Clinical spectrum of voltage-gated potassium channel autoimmunity

We were interested to see the report on the spectrum of voltage-gated potassium channel autoimmunity but feel that the results could be misleading.

Tan et al. only tested sera for VGKC antibodies by direct radioimmunoprecipitation (RIA) if they had previously been found positive for binding to the molecular layer of the cerebellum on routine screening for paraneoplastic antibodies. [1] Therefore, their sample does not include sera sent specifically for VGKC antibodies and is likely biased towards paraneoplastic cases as they state. This may explain why their numbers are surprisingly low: only 80 cases in six years. Over the last year, we received 3000 sera specifically for VGKC antibody testing by RIA, finding 250 positive sera (>0.1 nmol/L) of which 70 had values >0.4 nmol/L.

There were some clinical manifestations that were unexpected which were extrapyramidal and cranial nerve/brainstem disorders. Other syndromes that have been reported in patients with VGKC antibodies include: cortical and subcortical features; hypothalamic and sleep disturbance; myoclonus; and autonomic and peripheral nerve hyperexcitability. In particular, Morvan syndrome may be under-reported but can include the central nervous system and autonomic and peripheral disorders. [2]

Moreover, the bias towards paraneoplastic cases, confirmed by the finding that 47% had or were considered at high risk of developing tumors, indicates that some of the manifestations reported may represent features of a paraneoplastic panencephalitis rather than a syndrome specifically related to the VGKC antibodies. In addition, the levels of VGKC antibodies associated with any particular clinical manifestation, however broadly defined, were not stated.

For example, it is unclear whether the patients with extrapyramidal disorders had relatively low titers and associated tumors. Low VGKC titers have previously been reported in paraneoplastic limbic encephalitis and may represent part of the immune response to the tumor. [3] In our experience, high titers (above 0.4 nmol/L) are almost always associated with non-paraneoplastic limbic or epilepsy-related syndromes [4,5] although some (<_10 may="may" have="have" a="a" thymoma.="thymoma." p="p"/>We agree that VGKC antibody testing can be helpful in routine testing and that the full clinical spectrum needs to be described. However, this should be based on patients screened primarily with the RIA unless a better method is established. In addition, it should be described separately for paraneoplastic and non-paraneoplastic cases and include details of the titers of VGKC antibodies associated with the different clinical phenotypes.

References

1. Tan KM, Lennon VA, Klein CJ, Boeve BF, Pittock SJ. Clinical spectrum of voltage-gated potassium channel autoimmunity. Neurology 2008;70:1883-1890.

2. Liguori R, Vincent A, Clover L et al. Morvan's syndrome: peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels. Brain 2001;124:2417-2426.

3. Pozo-Rosich P, Clover L, Saiz A, Vincent A, Graus F. Voltage- gated potassium channel antibodies in limbic encephalitis. Ann Neurol 2003;54:530-533.

4. Vincent A, Buckley C, Schott JM et al. Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 2004;127:701-712.

5. Thieben MJ, Lennon VA, Boeve BF, Aksamit AJ, Keegan M, Vernino S. Potentially reversible autoimmune limbic encephalitis with neuronal potassium channel antibody. Neurology 2004;62:1177-1182.

Disclosure: The authors report that their department receives revenue for performing VGKC antibody assays (and others).

We thank Vincent et al. for their comments. Per their suggestion, we applied the high-titer threshold of 0.4 nmol/L to analyze our radioimmunoprecipitation assay (RIA) for VGKC autoantibodies and found that 51 of 72 patients (71%) in our report had high titers.

Median age at onset of neurological disorder was 64 years, 53% were female and 56% were smokers. [1] Of these patients, 31% had confirmed neoplasia and 14% had suspected neoplasia; 10% had neither seizures nor encephalopathy; and 41% had extra- cerebral manifestations. Extrapyramidal (20%) and brainstem/cranial nerve disorders (12%) remained prevalent in this high-titer cohort. To conclude, our experience does not support the correspondent's suggestion that "high-titers" of VGKC autoantibodies "are almost always associated with non-paraneoplastic limbic or epilepsy-related syndromes."

As we stated, the method of ascertaining patients is crucial to defining the clinical spectrum of VGKC autoimmunity. Previous literature has focused on the association of VGKC autoantibodies with neurologically-defined presentations including Isaacs syndrome, Morvan syndrome, and non-paraneoplastic limbic encephalitis. [2-5] The problem with defining the neurologic and oncologic associations of an autoantibody on the basis of physician-requested testing is that it precludes recognition of a broader immunobiological spectrum of disease, as we have previously demonstrated for other markers of neurological autoimmunity. [6,7,8,9]

Our serological evaluation for neurological autoimmunity is not restricted to an arbitrary panel of antigens. [9] It is an algorithmic cascade which includes reflexive testing prompted by findings on a standardized immunofluorescence assay (screening for IgG binding selectively to neural tissues) and RIAs for cation channel autoantibodies. It is our experience that patients for whom VGKC autoantibody testing is physician-requested on the basis of "syndromic" neurologic presentation are frequently seronegative. Supporting our recommendation for a comprehensive serological evaluation when an autoimmune neurological disorder is suspected, 46% of patients with Isaacs syndrome are VGKC antibody negative and 19% of those are ganglionic neuronal acetylcholine receptor antibody positive. [10]

Our study avoided the bias inherent in defining the clinical spectrum associated with VGKC autoantibodies because testing by RIA was performed algorithmically without knowledge of clinical presentation, prompted strictly by detection of a VGKC-compatible staining pattern in immunofluorescence screening.

We do not suggest that immunofluorescence is the most sensitive method for detecting VGKC autoantibodies. Our data support our conclusion "that VGKC autoantibody testing [is justified] in evaluation of patients with idiopathic neurologic disorders of subacute onset". [1]

References

6. Pittock SJ, Lucchinetti CF, Parisi JE, et al. Amphiphysin autoimmunity: paraneoplastic accompaniments. Ann Neurol 2005;58:96-107.

7. Pittock SJ, Yoshikawa H, Ahlskog JE, et al. Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction. Mayo Clin Proc 2006;81:1207-1214.

8. Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies. Neurology 1998;50:652-657.

9. Pittock SJ, Kryzer TJ, Lennon VA.Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol. 2004;56:715-719.

10. Vernino S, Lennon VA. Ion channel and striational antibodies define a continuum of autoimmune neuromuscular hyperexcitability. Muscle and Nerve 2002;26:702-707.

Disclosure: The authors report no disclosures.