Kinesigenic Dyskinesia in a Case of Voltage-Gated Potassium Channel–Complex Protein Antibody Encephalitis

OBSERVATION

ONLINE FIRST Kinesigenic Dyskinesia in a Case of Voltage-Gated Potassium Channel– Complex Protein Antibody Encephalitis

Enrique Aradillas, MD; Robert J. Schwartzman, MD

Objective: To describe the first case (to our knowledge) Results: Clinical examination revealed paroxysmal kine- of voltage-gated potassium channel–complex protein sigenic dyskinesia and fasciculations. Magnetic resonance antibody encephalitis with kinesigenic dyskinesia and imaging of the brain revealed a left caudate and left puta- cramp-fasciculation syndrome. men increased signal lesion on T2-weighted and fluid- attenuated inversion recovery sequences as well as in- Design: Case report. creased flow in the same region on single-photon emission computed tomographic scans. Electromyography and nerve conduction studies revealed significant afterdischarges, Setting: Hospitalized care. cramp potentials, and continuous motor activity. The video- electroencephalographic monitoring revealed no epilepti- Patient: A 38-year-old man with a history of bronchial form discharges. The patient dramatically improved after asthma, eczema, vitiligo, and immune complex mesan- 5 plasmapheresis exchange treatments and a course of in- giopathic glomerulonephritis presented with abnormal travenous immunoglobulin at 2 gm/kg over 5 divided doses. movements. Conclusion: To our knowledge, this is the first report of Main Outcome Measures: Clinical examination, mag- paroxysmal kinesigenic dyskinesia with voltage-gated po- netic resonance imaging, single-photon emission com- tassium channel–complex protein antibody encephalitis puted tomography, electromyography and nerve conduc- associated with the cramp fasciculation syndrome. tion studies, video-electroencephalographic monitoring, plasmapheresis exchange therapy, and intravenous im- Arch Neurol. 2011;68(4):529-532. Published online munoglobulin administration. December 13, 2010. doi:10.1001/archneurol.2010.317

O OUR KNOWLEDGE, THIS IS tiated by change of position or startle and the first description of a pa- would involve either the upper or the lower tient who had central neu- extremities. The movements occurred up rologic signs of seizures, to 40 to 50 times per day and were exac- encephalopathy, and kine- erbated by stress and lack of sleep. The pa- sigenicT dystonia as well as fasciculations tient subsequently developed clear cogni- and peripheral cramps. tive decline manifested as difficulty with short-term memory and concentration. The Video available online at episodes of anxiety increased in frequency and intensity and were followed by 2 wit- www.archneurol.com nessed generalized tonic-clonic seizures. The patient was admitted to an outlying hos- REPORT OF A CASE pital and underwent an extensive workup, which included routine magnetic reso- A 38-year-old man presented with the chief nance imaging without gadolinium, cere- complaint of the sudden onset of “stiff- bral arteriography, and routine blood, urine, ness” of both arms and legs. The problem and cerebrospinal fluid analysis, the re- had begun 8 weeks earlier, when the pa- sults of which were normal. He also had tient experienced 2 episodes of extreme bronchial asthma, eczema, vitiligo, and Author Affiliations: anxiety that lasted for approximately 30 sec- immune complex mesangiopathic glo- Department of Neurology, onds with no associated loss of conscious- merulonephritis. He was taking 500 mg of Drexel University College of ness or abnormal movements. A few days mycophenolate mofetil (CellCept [2-mor- Medicine, Philadelphia, after these 2 episodes, he noted the onset pholino-ethyl ester of mycophenolic acid]) Pennsylvania. of abnormal movements, which were ini- twice a day for his renal condition.

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Figure 1. Magnetic resonance images of the brain. Fluid-attenuated inverse recovery (FLAIR) sequence (A, axial; B, coronal), gadolinium (gad)-enhanced T1-weighted images (C), and T2-weighted images (D), all demonstrating increased signal intensity in the left caudate and putamen (arrows).

were stereotyped and lasted 3 to 10 seconds (video, http: //www.archneurol.com). He had full recollection of the events and had no loss of consciousness or confusion. He had 20 to 30 episodes per hour. He also demonstrated fasciculations at rest, most prominently of the quadriceps and gastrocnemius muscles. Magnetic resonance imaging of the brain with gadolinium revealed increased fluid-attenuated inverse recovery signal of the head of the left caudate and the middle of the left putamen (Figure 1). The lesions enhanced with gadolinium (Figure 1C). Single-photon emission computed tomography demonstrated increased uptake in similar regions (Figure 2). Autoantibody and paraneoplastic evaluation revealed an elevated voltage-gated potassium channel (VGKC) antibody titer (0.97 nmol/L; reference value, Ͻ0.02 nmol/L) and an elevated gangli- onic acetylcholine receptor antibody titer (0.45 nmol/L; reference value, 0.02 nmol/L). Electromyography and Figure 2. Single-photon emission computed tomographic scans of the brain nerve conduction studies using the cramp-fasciculation demonstrating increased flow in the left striatum region (arrows). protocol revealed significant afterdischarges with 3-Hz stimulation, significant cramp potentials with 5-Hz stimu- On admission, he was fully alert and oriented but had lation, and continuous motor activity with 10-Hz stimu- trouble with immediate recall and tasks that required con- lation (Figure 3). The serum sodium level on admis- centration (eg, serial 7s). He had slight forward flexed pos- sion was 128 mEq/L (to convert to millimoles per liter, ture but otherwise had full strength, sensation, and coor- multiply by 1.0). A 72-hour continuous video-electro- dination. He demonstrated multiple episodes of kinesigenic encephalographic monitoring system revealed nonspe- dyskinesia, which were always initiated by sudden move- cific slowing but no epileptiform activity. The results of ment (most often by reaching for objects or attempting to a complete malignancy workup, including total-body posi- get up from a sitting position). The movements were at tron emission tomography, were negative. times bilateral and at times unilateral. He would flex at the Levetiracetam therapy (1000 mg twice a day) was ini- elbow and wrist and extend his knees while dorsiflexing tiated and was continued throughout the course of the his foot. His face involved the orbicularis oculi, buccina- patient’s evaluation. The patient underwent 5 plasma ex- tor muscles, and lower facial musculature. The episodes changes during the first week. There was no clinical im-

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12345678910 12345678910 Amp 1: 2-10kHz Amp 1: 2-10kHz 200 uV 2 ms 200 uV 2 ms Stim Freq: 5 Hz No. in Train 900 Stim Freq: 10 Hz No. in Train 900 Stim Dur. 0.1 ms Stim Rjct 0.5 ms Stim Dur. 0.1 ms Stim Rjct 0.5 ms Stim Site: Ankle Stim Site: Ankle Time: 11:54:36 Time: 11:55:35 Comment: Comment: Pot. Peak Amp Area Area Stim Pot. Peak Amp Area Area Stim No. Amp Decr Decr Level No. Amp Decr Decr Level mV % mVms % mV % mVms % 1 1.06 0 6.07 0 46.2mA 1 1.05 0 6.19 0 46.2mA 2 1.06 0 6.04 0 46.2mA 2 0.97 8 6.17 0 46.2mA 3 1.16 – 9 6.09 0 46.2mA 3 0.96 9 6.12 1 46.2mA 4 1.13 – 7 6.04 0 46.2mA 4 0.99 6 5.87 5 46.2mA 5 1.19 – 12 6.09 0 46.2mA 5 1.06 – 1 5.59 10 46.2mA 6 1.15 – 8 6.12 – 1 46.2mA 6 0.98 7 5.57 10 46.2mA 7 1.10 – 4 3.78 38 Limit 7 1.37 – 30 5.70 8 46.2mA Included Stim: 5 Hz, 0.1 ms, #101 8 0.17 84 0.58 90 Limit Included Stim: 10 Hz, 0.1 ms, #188 8 0.80 24 5.48 11 46.2mA 9 0.11 90 0.42 93 Limit 9 1.37 – 30 5.65 9 46.2mA 10 0.07 93 0.11 98 Limit 10 1.11 – 6 5.53 11 46.2mA

Figure 3. Electromyography and nerve conduction studies demonstrating cramp potentials (left) and continuous motor unit activity (right) during tibial repetitive nerve stimulation at 5 Hz and 10 Hz, respectively.

provement. The second week, 5 intravenous immuno- kinesia and asymptomatic cramp-fasciculation syn- globulin infusions of 2 mg/kg were administered over 4 drome. Also, he did not complain of any of the typical to 5 hours with 30 mg of prednisone. On the 10th day symptoms of peripheral nerve hyperexcitability that have (third intravenous immunoglobulin infusion), the kine- been described in association with VGKC antibody spec- sigenic dyskinesia decreased dramatically to only 1 to 2 trum diseases (neuromyotonia or Isaacs syndrome, cramp- very mild episodes per day. The patient no longer had fasciculation syndrome, and Morvan syndrome).5-9 He did, spontaneous fasciculations. Topiramate (100 mg every however, have prominent fasciculations, especially in the night) was added to his regimen the last week of treat- lower extremities. ment. At the 8-week follow-up visit, his VGKC anti- Until recently, VGKCs were thought to be the antibody level was undetectable. genic target in these patients.8,9 The work by Lai et al10 and Irani et al11 has demonstrated that the antigenic targets are COMMENT proteins that form a complex with these VGKCs, ie, leucine- rich glioma-inactivated 1 and contactin-associated pro- To our knowledge, this is the first reported case involv- tein 2. Leucine-rich glioma-inactivated 1 associates with ing both VGKC complex protein antibody encephalitis the VGKC KV1.1, and, clinically, patients who had this and fasciculations associated with kinesigenic dyskine- antibody had more central nervous system manifesta- sia. Because of the patient’s history of 2 autoimmune dis- tions (limbic encephalitis, seizures, and altered mental sta- eases—vitiligo and immune complex mesangiopathic glo- tus). Contactin-associated protein 2 associates with both merulonephritis—and negative cancer evaluation findings, KV1.1 and KV1.2 VGKCs at the neural juxtaparanodal re- we believed that the VGKC encephalitis and the periph- gion, and patients with contactin-associated protein 2 an- eral cramp-fasciculation syndrome were on an autoim- tibodies present clinically with fewer nervous system symp- mune basis. He had the typical clinical presentation for toms and more features of peripheral nervous system the VGKC antibody spectrum disease, including sei- dysfunction. Of note, none of the patients described in these zures and memory and cognitive impairment, sup- 2 articles had dyskinesia or evidence of basal ganglia le- ported by the laboratory findings of a slow electroen- sions on magnetic resonance images. Although the exact cephalogram, hyponatremia, and an elevated antibody mechanism is unknown, it is probable that these antibod- titer. Two other patients have been described with cau- ies cause dysfunction of the VGKCs and increase their ex- date and putaminal lesions associated with this syn- citability. In our patient, this hyperexcitability of VGKC drome.1,2 Two clinically similar cases have also been re- may have led to the loss of inhibition of the globus palli- ported,3,4 but, unlike our patient, both patients had clear dus, with consequent disinhibition of the motor thala- electroencephalographic abnormalities, and neither had mus. The specific VGKCs (KV1.1 and KV1.2) are known basal ganglia lesions on magnetic resonance images. Our to be hyperpolarizing to neurons of the striatum and may patient is unique in that he developed kinesigenic dys- have been affected in this case.12-14

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©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Kinesigenic dyskinesia may include dystonia, ballism, 3. Toosy AT, Burbridge SE, Pitkanen M, et al. Functional imaging correlates of fronto- chorea,orathetosis.Itisinducedbysuddenvoluntarymove- temporal dysfunction in Morvan’s syndrome. J Neurol Neurosurg Psychiatry. 2008; 79(6):734-735. ment and may occur (secondary form) as a result of a wide 4. Barajas RF, Collins DE, Cha S, Geschwind MD. Adult-onset drug-refractory sei- variety of conditions, including trauma, metabolic abnor- zure disorder associated with anti-voltage-gated potassium-channel antibody. malities, multiple sclerosis, kernicterus, and central Epilepsia. 2010;51(3):473-477. nervous system infections.15-17 The literature supports 5. Thieben MJ, Lennon VA, Boeve BF, Aksamit AJ, Keegan M, Vernino S. Poten- treatment of this condition with a variety of immuno- tially reversible autoimmune limbic encephalitis with neuronal potassium chan- suppressive strategies.5,6,8,9,17-19 Our patient was treated with nel antibody. Neurology. 2004;62(7):1177-1182. 6. Reid JM, Foley P, Willison HJ. Voltage-gated potassium channel-associated lim- plasmapheresis, intravenous immunoglobulin, and anti- bic encephalitis in the West of Scotland: case reports and literature review. Scott convulsant agents. We are not sure which of the modali- Med J. 2009;54(4):27-31. ties that were used were effective in his treatment. 7. Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol. 2008;7(4):327-340. Accepted for Publication: September 28, 2010. 8. Vincent A, Buckley C, Schott JM, et al. Potassium channel antibody-associated Published Online: December 13, 2010. doi:10.1001 encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain. 2004;127(Pt 3):701-712. /archneurol.2010.317 9. Tan KM, Lennon VA, Klein CJ, Boeve BF, Pittock SJ. Clinical spectrum of voltage- Correspondence: Robert J. Schwartzman, MD, Depart- gated potassium channel autoimmunity. Neurology. 2008;70(20):1883-1890. ment of Neurology, Drexel University College of Medi- 10. Lai M, Huijbers MG, Lancaster E, et al. Investigation of LGI1 as the antigen in cine, 245 N 15th St, MS 423, Philadelphia, PA 19102- limbic encephalitis previously attributed to potassium channels: a case series. 1192 ([email protected]). Lancet Neurol. 2010;9(8):776-785. 11. Irani SR, Alexander S, Waters P, et al. Antibodies to Kv1 potassium channel- Author Contributions: Study concept and design: Aradil- complex proteins leucine-rich, glioma inactivated 1 protein and contactin- las and Schwartzman. Acquisition of data: Aradillas. Analy- associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired sis and interpretation of data: Aradillas and Schwartz- neuromyotonia. Brain. 2010;133(9):2734-2748. man. Drafting of the manuscript: Aradillas. Critical revision 12. Demirkiran M, Jankovic J. Paroxysmal dyskinesias: clinical features and of the manuscript for important intellectual content: classification. Ann Neurol. 1995;38(4):571-579. Schwartzman. Administrative, technical, and material sup- 13. Wulff H, Castle NA, Pardo LA. Voltage-gated potassium channels as therapeutic targets. Nat Rev Drug Discov. 2009;8(12):982-1001. port: Aradillas. Study supervision: Schwartzman. 14. Vernino S. Autoimmune and paraneoplastic channelopathies. Neurotherapeutics. Financial Disclosure: None reported. 2007;4(2):305-314. Online-Only Material: The video is available at http: 15. Blakeley J, Jankovic J. Secondary paroxysmal dyskinesias. Mov Disord. 2002;17 //www.archneurol.com. (4):726-734. 16. Lotze T, Jankovic J. Paroxysmal kinesigenic dyskinesias. Semin Pediatr Neurol. 2003;10(1):68-79. REFERENCES 17. van Rootselaar AF, van Westrum SS, Velis DN, Tijssen MA. The paroxysmal dyskinesias. Pract Neurol. 2009;9(2):102-109. 1. Irani SR, Buckley C, Vincent A, et al. Immunotherapy-responsive seizure-like epi- 18. Mittal M, Hammond N, G Lynch S. Immunotherapy responsive autoimmune sub- sodes with potassium channel antibodies. Neurology. 2008;71(20):1647-1648. acute encephalitis: a report of two cases. Case Report Med. 2010;2010:837371. 2. Hiraga A, Kuwabara S, Hayakawa S, et al. Voltage-gated potassium channel an- 19. Ohshita T, Kawakami H, Maruyama H, Kohriyama T, Arimura K, Matsumoto M. tibody-associated encephalitis with basal ganglia lesions. Neurology. 2006; Voltage-gated potassium channel antibodies associated limbic encephalitis in a 66(11):1780-1781. patient with invasive thymoma. J Neurol Sci. 2006;250(1-2):167-169.

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