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A 49-year-old woman is brought to the emergency department by her daughter due to episodes of twitching and acute confusion. The daughter explains that she visited her mother on the previous day and she seemed to be having "some kind of a spell." She says her mother began staring at her without a reaction for 5-6 seconds, and then appeared confused and began repeatedly asking questions such as "Where am I?" The daughter notes that her mother had seemed fine the day before these episodes, although she had complained of feeling dizzy the week before. The patient's medical history and family history are both unremarkable.

Due to the reports of vertigo, the patient's regular family physician had ordered 24-hour ambulatory blood pressure monitoring, which did not identify the suspected arterial hypotonia. The patient declined to take the recommended probatory betahistine.

Emergency physicians performed a neurological examination, which finds the patient to be disoriented and unaware of where she is or why she is there. She is inattentive and unable to respond to simple mathematical questions or spell single words backwards (e.g., the forward digit-span was three out of five digits). No other pathological somatic neurological findings are noted.

The patient is admitted and laboratory investigations were performed, with the following results:

• Normal creatinine, C-reactive protein, aspartate aminotransferase, γ-glutamyl transferase, lactic acid dehydrogenase, creatinine kinase, troponin T, thyroid-stimulating hormone, blood glucose, hemogram, and coagulation parameters

• Moderate hyponatremia (130 mmol/L; normal range 136-145 mmol/L)

• Elevated N-terminal prohormone of brain natriuretic peptide (261 pg/mL; normal is less than 169 pg/mL)

• Cerebrospinal fluid (CSF) analysis shows no abnormalities or intrathecal antibody production -- findings include protein 0.24 g/l, glucose 3.68 mmol/l, lactate 1.5 mmol/l, erythrocyte count less than 1.106/l, cell-count 1.106/l, and albumin 144 g/l

• Although magnetic resonance imaging (MRI) of the patient's head finds no suspicious pathology, emergency physicians observe intermittent involuntary dystonic twitching of the patient's right arm. The twitching is determined to be focal seizures, based on the correlation with electroencephalographic seizure activity, starting focally in the contralateral left hemisphere (Figure).

While the patient is lying down being monitored, a syncope due to a 17-s sinus arrest without ventricular escape beat emerges, preceded by a short period of sinus bradycardia without atrioventricular block. The patient is transferred to intensive care and a temporary cardiac pacemaker is implanted.

Additional testing is performed. Immune-serology testing is positive for leucine-rich glioma inactivated (LGI)1 antibodies in serum (1:80, normal <1:10). CSF analysis is negative for LGI1 antibodies, as are further tests for infectious diseases, autoimmune, and paraneoplastic antibodies.

On the slim chance that the symptoms are related to a paraneoplastic process, clinicians perform a gynecological assessment and order a computed tomography scan of the patient's chest and abdomen – as expected, no evidence of cancer is found.

Treatment and Outcome

To suppress the seizure activity, initial treatment involves intravenous pulse therapy with 1 g methylprednisolone over 5 days, followed by oral prednisolone (1 mg/kg with tapering over 3 months). The patient also receives levetiracetam 1 g twice daily. However, the patient's focal seizures persist, and clinicians add gabapentin and valproate extended release (1,200 mg/day each) to her regimen. Under this treatment regimen, the seizures cease within a few days.

She has no further episodes of sinus arrest, and after 9 days the temporary cardiac pacemaker is removed and the patient receives inpatient rehabilitation at the hospital clinic.

Her symptoms of inattention persist and there is evidence of impaired short-term memory and executive function, as well as visuoconstruction. She is also experiencing depressive symptoms, and is started on venlafaxine therapy.

Case Follow-up

One month later, the patient's neurocognitive status is assessed and has returned to normal.

One year later, she continues to struggle with depressive symptoms, and begins receiving psychiatric treatment on an outpatient basis. She is also bothered by ongoing migraine-like headaches.

At 2 years, the patient has had no further seizures following her release from the hospital. Routine electroencephalography detects no further epileptic activity. Treatment with gabapentin and levetiracetam is discontinued. The patient continues taking valproate extended-release 1,200 mg/day to manage her persisting episodic migraine-like headaches. She continues outpatient psychiatric treatment for her mild depressive symptoms and a recently developed anxiety disorder. These, though, are the extent of her clinical problems 2 years after the initial presentation to the emergency department.

Discussion

The clinicians who reported this case of autoimmune anti-LGI1 encephalitis¹ aimed to elucidate features of anti-LGI1 limbic encephalitis -- in particular, its rare association with sinus arrest. The patient's normal findings on MRI of the head and basic CSF analysis also made diagnosis more challenging.

In early stage disease, diagnosis of this condition is best recognized based on clinical presentation: as in this patient's case, the combination of repetitive focal dystonic seizures, confusion, and amnestic deficits raised clinicians' suspicions.^2-8 Faciobrachial dystonic seizures are highly pathognomonic for anti-LGI1 limbic encephalitis,⁶ particularly when combined with confusion, amnestic deficits, sinus arrest, and hyponatremia.

Features noted in other cases include the following:

• Isolated involvement of one arm⁵

• Epileptic seizures with temporal focus and potentially, secondary generalization and impaired consciousness

• Problems with short-term memory, attention, and orientation

• Psychiatric symptoms such as paranoia, depression, dysphoria, anxiety, and visual hallucinations

• Sleep disorders and autonomic dysfunction (e.g., cardiac arrhythmia, sexual dysfunction, and sweating)

The case report authors cited a case series of 38 patients with anti-LGI1 encephalitis that noted hippocampal lesions in 74% of patients, an unremarkable basic CSF examination result in 75%, and hyponatremia in 65%.²

Syncopes – often due to sinus arrest preceded by sinus dysrhythmia/bradycardia – have been linked in cases of limbic encephalitis, mostly of the anti-NMDA, but also GABA-B-receptor type.^9-13 The authors found only four published cases of sinus arrest related to anti-LGI1 limbic encephalitis: two with syncope^14,15 and two with bradycardia.⁴

Various pathophysiological mechanisms for sinus arrest in limbic encephalitis have been proposed. Dysfunction of the structures involved in autonomic cardiac rhythm control seems plausible, since attacked receptors are expressed in them as follows:^7,16

• N-methyl-D-aspartate receptor are scattered along the intra-cardiac conduction system, the vagal nuclei, and the nucleus of the solitary tract (NST)¹³

• GABA (gamma-aminobutyric acid)-B receptors are present in the NST and vagal nuclei¹¹

• LGI1 protein is present throughout the neocortex, such as in the temporal lobe, the insular region, the hippocampus, and the hypothalamus^8,14,15,17

On the other hand, sinus arrest in limbic encephalitis might also be an ictal or a postictal phenomenon since it affects the temporal lobe, as has been previously described.¹⁶

The case authors noted that their patient's episode of vertigo 1 week before presenting to the emergency room may have been an initial manifestation of cardiac arrhythmia related to the autoimmune anti-LGI1 limbic encephalitis. And while the reasons for the patient's sinus arrest remain uncertain, the authors noted that it occurred after onset of focal seizures and confusional state and not as a prodromal phenomenon or after a vagal stimulus.^14,15

The fact that this patient's seizures stopped within a few days of treatment is unusual, the authors emphasized. This has been noted in only about 10% of patients with anti-LGI1 limbic encephalitis, despite having seizure-suppressant therapy, and in 51% and 88% of patients after 30 and 90 days, respectively, in patients receiving additional immunosuppressive therapy.⁷

The typical course of anti-LGI1 encephalitis begins with unilateral tonic-dystonic seizures, which then become bilateral; there may be frontal or temporal lobe epilepsy, and finally, persistent cognitive impairment and status epilepticus.⁵

Cognitive impairment has been linked with the duration of faciobrachial dystonic seizures; it has been reported in 38% of patients after 30 days, and in 56% of patients after 90 days.⁷ This case is also uncommon in the patient's complete cognitive recovery, which is reported in only about 35% of patients.¹⁸ The case authors attributed their patient's positive cognitive outcome to early detection and initiation of immunosuppressive therapy.^5-7,19

The posed by the negative findings of the test for LGI-1 antibodies in CSF highlights the higher sensitivity of detection of anti-LGI1 antibodies in serum compared with CSF,^4,9 the authors noted. In addition, they stated, involvement of anti-LGI1 immunoglobulin (Ig)G1 antibodies, which fixate complement, has recently been linked with increased cognitive impairment and long-term disability, compared with involvement of non-fixating complement anti-LGI1 IgG4 antibodies.⁷

The clinicians advised long-term patient follow-up, cautioning that as many as one in three² or four¹⁸ such patients may relapse up to 8 years² after disease onset.

Conclusion

Early recognition of anti-LGI1 encephalitis and initiation are of utmost importance for a favorable clinical outcome.

References

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