mystery of yawning
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La parakinésie brachiale oscitante
Yawning: its cycle, its role
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Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal
Le bâillement, du réflexe à la pathologie
Le bâillement : de l'éthologie à la médecine clinique
Le bâillement : phylogenèse, éthologie, nosogénie
 Le bâillement : un comportement universel
La parakinésie brachiale oscitante
Yawning: its cycle, its role
Warum gähnen wir ?
 
Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal
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19 décembre 2011
Epilepsy Behav.
2011;22(4):799-803.
Recurrent partial seizures with ictal yawning as atypical presentation of Hashimoto's encephalopathy
(steroid-responsive encephalopathy associated with autoimmune thyroiditis).
 
Casciato S, Di Bonaventura C, Lapenta L, Fattouch J, Ferrazzano G, Fanella M, Di Fabio F, Pasquini M, Amendolea MA, Manfredi M, Prencipe M, Giallonardo AT.
Neurology Unit, Department of Neuroscience, Sapienza University of Rome Italy.

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Bâillements et épilepsie Yawning and seizure
 
Abstract
 
Hashimoto's encephalopathy (HE), also known as steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), is a rare condition whose pathogenesis is unknown, though autoimmune-mediated mechanisms are thought to be involved. The prevalent neurological manifestations of this disorder are epileptic seizures and psychocognitive disorders associated with EEG alterations. High anti-thyroid antibody titers (particularly in cerebrospinal fluid) and the effectiveness of steroid therapy are usually considered to be crucial elements in the diagnostic process. We describe a 19-year-old female patient who had been referred to the psychiatric unit because of behavioral disorders characterized predominantly by delirium with sexual content. She developed recurrent focal seizures characterized by atypical ictal semiology (repetitive forceful yawning) and a rare EEG pattern (recurrent seizures arising from the left temporal region without evident "encephalopathic" activity). The presence of anti-thyroperoxidase antibodies in her cerebrospinal fluid and a good response to steroids confirmed the diagnosis of HE. The atypical presentation in the case we describe appears to widen the electroclinical spectrum of HE and highlights its importance for differential diagnosis purposes in the neuropsychiatric setting.
 
1. Introduction
 
Hashimoto's encephalopathy (HE), also called steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), is a rare condition whose etiology is unknown, though autoimmunemediated mechanisms are believed to be involved in its pathogenesis [1, 2]. The clinical onset of this condition is insidious or acute, whereas its course is relapsing&endash;remitting or monophasic in nature, with varying neurological and, more rarely, psychiatric symptoms (confusion, seizures, myoclonus, personality changes, psychosis, dementia, or strokelike episodes). High anti-thyroid antibody titers (mainly antithyroperoxidase [TPO-Ab], though also anti-thyroglobulin [TG-Ab]) in serum and cerebrospinal fluid (CSF) are the most important diagnostic clues to the disease [3, 4]. Neurological investigations do not yield specific results, revealing, in the majority of the cases, diffuse EEG abnormalities, a moderately high CSF protein content, and normal imaging. Current diagnostic criteria include an excellent response to corticosteroid therapy (observed in approximately 50% of patients), which is consequently the treatment of choice and results in complete recovery [2].
 
We describe a 19-year-old woman with SREAT whose first symptom at onset appears to have been a primary behavior disorder. She developed recurrent focal seizures characterized by an atypical ictal semiology, that is, repetitive yawning, associated with a rarely described EEG pattern.
 
yawning seizures
 
2. Case report
 
We describe a 19-year-old, right-handed woman who has, since childhood, had Graves&endash;Basedow disease, which has responded well to methimazole therapy. One month prior to admission to our department, the patient developed highly distressing insomnia, anxiety, depressed mood, poor motivation, and social withdrawal, which were apparently due to a recent stressful event. In the days following hospitalization, she manifested an acute state of psychomotor agitation and a delirious syndrome, disinhibition, persecutory ideation, incoherent speech, and psychotic disorder with sexual content. She was admitted to the psychiatric care unit so that the causes of the primary psychotic disorder could be investigated. The brain CT scan was normal and routine blood tests did not reveal any significant alterations; the patient was treated with antipsychotic medication (olanzapine up to 10 mg/day), though with no significant improvement. Some days later, she experienced sudden brief episodes characterized by repetitive forceful yawning, followed by oroalimentary automatisms. Following speculation regarding the possible presence of a psycho-organic syndrome (after other toxic, metabolic, and infectious causes of encephalopathy had been excluded), the patient was admitted to our neurological unit.
 
Her physical and neurological examinations were unremarkable, if we exclude a lack of initiative, bradykinesia, and mild postural tremor in the left arm. The behavioral disorder was characterized predominantly by akathisia, disinhibition, and an excessive freehand drawing tendency . The neuroimaging study (brain MRI scan) did not disclose any significant structural alterations (see below). No blood count, electrolyte, clotting, or renal or hepatic enzyme abnormalities were detected; VDRL, TPHA, HIV, and serum vitamin B12 levels were normal; autoimmune disease markers (antinuclear antibody, rheumatoid factor level, anti-double-stranded DNA antibody, anti-SS-A antibody, anti-SS-B antibody, anticardiolipin antibody, and myeloperoxidase anti-neutrophil cytoplasmic antibody) were negative; thyroid function tests disclosed a euthyreosis status with high TG-Ab and TPO-Ab titers in serum (1393.5 and 41.0 IU/mL, normal values: b100 IU/mL).
 
The CSF examination revealed a normal total protein content (41 mg/dL), negative oligoclonal bands, but high anti-thyroid antibody titers, particularly those of TPO-Ab (1040.85 IU/mL, normal level: 0) and TG-Ab (17.46 IU/mL, normal level: 0); CSF findings also included a normal Qalb (albumin CSF/serum quotient) that reflected the integrity of the blood&endash;brain barrier and the intrathecal synthesis of thyroid autoantibodies. Serological and CSF screening was performed to exclude toxic, metabolic, infectious, and paraneoplastic etiologies. Video/EEG monitoring allowed us to record several focal epileptic seizures. The EEG patterns were characterized by rhythmic monomorphic, mean-amplitude, 1.5- to 2-Hz, slow-wave delta activity and, less frequently, slow spike-and-wave complexes involving the left temporal region and spreading over homologous contralateral areas. The ictal clinical semiology was characterized exclusively by repetitive, stereotyped forceful yawning, followed by oroalimentary automatisms (chewing) and an inconstant unresponsive state. Video/EEG examinations performed over time did not yield any other clues (such as the presence of a photoparoxysmal response) to help make a diagnosis in this patient. The neuropsychological evaluation was unfortunately limited and incomplete because of the sedative effect of drugs (administered for the behavioral disorders) and the poor level of collaboration offered by the patient herself. However, an interesting and curious finding emerged from the Rey&endash;Osterrieth Complex Figure Test, which, when occasionally performed during the peri-ictal phase, revealed a transient impairment that was closely related to the seizure activity of the specific performances. A further MRI scan revealed mild unspecific periventricular white matter hyperintensities on fluid-attenuated inversion&endash;recovery (FLAIR) and T2-weighted images.
 
In the acute phase, high-dose intravenous steroid therapy was started (methylprednisolone at 1000 mg daily for 5 days), followed by an oral formulation (dexamethasone at an initial daily dose of 1 mg/kg). Steroid therapy led to progressive improvement in the patient. The epileptic seizures promptly disappeared and the psychiatric manifestations resolved completely within a few days. Periodic follow-up EEGs revealed normal background activity without focal or diffuse epileptiform discharges. Steroids were maintained for almost 6 months (0.5 mg/day), after which they were gradually suspended. Antipsychotic medications were tapered and withdrawn after 2 weeks. During an 8-month follow-up, the patient did not experience any additional seizures and her psychocognitive disorders fully resolved. At the last visit, the patient did not need any therapy and had regained her ability to perform all her daily activities (including her studies).
 
3. Discussion
 
Hashimoto's encephalopathy, also referred to as SREAT, is a rare condition whose etiology is unknown, though autoimmune-mediated mechanisms are believed to be involved in its pathogenesis [1, 2]. The pathogenetic hypotheses include autoimmune vasculitis, autoimmune reaction to antigens shared by the thyroid gland and the central nervous system, cerebral hypoperfusion, and the toxic effect of thyrotropin- releasing hormone [4, 5]. To date, HE is described as a disease affecting both the neuroendocrine and nervous systems. Existing pathological reports have demonstrated the presence of gliosis and mild lymphocyte infiltration in brain parenchyma around small vessels [6&endash;8]. The pathophysiology includes brain microvascular inflammation resulting from immune complex deposition and autoimmune mediated thyroiditis. Thyroid antibodies or unknown anti-neuron antibodies may lead to damage in both thyroid and neural tissue [8, 9].
 
Misdiagnosis of HE at presentation is common, while diagnosis is based above all on the exclusion of more common diseases owing to the variability of the symptoms [1, 5]. Peschen-Rosin and co-workers [10] first suggested that HE could be diagnosed on the basis of the unexplained occurrence of relapsing myoclonus, generalized or focal seizures, psychiatric disorders, or focal neurological deficits associated with three of the following conditions: abnormal EEG, high thyroid autoantibodies, high CSF protein, excellent response to steroids, or unrevealing cerebral MRI [2, 11]. The range of clinical symptoms and signs has, since this early proposal, been extended considerably, whereas the response to steroids has been shown to vary substantially. Some authors have also suggested that, besides high serum levels, high CSF anti-thyroid antibody titers may be more pathognomonic [4] than responsiveness to corticosteroid therapy, which occurs in only 50% of patients [10]. Other authors have instead recently supported responsiveness to corticosteroid therapy as a means of diagnosing HE [11]. In 2006, Ferracci and Carnevale [3] summarized the diagnostic principles followed by the majority of authors: after ruling out other diseases, high serum anti-thyroid antibody levels may be considered to support the diagnosis of HE, but should not be considered as definitive proof of this disease.
 
With respect to immunological aspects, this case seems to relaunch the crucial role of dysimmune mechanisms in some rare epilepsy conditions that are clinically characterized by an association between seizures and psychocognitive disturbances. These conditions usually include systemic autoimmune diseases with secondary brain involvement (such as systemic lupus erythematosus, Sjogren's syndrome, anti-phospholipid syndrome, systemic vasculitis, and coeliac disease) [12] and autoimmune encephalitis electively affecting the central nervous system (paraneoplastic and non-paraneoplastic limbic encephalitis, encephalitis associated with VGKC-complex-Ab , anti-NMDARs, AMPARs-Ab, GABA(B)Rs-Ab, GlyRs-Ab, and GAD-Ab) [13, 14]. Although we had contemplated other autoimmune steroidresponsive encephalopathies in our case, the serum and CSF findings (high serum and CSF levels of TPO-Ab, normal Qalb pointing to the integrity of the blood&endash;brain barrier and confirming the presence of intrathecal synthesis of these autoantibodies), the responsiveness to steroids, and the patient's medical history supported a diagnosis of HE. The normal titers of the other autoantibodies allowed us to rule out the aforementioned systemic conditions. As regards pathologies that more specifically affect the central nervous system, we decided not to perform the complete autoimmune screening (i.e., VGKCcomplex- Ab, antiNMDARs, AMPARs-Ab, GABA(B)Rs-Ab, GlyRs-Ab, and GAD-Ab), though we recognize that it should have been conducted according to a modern approach to seizure disorders of unknown origin.
 
The case we describe may be considered of considerable interest for several reasons. From an electroclinical point of view, the repetitive, stereotyped yawning observed in our patient as the main, unusual ictal clinical manifestation during recurrent partial seizures arising from the left temporal regions and spreading to the contralateral areas is particularly worthy of note. The occurrence of yawning in relation to epileptic seizures has rarely been described in the clinical setting [15&endash;21]. Neural structures underlying this complex spatiotemporal physiological reflex are presumably located in the brainstem. Different mechanisms might explain peri-ictal yawning, including direct activation of the brainstem structures by the epileptic discharge, seizure-mediated secretion of endogenous neurohumoral substances (such as prolactin and oxytocin), and functional changes of the brainstem related to the level of alertness. As it has usually been reported in seizures involving primarily the nondominant hemisphere, some authors have attributed a lateralizing value to this phenomenon [15, 16]. In contrast to this observation, though in agreement with other articles reporting left temporal or bitemporal ictal discharges [18, 21&endash;23], the seizures in our case appeared to involve primarily the left hemisphere.
 
An EEG corresponding to forceful yawning and consisting of a focal ictal pattern has also rarely been observed in this syndrome. Yet another interesting finding is that the EEG tracing did not, if we exclude the recurrent seizures, reveal any "encephalopathic" pattern, but instead showed normal background activity. The most frequently reported abnormal patterns in the few studies that have focused on EEG findings in HE [3, 17, 22, 24] are: (1) slowing, continuous or intermittent background activity, often associated with diffuse, highamplitude, theta&endash;delta rhythms [3, 22, 24] and (2) epileptic ictal activity, sometimes structured as focal or generalized status epilepticus [8, 17, 23].
 
From a psychocognitive point of view, the psychiatric manifestations of HE in our case were characterized by delirium with sexual content and compulsive drawing and writing, which were similar to and could easily be misdiagnosed as the typical onset of primary psychotic disorder. However, the combination of a poor response to antipsychotic agents, epileptic seizures, EEG alterations, and a surprisingly prompt response to steroids (worsening of the psychiatric manifestations might have been expected instead) supported, in our case, the hypothesis of a psycho-organic condition and oriented the diagnostic process. With respect to the cognitive and behavioral aspects of HE, some alterations are secondary to the encephalopathy itself and to recurrent seizures. Indeed, seizures, which occasionally occurred during the neuropsychological evaluation in our patient, produced a further transient worsening in the cognitive deficits.
 
In keeping with published reports, according to which normal neuroimaging or nonspecific white matter abnormalities are the most common imaging findings in HE [1, 2, 25], the MRI scan obtained did not disclose any significant structural abnormality. Zhao and colleagues [26] recently described atypical neuroimaging changes in a patient with HE, consisting of multifocal abnormalities in cortical and subcortical areas not enhanced by gadolinium that rapidly resolved, together with the clinical symptoms, after high doses of corticosteroid therapy. In our patient, the SPECT scan revealed a focal area of hypoperfusion involving mainly the left temporal regions and other areas of abnormal perfusion in the homolateral frontal and parietal lobes; this neuroimaging pattern was highly concordant with the electroclinical findings.
 
In conclusion, the case we describe not only appears to widen the electroclinical patterns associated with HE, thereby confirming the fact that our knowledge of this disease remains incomplete, but also lends further support to both the central role of anti-thyroid antibodies in the CSF for diagnostic purposes and the effectiveness of steroid therapy. Within the context of a differential diagnosis, psychiatric disorders associated with epileptic seizures with atypical features, particularly in patients with a history of autoimmune thyroiditis, should always raise suspicions for this condition so that prompt and effective treatment may be provided.