Case Challenge: Behavior Changes, Seizures, and Hyponatremia

Extensive workup is necessary when evaluating individuals with seizures and behavioral changes.

By Elena Grebenciucova, MD
 

Case

Clinical Presentation

Mr. L. is a white man, age 67, who presented after several weeks of personality changes, paranoid behavior, emotional lability, and encephalopathy. At admission, he experienced a generalized tonic-clonic seizure and was found to have hyponatremia (Na+ = 119 mEq/L), which was treated. When his sodium levels had normalized, he was discharged. Later he returned, having another generalized tonic-clonic seizure and was again noted to have hyponatremia. Despite sodium correction, his mental status continued to deteriorate. He appeared confused with difficulty remembering, paranoia, and emotional lability.

Diagnostic Testing & Diagnosis

Mr. L had a brain MRI with and without contrast, lumbar puncture and cerebrospinal fluid (CSF) analysis, video-EEG, a full-body fluorodeoxyglucose positron emission tomography (FDG-PET) scan, and serum antibody testing (Table). He also had video-EEG that showed mild generalized slowing but no ictal foci. During monitoring, he had subtle twitches of the left side of the face, shoulder, and arm intermittently.

Serum and CSF were sent for an autoimmune encephalitis panel test, and results were positive for antibodies to leucine-rich glioma-inactivated protein 1 (LGI1), confirming the diagnosis of anti-LGI1 autoimmune encephalitis.

Treatment and Follow-Up

Mr. L. was treated with intravenous high-dose steroids, and his encephalopathy and hyponatremia gradually resolved, with some persistent difficulties with memory. He subsequently received 1 gram rituximab to achieve B-cell depletion in an attempt to decrease the risk of relapses. At 6-month follow-up, he was relapse free and improving.

Challenge Questions

1. LGI1 antibody-mediated autoimmune encephalitis typically affects:
A. Women more than men
B. Older adults
C. Younger adults
D. People of all ages

2. Anti-LGI1 antibody encephalitis typically takes the following clinical course:

A. A monophasic illness
B. A progressive illness despite immunotherapy
C. Relapsing in about
D. Relapsing in nearly 35% of patients 100% of patients

3. Anti-LGI1 antibody encephalitis is:
A. Most often associated
B. Occasionally associated with small cell lung cancer with thymomas
C. Never paraneoplastic
D. Always paraneoplastic

4. Faciobrachial dystonic seizures (FBDS) with anti- LGI1 antibody-mediated encephalitis respond best to:
A. Levetiracetam
B. Phenytoin
C. Intravenous corticosteroids
D. Valproic acid

Personality and Behavior Changes, Seizure, and Hyponatremia

Discussion

Leucine-rich, glioma inactivated 1 (LGI1) protein binds ADAM23 to ADAM22 and facilitates inhibitory signal transmission between the presynaptic potassium channel and the postsynaptic AMPA receptor. Previously, LGI1 was classified as a part of voltage-gated potassium-channel (VGKC) complex, but this term has been abandoned because it was shown that antibodies to LGI1 are not directed against the potassium channel itself, but rather against some associated proteins. Patients who are positive for antibodies to VGKC may also be positive for LGI1 antibodies and CASPR-2 antibodies. The 3 groups exhibit strikingly different clinical phenotypes, however, and in the absence of LGI1 or CASPR-2 antibodies, the positivity to VGKC antibodies is of questionable clinical significance.1

Anti-LGI1 antibody-mediated autoimmune encephalitis typically occurs in older adults (median age 60). Men are affected more commonly than women. It can present with twitches in the face and upper extremity termed faciobrachial dystonic seizures (FBDS) and subacute personality and behavioral changes that are typical of limbic encephalitis. These patients can also experience generalized tonic-clonic and autonomic seizures (ie, flushing, shivering, and pilomotor). Hyponatremia is observed in 60% to 70% of patients with anti-LGI1 antibody encephalitis.2-4

Presenting as simultaneous twitches of the ipsilateral face, shoulder, and arm (or leg) that are typically brief (< 3 seconds), FBDS occur in clusters up to hundreds of times per day. The FBDS are rarely associated with ictal abnormalities on EEG. These seizures frequently fail to respond to the standard antiepileptic medications but are typically highly responsive to immune therapies, such as intravenous corticosteroids.5

Anti-LGI1 antibody-mediated encephalitis is only rarely associated with tumors, including thymoma.6,7 The majority of cases are nonparaneoplastic autoimmune in etiology.

Anti-LGI1 antibody-mediated encephalitis typically responds well to intravenous corticosteroids followed by prednisone taper, but about 35% of patients experience relapses. Patients must be weaned off steroids slowly, and preventive treatment with rituximab, which depletes B cells, should be considered because of the risk of relapse.7,8 It is not known for how long rituximab should be continued, but most clinicians will continue it for 1 to 2 years, administered every 6 months, and then attempt to stop.

1. Van Sonderen A, Schreurs MW, Wirtz PW, Sillevis Smitt PA, Titulaer MJ. From VGKC to LGI1 and Caspr2 encephalitis: the evolution of a disease entity over time. Autoimmun Rev. 2016 Oct;15(10):970-974.

2. Lai M, Huijbers MG, Lancaster E, et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol. 2010;9(8):776Y785.

3. Blume WT, Lüders HO, Mizrahi E, et al. Glossary of descriptive terminology for ictal semiology: report of the ILAE Task Force on Classification and Terminology. Epilepsia. 2001;42(9):1212-1218.

4. Bien CG, Elger CE. Limbic encephalitis: a cause of temporal lobe epilepsy with onset in adult life. Epilepsy Behav. 2007;10(4):529-538.

5. Van Sonderen A, Thijs RD, Coenders EC, et al. Anti-LGI1 encephalitis: clinical syndrome and long-term follow-up. Neurology. 2016;87(14):1449Y1456.

6. Thompson J, Bi M, Murchison AG, et al. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain. 2018;141(2):348-356.

7. Lancaster E. Paraneoplastic disorders. Continuum (Minneap Minn). 2017;23(6, Neur-ooncology):1653-1679.

8. Hor JY, Lim TT, Cheng MC, et al. Thymoma-associated myasthenia gravis and LGI1-encephalitis, with nephrotic syndrome post-thymectomy. J Neuroimmunol. 2018 Apr 15;317:100-102.

Elena Grebenciucova, MD

Northwestern University
Department of Neurology
Chicago, IL

 

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