Limbic encephalitis associated with voltage-gated potassium channel antibodies

Grand Rounds presentation
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By Douglas J Lanska MD MS MSPH

In 2001, Buckley and colleagues reported 2 cases with reversible limbic encephalitis associated with voltage-gated potassium channel antibodies.

More than 25 patients have now been reported with limbic encephalitis associated with voltage-gated potassium channel antibodies. Patients ranged in age from 44 to 79 years (median 64 years). Patients were predominantly male (approximately 4:1).

All reported patients with voltage-gated potassium channel antibody-related limbic encephalitis had acute or subacute cognitive and behavioral changes, including most commonly, impaired memory, inattention, and confusion, but some cases also demonstrated general intellectual decline, irritability, physical aggression, apathy, lethargy, frontal dysexecutive symptoms and signs, or paranoia.

Epileptiform EEG abnormalities and seizures are common. EEGs are typically abnormal with reported EEG abnormalities including temporal or bitemporal spikes and sharp waves, recorded seizures, and focal or diffuse slowing. Seizures (where adequately described) are usually temporal-onset partial complex seizures, some with secondary generalization. One case of status epilepticus has been reported (Thieben et al 2004). Voltage-gated potassium channel antibodies may also occur in association with seizures even in the absence of cognitive or behavioral changes and in the absence of MRI changes, but the highest titers of voltage-gated potassium channel antibodies are typically found in older-onset patients with acute or subacute amnestic encephalopathies (McKnight et al 2005). The relationship between the occurrence of seizures and the degree of associated hyponatremia has not been adequately described in these patients.

Only 1 reported patient with voltage-gated potassium channel antibody-related limbic encephalitis has had manifestations of neuromuscular hyperexcitability, with other manifestations of Morvan syndrome (ie, acquired neuromyotonia, myokymia, severe insomnia, hypersalivation, excess sweating, and encephalopathy) (Vincent et al 2004). EMG in this patient showed neuromyotonia, but EMG has otherwise been normal in reported cases (Vincent et al 2004). Several other reported patients have had excessive sweating, salivation, lacrimation, or bronchorrhea without manifestations of neuromuscular hyperexcitability (Buckley et al 2001; Thieben et al 2004). The relative rarity of such symptoms in patients with voltage-gated potassium channel antibody-related limbic encephalitis is interesting because voltage-gated potassium channel antibodies are present in the majority of patients with acquired isolated neuromyotonia (Isaac syndrome) and in patients with Morvan syndrome (Lee et al 1998; Liguori et al 2001; Vernino et al 2002)

Hyponatremia is common with reported serum sodium levels as low as 113 mEq/L. Most cases have been attributed to the syndrome of inappropriate antidiuretic hormone secretion, but 1 recent case was attributed to psychogenic polydipsia (Harrower et al 2006). Hyponatremia may contribute to the cognitive abnormalities and the frequency of seizures. Hyponatremia improves with steroid treatment.

Voltage-gated potassium channel antibody-related limbic encephalitis also appears to be associated with REM sleep behavior disorder (Iranzo et al 2006), suggesting that REM behavior disorder can be related to an autoimmune process.

MRI shows mesial temporal lobe abnormalities, usually evident bilaterally, with increased signal on T2 and fluid-attenuated inversion recovery (FLAIR) images. MRI abnormalities are best visualized on coronal FLAIR images. 18F-fluorodeoxyglucose (FDG)-PET scanning has also been utilized (Fauser et al 2005; Harrower et al 2006), and may demonstrate bitemporomesial hypermetabolism corresponding to frequent bitemporal independent seizure patterns (Fauser et al 2005), or diffuse bihemispheric cerebral hypometabolism (Harrower et al 2006). FDG-PET may be more sensitive than MRI in showing initial bitemporal involvement and correlates well with EEG findings and neuropsychological impairment in the acute phase of the illness (Fauser et al 2005). Structural findings on MRI correlate better with persistent neuropsychological deficits (Fauser et al 2005).

All patients had antibodies specific for neuronal voltage-gated potassium channels at initial evaluation. Serum levels of these antibodies corresponded to the degree of neurologic dysfunction over time, with decreases in titers accompanying clinical improvements either spontaneously or with immunotherapies.

CSF protein may be mildly elevated, but none of the reported patients have had CSF pleocytosis. Patients may have detectable antibodies to voltage-gated potassium channels in the CSF, but none have had evidence of intrathecal synthesis (ie, normal IgG indices and synthesis rates).

Unlike paraneoplastic limbic encephalitis (which is commonly associated with small cell lung cancer, and other malignancies of the lung, testis, thymus, and breast), patients with voltage-gated potassium channel antibody-related limbic encephalitis uncommonly have coexistent cancer. Furthermore, the identified malignancies in some cases of voltage-gated potassium channel antibody-related limbic encephalitis seem to have been incidental, including a single case of adenocarcinoma of the prostate and a case with a remote history of cancer of the tongue. Nevertheless, voltage-gated potassium channel antibodies can occur with thymoma and lung carcinoma (Buckley et al 2001; Pozo-Rosich et al 2003; Vernino et al 2003). In any case, in patients with limbic encephalitis a cautious approach is warranted including thorough diagnostic evaluation. As stated by Thieben and colleagues, "Patients with subacute limbic encephalitis require thorough and repeated evaluation for malignancy regardless of their antibody status" (Thieben et al 2004). In some cases this has included whole-body PET scanning (Harrower et al 2006).

Autoimmune limbic encephalitis with neuronal potassium channel antibodies is potentially reversible. Although occasional patients may improve spontaneously, it is important to recognize this newly identified condition, as it is potentially reversible with prompt administration of immunosuppressant therapy, and delayed initiation of treatment may produce significant unnecessary permanent cognitive and behavioral sequelae. Most patients have been treated with corticosteroids (typically high-dose intravenous methylprednisolone [eg, 1 gm daily for 5 days]), intravenous immunoglobulin, or plasmapheresis, often in combination (eg, intravenous immunoglobulin plus corticosteroids, or intravenous immunoglobulin plus plasmapheresis).

Misdiagnosis as herpes simplex encephalitis, Korsakoff psychosis, Hashimoto encephalitis, or presumed paraneoplastic limbic encephalitis could result in inappropriate treatment and permanent disabling cognitive sequelae.

In the patients who were treated within 2 months of symptom onset, neurologic improvement was prompt and dramatic (Thieben et al 2004). In contrast, neurologic improvement was relatively minimal in patients who were treated more than 9 months after symptom onset (Thieben et al 2004).

At follow-up, patients may have no evident cognitive deficits, persistent mild anterograde memory dysfunction, or persistent disabling behavioral abnormalities. Available evidence suggests that a major prognostic factor is the promptness of administration of appropriate therapy.