as seen in Video 1, could not be witnessed during the hospital stay. Brisk deep tendon reflexes and bilateral extensor plantar responses were present. No other neurological deficits were found. Complete blood count and liver, renal, and thyroid function tests were normal. Serum creatine kinase (CK) was elevated at 22,500 IU/L. Magnetic resonance imaging (MRI) of the brain and spine was normal. Needle electromyography (EMG) showed continuous firing of normal motor unit potentials at rest in the bilateral rectus femoris and biceps muscles, with intermittent myoclonic bursts lasting 50 ms–80 ms, suggestive of a subcortical origin. Electroencephalogram (EEG) revealed symmetrical, diffuse slowing in the delta range, without epileptiform discharges. CSF cytology, protein, and glucose levels were normal. Serum and CSF samples were tested for autoimmune antibodies—anti-N-Methyl D aspartate (anti-NMDAR), anti-leucine-rich glioma-inactivated 1 (anti-LGI-1), anti- Contactin-Associated Protein-Like 2(anti-CASPR2), anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (anti-AMPAR) (1 and 2), anti- gamma-aminobutyric acid type B receptor (GABA-B), anti gamma-aminobutyric acid (anti-GABA-A), and anti- IgLON 5—and paraneoplastic antibodies— Anti-glial nuclear antibody (AGNA), Antineuronal Nuclear Antibody (ANNA), anti- Collapsin Response Mediator Protein 5 (CRMP-5), anti-Glutamic Acid Decarboxylase 65 (GAD-65), anti-Hu, anti-Yo, anti Ri, amphiphysin, anti-glycine, anti-Ma, Anti-Sry-like high mobility group box (SOX) 1 antibodies, anti- Purkinje cell cytoplasmic antibody (PCA), titin, and recoverin—all of which were negative. Anti-thyroid peroxidase (TPO) antibody levels were elevated at 1200 IU/L, whereas anti-thyroglobulin antibodies were negative. Computed tomography (CT) of the chest, abdomen, and pelvis was normal. She was treated with intravenous methylprednisolone 500 mg daily for 5 days, followed by oral prednisolone 50 mg daily, with which she showed a marked response. Serum CK, anti-TPO antibody levels, and the EEG background normalized at 4 weeks of follow-up [Video 2]. At the time of writing this case report, she was receiving 10 mg of prednisolone daily and remained in complete remission at 9 months. {"href":"Single Video Player","role":"media-player-id","content-type":"play-in-place","position":"float","orientation":"portrait","label":"Video 1","caption":"","object-id":[{"pub-id-type":"doi","id":""},{"pub-id-type":"other","content-type":"media-stream-id","id":"1_vzwvn1lz"},{"pub-id-type":"other","content-type":"media-source","id":"Kaltura"}]} {"href":"Single Video Player","role":"media-player-id","content-type":"play-in-place","position":"float","orientation":"portrait","label":"Video 2","caption":"","object-id":[{"pub-id-type":"doi","id":""},{"pub-id-type":"other","content-type":"media-stream-id","id":"1_tvq026hq"},{"pub-id-type":"other","content-type":"media-source","id":"Kaltura"}]} A 33 year-old woman presented with perioral involuntary movements [Video 3], along with insomnia, emotional lability, and memory impairment for 6 months. Two months after symptom onset, she had been treated elsewhere with trihexiphenidyl, clonazepam, baclofen, and botulinum toxin, without benefit. She denied any past or current drug use or a family history of similar illness. On presentation to our clinic, higher function examination revealed a MMSE score of 28/30, with a point lost in recall, and no other neurological deficits. Additionally, abnormal involuntary movements in the perioral region, characterized by intermittent mouth opening and pouting that resulted in lateral tongue bites, suggestive of oro-mandibular dyskinesias, were observed. Complete blood count, liver, renal, and thyroid function tests, as well as syphilis serology, were normal. Serum and CSF samples were tested for autoimmune and paraneoplastic autoantibodies (the same panel as in the previous case) and were negative. Her anti-TPO antibody level was elevated at 2230 IU/L (reference range: up to 100 IU/L). EEG, MRI of the brain, and CSF analysis were normal. CT of the chest, abdomen, and pelvis was normal. She was treated with intravenous methylprednisolone 500 mg daily for 5 days, followed by oral prednisolone 50 mg daily, with complete response. At the time of writing this case report, she was receiving 5 mg of prednisolone daily and remained in complete remission at 6 months. {"href":"Single Video Player","role":"media-player-id","content-type":"play-in-place","position":"float","orientation":"portrait","label":"Video 3","caption":"","object-id":[{"pub-id-type":"doi","id":""},{"pub-id-type":"other","content-type":"media-stream-id","id":"1_0isyu71k"},{"pub-id-type":"other","content-type":"media-source","id":"Kaltura"}]} Discussion We describe two patients with HE presenting with an unusual combination of movement disorders. The presence of neuropsychiatric symptoms strongly pointed toward HE. The first patient presented with a constellation of rigidity, painful axial muscle spasms, multifocal myoclonus, and elevated CK levels, whereas the second patient exhibited oromandibular dyskinesias in association with neuropsychiatric symptoms. In keeping with the proposed diagnostic criteria, the subacute onset and coexistent neurocognitive symptoms in both patients, in conjunction with the movement disorders, pointed towards an autoimmune etiology. Neuroimaging and CSF studies excluded structural and infectious causes. Drug and toxin exposures were also excluded. A favorable response to steroids and the presence of anti-TPO antibodies further supported the diagnosis of HE.[3] In view of the variable response to steroids and the limited specificity of anti-TPO autoantibodies, it becomes pivotal to search for disease-defining autoantibodies in such patients,[6] which were notably absent in both our patients. This included GABA-R and GAD65 antibodies, which are commonly associated with thyroid autoimmunity[6] and were present in a manner similar to that observed in our first patient. Progressive encephalomyelitis with rigidity and myoclonus (PERM), a largely under-recognized entity, has recently been identified, with major criteria including a typical clinical presentation of axial and limb spasms; triggers for spasms or increased rigidity; encephalopathy; severe torso rigidity and/or myoclonus (multifocal or generalized); high titers of serum autoantibodies to GAD65, glycine receptor or amphiphysin; and EEG findings of generalized slowing and/or epileptic discharges, along with the exclusion of alternative diagnoses. The minor criteria involve abnormal CSF with the presence of CSF autoantibodies and oligoclonal bands, as well as abnormal EMG and MRI findings. Our first patient had typical axial rigidity and spasms involving the trunk and limbs, albeit without any stimulus-induced exaggeration. There were features of encephalopathy (cognitive impairment), generalized myoclonus, elevated CK, and EMG findings suggestive of continuous muscle activity in the involved muscle groups, fulfilling the criteria for probable PERM with three major criteria and one minor criterion.[7] Since the disease-defining autoantibodies were absent in our patient, she did not fulfil the criteria for definite PERM.[7] Shen and colleagues reported a case similar to ours, with additional presence of autonomic dysfunction and coexistent GAD65 positivity,[8] which was absent in our patient, both in the serum and CSF. Therefore, it was unclear whether PERM in their patient was secondary to the overlapping presence of anti-GAD 65 autoantibodies. Rugole and colleagues reported an elderly man who presented with rigidity and elevated CK along with anti-TPO positivity.[9] However, multifocal myoclonus and axial spasms were absent in their case, unlike in our patient. Neuroleptic malignant syndrome was an important differential diagnosis in our patient, given the unusual coexistence of the above findings. However, the patient had neither fever nor any relevant drug intake. The mechanism of CK elevation in this patient could be manifold, resulting from sustained rigidity causing prolonged rhabdomyolysis, subclinical hypothyroidism, or an autoimmune mechanism similar to that seen in stiff person spectrum disorder. The normalization of CK levels with clinical improvement following steroid therapy suggest an underlying reversible etiology, likely immune-mediated. Focal, partially rhythmic, jerky, and dystonic movements of the mouth and tongue have been reported in a case of thyrotoxic HE earlier.[10] While orofacial dyskinesias with impaired consciousness have been described as a hallmark of anti-NMDAR encephalitis,[11] orolingual dyskinesias in a nonencephalopathic patient without any offending drugs or structural or degenerative etiologies could suggest HE, as seen in this case. These cases expand the variable phenotypic spectrum of movement disorders associated with HE. The highly variable clinical presentation of the disease should not be misleading, and appropriate clinical suspicion should guide early management and lead to good outcomes. Further investigations are required to establish the pathophysiology and optimal long-term therapeutic approach in HE. Acknowledgements Nil. Author contribution A. Research project: Conception: Shreyashi Jha Organization: Shreyashi Jha Execution: Shreyashi Jha, Santosh Kumar Pendyala B. Statistical analysis: Design: Shreyashi Jha Execution: Shreyashi Jha Review and Critique: Shreyashi Jha C. Manuscript preparation: Writing of the first draft: Shreyashi Jha, Santosh Kumar Pendyala Review and Critique: Shreyashi Jha, Santosh Kumar Pendyala. Ethical compliance statement The present work respects ethical guidelines. The author confirms that approval by an institutional review board was not required for this work. Written consent was obtained for showing the patients’ videos. We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Financial support and sponsorship Nil. Conflict of interest There are no conflict of interest.