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Auditory seizures in autoimmune epilepsy: a case with anti-thyroid antibodies Volume 19, numéro 1, March 2017

Illustrations


  • Figure 1

  • Figure 2

Autoimmune encephalopathies frequently present with new-onset recurrent seizures, and rarely with refractory status epilepticus (r-SE). Pathogenic intracellular or surface antibodies are detected in the majority of cases, but few are of undetermined origin, such as Hashimoto's encephalopathy (HE or steroid-responsive encephalopathy associated with autoimmune thyroiditis) (Davis and Dalmau, 2013). HE is associated with elevated anti-thyroperoxidase antibodies (A-TPOs) and anti-thyroglobulin antibodies (A-TAs) both in the serum and the cerebrospinal fluid (CSF). However, the diagnostic significance of the CSF assay has not yet been clarified (Ferracci et al., 2003). HE prevalence is estimated to be two cases per 100.000, and predominantly affects women (Olmez et al., 2013). Some patients have no history of thyroid disorders and normal hormone function (Olmez et al., 2013). Classically, HE is a complex neuropsychiatric syndrome, including acute or sub-acute cognitive impairment, hallucinations, myoclonus, tremor or ataxia (Kirshner, 2014). Seizures occur in 60-70% of cases, and the incidence of r-SE varies from 4 to 40% of epileptic events (Monti et al., 2011; Tsai et al., 2015). On the other hand, acoustic hallucinations are encountered typically in NMDAR-antibody encephalitis and have not been reported in other forms of autoimmune epilepsy, especially HE (Gaspard et al., 2015).

Here, we describe a man with abrupt onset of ictal auditory manifestations, followed by r-SE, related to an autoimmune epileptic encephalopathy with anti-thyroid antibodies.

Case study

A 48-year-old Italian man was referred to our Neurological Department with a one-month history of recurrent episodes of unilateral left-sided auditory hallucinations. Occasionally, he also complained of associated dysgeusia and bizarre behaviour with irritability. These symptoms occurred once or twice a week, at the very onset, but daily when he was admitted to hospital. No concurrent headache or fever was described. Familial and personal medical history was unremarkable, except for type 1 diabetes mellitus since the age of 15. Neurological examination was normal, and cognitive dysfunction, anxiety or depression were excluded. Routine blood tests and metabolic, endocrine, infectious and autoimmune markers were non-remarkable, except for high blood glucose; ATAs: 218 IU/ml (normal range: 0-60); A-TPOs: 541 IU/ml (normal range: 0-60). The thyroid and TSH profile was normal.

Video-EEG monitoring allowed recording of three focal left-onset seizures, when the patient described “buzzing and ticking followed by strong unclear noises in the left ear”. There was no confusion or alteration of consciousness. Seizures were stereotyped and prolonged, lasting 4 to 5 minutes. Ictal EEG showed a left fronto-temporal rhythmic theta activity, with subsequent spreading to the left and then bilateral posterior regions (figure 1A-D). MRI showed two FLAIR hyperintense lesions, figure 2). A first lumbar puncture was performed, and CSF analysis showed no cells, 37 mg/dl protein, and identical IgG bands in the serum and the CSF with a Link index of 0.4, suggesting a systemic immune reaction. The screening for neurotropic viruses was negative. No intracellular or neuronal cell surface antibodies were detected in either the serum or the CSF (against Hu, Yo, Ri, CRMP5, amphiphysin, MA2, NMDA receptor, Ampar, GABAB1R, LGI1, GAD and CASPR2).

First-line medication, such as intravenous diazepam (20 mg) and intravenous phenytoin (PHT; load: 10 mg/kg; maintenance: 400 mg/day), were ineffective. Levetiracetam (LEV) and lacosamide (LCS) were gradually started as add-on since carbamazepine (CBZ) was immediately stopped due to a diffuse skin rash. Six days later, the patient was on LEV at 2,000 mg, LCS at 200 mg, and PHT at 600 mg daily, yet he presented with very frequent (almost 10 daily) focal seizures. Brain MRI and lumbar puncture were repeated (and were unchanged), and total-body CT and PET scans and testicular and thyroid echography were normal.

Ten days later, the patient developed a refractory non-convulsive (NC) SE presenting with a stuporous state and was moved to the Intensive Care Unit. A 24-hour treatment with midazolam and propofol had no benefit. Therefore, the patient was given thiopental (5 mg/kg/h) for three days. Concurrent EEG monitoring showed a burst-suppression pattern with intermittent epileptic discharges (figure 1E), which prevailed on the left fronto-temporal regions. MRI, performed for the third time, was unchanged. NCSE persisted after thiopental discontinuation (figure 1F) and the patient appeared with eyes open, mute, and not responding to orders.

With a suspicion of immune-mediated encephalitis, intravenous immunoglobulins (IVIG; 0.4 g/kg/day) were administered over five days, with a significant clinical improvement three days later. Methyl-prednisolone, 1,000 mg IV for five days, was also added, inducing a complete clinical recovery and EEG normalization within 10 days. Brain MRI hyperintensities resolved within three months. LCS and LEV were gradually tapered off, whereas PHT continued to prevent seizure relapses. The final CSF analysis showed elevated A-TA and A-TPO indices (AI), respectively (AIATA=4.00 [normal range: 0.30-1.50] and AIantiTPO=1.57 [normal range: 0.30-1.50]). Six months later, the patient was able to resume work and everyday activities, and one year later, he was relapse-free without any immunotherapy and no antiepileptic drugs.

Discussion

To the best of our knowledge, this is the first report of an acute onset of recurrent auditory seizures, resulting in r-SE, in a patient suffering from an autoimmune encephalopathy with elevated serum and CSF anti-thyroid antibodies. While no antiepileptic drug was successful, the r-SE, as well as the patient overall, dramatically improved after treatment with steroids and IVIGs.

As shown by the ictal video-EEG, left-sided auditory hallucinations were ipsilateral to the seizure discharge. It is generally assumed that unilateral auditory aura relates to the contralateral cortex. However, a study on a large cohort of patients did not confirm such a lateralizing value (Clarke et al., 2003; Florindo et al., 2006).

At first, we excluded metabolic, endocrine, infectious or other anatomical causes of acute encephalopathy. The immunological hypothesis was considered later, because of the drug-resistant SE. The patient had type 1 diabetes, strongly suggesting an autoimmune susceptibility. However, an extensive panel of anti-neuronal antibodies were shown to be negative, which delayed treatment. Initially, HE was not considered because of the rather atypical presentation, including the fact that the patient was male, with no history of thyroid disease, and had normal thyroid function. Moreover, the EEG showed recurrent left fronto-temporal focal seizures without any slowing of the background activity. Initially, brain MRI was not helpful, since it did not show any lesion related to the seizure onset zone. Rather, it revealed some mild cortical abnormalities on the contralateral side that could possibly suggest an immune-mediated process, but only retrospectively. This is not surprising since imaging of HE may show non-specific white matter hyperintensities in half of the cases (Laurent et al., 2016) and be completely normal in the remainder (Castillo et al., 2006, Hilberath et al., 2014). Therefore, the diagnosis of HE relied on the unexpected evidence of intrathecal A-TA and A-TPO antibodies. A focus on CSF did not show any intrathecal IgG synthesis, however A-TA and A-TPO indices are comparatively more effective in revealing antigen-specific IgGs (Jarius et al., 2012). A-TA and A-TPO in the CSF are not routinely tested when HE is suspected, since their role has not yet been entirely clarified. However, up to 75% of HE cases, when investigated, presented with CSF antibodies, which are absent in the healthy population (Ilias et al., 2015). Autoimmune encephalopathy related to anti-thyroid antibodies is a treatable condition that can become severe, resulting in r-SE. Thus, clinicians should also consider “atypical” forms of HE without any previous thyroid dysfunction.

Conclusion

In HE patients presenting with only some of the associated features, epileptic autoimmune encephalopathy can be determined based on the presence of anti-thyroid antibodies. This condition should be suspected in cases with unexplained new-onset recurrent seizures, with focal origin and auditory manifestations which do not respond to first and second-line antiepileptic treatments. The finding of anti-thyroid antibodies in the CSF supports this diagnosis.

Disclosures

None of the authors has any conflict of interest to disclose.