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

Enrique Aradillas, MD; Robert J. Schwartzman, MD
[+] Author Affiliations

Author Affiliations: Department of Neurology, Drexel University College of Medicine, Philadelphia, Pennsylvania.


Arch Neurol. 2011;68(4):529-532. doi:10.1001/archneurol.2010.317.
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To our knowledge, this is the first description of a patient who had central neurologic signs of seizures, encephalopathy, and kinesigenic dystonia as well as fasciculations and peripheral cramps.

REPORT OF A CASE

A 38-year-old man presented with the chief complaint of the sudden onset of “stiffness” of both arms and legs. The problem had begun 8 weeks earlier, when the patient experienced 2 episodes of extreme anxiety that lasted for approximately 30 seconds with no associated loss of consciousness or abnormal movements. A few days after these 2 episodes, he noted the onset of abnormal movements, which were initiated by change of position or startle and would involve either the upper or the lower extremities. The movements occurred up to 40 to 50 times per day and were exacerbated by stress and lack of sleep. The patient subsequently developed clear cognitive decline manifested as difficulty with short-term memory and concentration. The episodes of anxiety increased in frequency and intensity and were followed by 2 witnessed generalized tonic-clonic seizures. The patient was admitted to an outlying hospital and underwent an extensive workup, which included routine magnetic resonance imaging without gadolinium, cerebral arteriography, and routine blood, urine, and cerebrospinal fluid analysis, the results of which were normal. He also had bronchial asthma, eczema, vitiligo, and immune complex mesangiopathic glomerulonephritis. He was taking 500 mg of mycophenolate mofetil (CellCept [2-morpholino-ethyl ester of mycophenolic acid]) twice a day for his renal condition.

On admission, he was fully alert and oriented but had trouble with immediate recall and tasks that required concentration (eg, serial 7s). He had slight forward flexed posture but otherwise had full strength, sensation, and coordination. He demonstrated multiple episodes of kinesigenic dyskinesia, which were always initiated by sudden movement (most often by reaching for objects or attempting to get up from a sitting position). The movements were at times bilateral and at times unilateral. He would flex at the elbow and wrist and extend his knees while dorsiflexing his foot. His face involved the orbicularis oculi, buccinator muscles, and lower facial musculature. The episodes were stereotyped and lasted 3 to 10 seconds (video). 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, <0.02 nmol/L) and an elevated ganglionic acetylcholine receptor antibody titer (0.45 nmol/L; reference value, 0.02 nmol/L). Electromyography and nerve conduction studies using the cramp-fasciculation protocol revealed significant afterdischarges with 3-Hz stimulation, significant cramp potentials with 5-Hz stimulation, and continuous motor activity with 10-Hz stimulation (Figure 3). The serum sodium level on admission was 128 mEq/L (to convert to millimoles per liter, multiply by 1.0). A 72-hour continuous video-electroencephalographic monitoring system revealed nonspecific slowing but no epileptiform activity. The results of a complete malignancy workup, including total-body positron emission tomography, were negative.

Place holder to copy figure label and caption
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).

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Place holder to copy figure label and caption
Figure 2.

Single-photon emission computed tomographic scans of the brain demonstrating increased flow in the left striatum region (arrows).

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location

Levetiracetam therapy (1000 mg twice a day) was initiated and was continued throughout the course of the patient's evaluation. The patient underwent 5 plasma exchanges during the first week. There was no clinical improvement. The second week, 5 intravenous immunoglobulin infusions of 2 mg/kg were administered over 4 to 5 hours with 30 mg of prednisone. On the 10th day (third intravenous immunoglobulin infusion), the kinesigenic dyskinesia decreased dramatically to only 1 to 2 very mild episodes per day. The patient no longer had spontaneous fasciculations. Topiramate (100 mg every night) was added to his regimen the last week of treatment. At the 8-week follow-up visit, his VGKC antibody level was undetectable.

COMMENT

To our knowledge, this is the first reported case involving both VGKC complex protein antibody encephalitis and fasciculations associated with kinesigenic dyskinesia. Because of the patient's history of 2 autoimmune diseases—vitiligo and immune complex mesangiopathic glomerulonephritis—and negative cancer evaluation findings, we believed that the VGKC encephalitis and the peripheral cramp-fasciculation syndrome were on an autoimmune basis. He had the typical clinical presentation for the VGKC antibody spectrum disease, including seizures and memory and cognitive impairment, supported by the laboratory findings of a slow electroencephalogram, hyponatremia, and an elevated antibody titer. Two other patients have been described with caudate and putaminal lesions associated with this syndrome.1,2 Two clinically similar cases have also been reported,3,4 but, unlike our patient, both patients had clear electroencephalographic abnormalities, and neither had basal ganglia lesions on magnetic resonance images. Our patient is unique in that he developed kinesigenic dyskinesia and asymptomatic cramp-fasciculation syndrome. Also, he did not complain of any of the typical symptoms of peripheral nerve hyperexcitability that have been described in association with VGKC antibody spectrum diseases (neuromyotonia or Isaacs syndrome, cramp-fasciculation syndrome, and Morvan syndrome).59 He did, however, have prominent fasciculations, especially in the lower extremities.

Until recently, VGKCs were thought to be the antigenic target in these patients.8,9 The work by Lai et al10 and Irani et al11 has demonstrated that the antigenic targets are proteins that form a complex with these VGKCs, ie, leucine-rich glioma-inactivated 1 and contactin-associated protein 2. Leucine-rich glioma-inactivated 1 associates with the VGKC KV1.1, and, clinically, patients who had this antibody had more central nervous system manifestations (limbic encephalitis, seizures, and altered mental status). Contactin-associated protein 2 associates with both KV1.1 and KV1.2 VGKCs at the neural juxtaparanodal region, and patients with contactin-associated protein 2 antibodies present clinically with fewer nervous system symptoms and more features of peripheral nervous system dysfunction. Of note, none of the patients described in these 2 articles had dyskinesia or evidence of basal ganglia lesions on magnetic resonance images. Although the exact mechanism is unknown, it is probable that these antibodies cause dysfunction of the VGKCs and increase their excitability. In our patient, this hyperexcitability of VGKC may have led to the loss of inhibition of the globus pallidus, with consequent disinhibition of the motor thalamus. The specific VGKCs (KV1.1 and KV1.2) are known to be hyperpolarizing to neurons of the striatum and may have been affected in this case.1214

Kinesigenic dyskinesia may include dystonia, ballism, chorea, or athetosis. It is induced by sudden voluntary movement and may occur (secondary form) as a result of a wide variety of conditions, including trauma, metabolic abnormalities, multiple sclerosis, kernicterus, and central nervous system infections.1517 The literature supports treatment of this condition with a variety of immunosuppressive strategies.5,6,8,9,1719 Our patient was treated with plasmapheresis, intravenous immunoglobulin, and anticonvulsant agents. We are not sure which of the modalities that were used were effective in his treatment.

ARTICLE INFORMATION

Correspondence: Robert J. Schwartzman, MD, Department of Neurology, Drexel University College of Medicine, 245 N 15th St, MS 423, Philadelphia, PA 19102-1192 (Robert.Schwartzman@drexelmed.edu).

Accepted for Publication: September 28, 2010.

Published Online: December 13, 2010. doi:10.1001/archneurol.2010.317

Author Contributions:Study concept and design: Aradillas and Schwartzman. Acquisition of data: Aradillas. Analysis and interpretation of data: Aradillas and Schwartzman. Drafting of the manuscript: Aradillas. Critical revision of the manuscript for important intellectual content: Schwartzman. Administrative, technical, and material support: Aradillas. Study supervision: Schwartzman.

Financial Disclosure: None reported.

REFERENCES

Irani  SRBuckley  CVincent  A  et al.  Immunotherapy-responsive seizure-like episodes with potassium channel antibodies. Neurology 2008;71 (20) 1647- 1648
PubMed Link to Article
Hiraga  AKuwabara  SHayakawa  S  et al.  Voltage-gated potassium channel antibody-associated encephalitis with basal ganglia lesions. Neurology 2006;66 (11) 1780- 1781
PubMed Link to Article
Toosy  ATBurbridge  SEPitkanen  M  et al.  Functional imaging correlates of fronto-temporal dysfunction in Morvan's syndrome. J Neurol Neurosurg Psychiatry 2008;79 (6) 734- 735
PubMed Link to Article
Barajas  RFCollins  DECha  SGeschwind  MD Adult-onset drug-refractory seizure disorder associated with anti-voltage-gated potassium-channel antibody. Epilepsia 2010;51 (3) 473- 477
PubMed Link to Article
Thieben  MJLennon  VABoeve  BFAksamit  AJKeegan  MVernino  S Potentially reversible autoimmune limbic encephalitis with neuronal potassium channel antibody. Neurology 2004;62 (7) 1177- 1182
PubMed Link to Article
Reid  JMFoley  PWillison  HJ Voltage-gated potassium channel-associated limbic encephalitis in the West of Scotland: case reports and literature review. Scott Med J 2009;54 (4) 27- 31
PubMed Link to Article
Dalmau  JRosenfeld  MR Paraneoplastic syndromes of the CNS. Lancet Neurol 2008;7 (4) 327- 340
PubMed Link to Article
Vincent  ABuckley  CSchott  JM  et al.  Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 2004;127 (Pt 3) 701- 712
PubMed Link to Article
Tan  KMLennon  VAKlein  CJBoeve  BFPittock  SJ Clinical spectrum of voltage-gated potassium channel autoimmunity. Neurology 2008;70 (20) 1883- 1890
PubMed Link to Article
Lai  MHuijbers  MGLancaster  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) 776- 785
PubMed Link to Article
Irani  SRAlexander  SWaters  P  et al.  Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia. Brain 2010;133 (9) 2734- 2748
PubMed Link to Article
Demirkiran  MJankovic  J Paroxysmal dyskinesias: clinical features and classification. Ann Neurol 1995;38 (4) 571- 579
PubMed Link to Article
Wulff  HCastle  NAPardo  LA Voltage-gated potassium channels as therapeutic targets. Nat Rev Drug Discov 2009;8 (12) 982- 1001
PubMed Link to Article
Vernino  S Autoimmune and paraneoplastic channelopathies. Neurotherapeutics 2007;4 (2) 305- 314
PubMed Link to Article
Blakeley  JJankovic  J Secondary paroxysmal dyskinesias. Mov Disord 2002;17 (4) 726- 734
PubMed Link to Article
Lotze  TJankovic  J Paroxysmal kinesigenic dyskinesias. Semin Pediatr Neurol 2003;10 (1) 68- 79
PubMed Link to Article
van Rootselaar  AFvan Westrum  SSVelis  DNTijssen  MA The paroxysmal dyskinesias. Pract Neurol 2009;9 (2) 102- 109
PubMed Link to Article
Mittal  MHammond  NG Lynch  S Immunotherapy responsive autoimmune subacute encephalitis: a report of two cases. Case Report Med 2010;2010837371
PubMed
Ohshita  TKawakami  HMaruyama  HKohriyama  TArimura  KMatsumoto  M Voltage-gated potassium channel antibodies associated limbic encephalitis in a patient with invasive thymoma. J Neurol Sci 2006;250 (1-2) 167- 169
PubMed Link to Article

Figures

Place holder to copy figure label and caption
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).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Single-photon emission computed tomographic scans of the brain demonstrating increased flow in the left striatum region (arrows).

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location

Tables

References

Irani  SRBuckley  CVincent  A  et al.  Immunotherapy-responsive seizure-like episodes with potassium channel antibodies. Neurology 2008;71 (20) 1647- 1648
PubMed Link to Article
Hiraga  AKuwabara  SHayakawa  S  et al.  Voltage-gated potassium channel antibody-associated encephalitis with basal ganglia lesions. Neurology 2006;66 (11) 1780- 1781
PubMed Link to Article
Toosy  ATBurbridge  SEPitkanen  M  et al.  Functional imaging correlates of fronto-temporal dysfunction in Morvan's syndrome. J Neurol Neurosurg Psychiatry 2008;79 (6) 734- 735
PubMed Link to Article
Barajas  RFCollins  DECha  SGeschwind  MD Adult-onset drug-refractory seizure disorder associated with anti-voltage-gated potassium-channel antibody. Epilepsia 2010;51 (3) 473- 477
PubMed Link to Article
Thieben  MJLennon  VABoeve  BFAksamit  AJKeegan  MVernino  S Potentially reversible autoimmune limbic encephalitis with neuronal potassium channel antibody. Neurology 2004;62 (7) 1177- 1182
PubMed Link to Article
Reid  JMFoley  PWillison  HJ Voltage-gated potassium channel-associated limbic encephalitis in the West of Scotland: case reports and literature review. Scott Med J 2009;54 (4) 27- 31
PubMed Link to Article
Dalmau  JRosenfeld  MR Paraneoplastic syndromes of the CNS. Lancet Neurol 2008;7 (4) 327- 340
PubMed Link to Article
Vincent  ABuckley  CSchott  JM  et al.  Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 2004;127 (Pt 3) 701- 712
PubMed Link to Article
Tan  KMLennon  VAKlein  CJBoeve  BFPittock  SJ Clinical spectrum of voltage-gated potassium channel autoimmunity. Neurology 2008;70 (20) 1883- 1890
PubMed Link to Article
Lai  MHuijbers  MGLancaster  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) 776- 785
PubMed Link to Article
Irani  SRAlexander  SWaters  P  et al.  Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia. Brain 2010;133 (9) 2734- 2748
PubMed Link to Article
Demirkiran  MJankovic  J Paroxysmal dyskinesias: clinical features and classification. Ann Neurol 1995;38 (4) 571- 579
PubMed Link to Article
Wulff  HCastle  NAPardo  LA Voltage-gated potassium channels as therapeutic targets. Nat Rev Drug Discov 2009;8 (12) 982- 1001
PubMed Link to Article
Vernino  S Autoimmune and paraneoplastic channelopathies. Neurotherapeutics 2007;4 (2) 305- 314
PubMed Link to Article
Blakeley  JJankovic  J Secondary paroxysmal dyskinesias. Mov Disord 2002;17 (4) 726- 734
PubMed Link to Article
Lotze  TJankovic  J Paroxysmal kinesigenic dyskinesias. Semin Pediatr Neurol 2003;10 (1) 68- 79
PubMed Link to Article
van Rootselaar  AFvan Westrum  SSVelis  DNTijssen  MA The paroxysmal dyskinesias. Pract Neurol 2009;9 (2) 102- 109
PubMed Link to Article
Mittal  MHammond  NG Lynch  S Immunotherapy responsive autoimmune subacute encephalitis: a report of two cases. Case Report Med 2010;2010837371
PubMed
Ohshita  TKawakami  HMaruyama  HKohriyama  TArimura  KMatsumoto  M Voltage-gated potassium channel antibodies associated limbic encephalitis in a patient with invasive thymoma. J Neurol Sci 2006;250 (1-2) 167- 169
PubMed Link to Article

Correspondence

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Kinesigenic dyskinesia or another case of autoimmune faciobrachial dystonic seizures?
Posted on May 5, 2011
Sarosh R Irani, MD DPhil
Nuffield Department of Neurosciences, University of Oxford*,
Conflict of Interest: None Declared
Aradillas and Schwartzmann report the case of a 38 year-old male with very frequent (40-50 per day), paroxysmal, kinesigenic dystonic face and limb movements, each lasting a few seconds.1 Onset of these events was contemporaneous with new-onset medial temporal lobe seizures and was followed by the development of generalised tonic-clonic seizures and marked amnesia. The patient was found to have serum hyponatraemia, voltage -gated potassium channel (VGKC) complex antibodies and also ganglionic AChR antibodies. No cancer was detected. 72 hours of video telemetry was said to have revealed no epileptiform activity. These paroxysmal kinesigenic attacks were responsive to immunotherapies. We have recently described 29 patients with identical paroxysmal attacks – also found in association with VGKC-complex (consistently LGI1) antibodies – which we have termed faciobrachial dystonic seizures (FBDS).2 These patients typically developed frequent (median of 50 times per day), stereotyped, brief dystonic events involving the arm and ipsilateral face which often preceded the development of a non-paraneoplastic limbic encephalitis, as characterised by amnesia and confusion. Movements triggered some of the events in 3 of 29 cases (10%). Other triggers included auditory startle in 6 (21%) and high levels of emotion in 2 (7%) cases. We identified ictal epileptiform changes in 7 (24%) and ictal impairment of consciousness in 19 (66%) of the cases, although the latter was not present in all seizures in an individual. However, some patients had no epileptiform discharges detected despite prolonged video telemetry: in common with other brief focal seizures (e.g. déjà-vu) we attribute this to the seizures arising from a deep epileptic focus. Importantly, these FBDS were often antiepileptic drug refractory but responsive to immunotherapies. Classical paroxysmal kinesigenic dyskinesia (PKD) is a discrete disorder (without other interictal features), occurring both on a sporadic and genetic basis, with onset below 20 years. However, secondary forms of PKD can present in later life. PKD is considered by many as a movement disorder but accumulating evidence is suggestive of an epileptiform physiological basis.4 In the video footage accompanying the cases described by Aradillas and Schwartzmann, of the four ‘PKD’ attacks we were only able to identify one which appeared to be precipitated by movement: three appeared spontaneous. All four attacks involved the arm, three involved the ipsilateral face and two the leg. Given the similarities in the semiology of the attacks, their association with VGKC-complex antibodies and the subsequent clinical course, we suggest that these attacks are consistent with those we have described as FBDS.2,3 Interest in pathophysiology aside, consistent nomenclature within the literature will help clinicians to recognise and correctly interpret these attacks. Such consistency is particularly important as it has the potential to alter clinical practice: confident identification of LGI1- antibody mediated FBDS leading to prompt treatment with immunotherapies may prevent the development of florid limbic encephalitis with its cognitive and social sequelae.5 References
1. Aradillas E and Schwartzmann RJ. Kinesigenic dyskinesia in a case of voltage-gated potassium channel-complex protein antibody encephalitis. Arch Neurol. 2011;68(4):529-32.
2. Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol. 2011 May;69(5):892-900. doi: 10.1002/ana.22307.
3. Irani SR, Buckley C, Vincent A, et al. Immunotherapy-responsive seizure-like episodes with potassium channel antibodies. Neurology. 2008;71(20):1647-1648.
4. Bhatia KP. The paroxysmal dyskinesias. J Neurol. 1999;246(3):149- 55.
5. Irani SR, Alexander S, Waters P, et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia. Brain 2010;133(9):2734-2748.

Conflict of Interest: AV and the Department of Clinical Neurology in Oxford receive royalties and payments for antibody assays. AV is the inventor on patent application WO/2010/046716 entitled 'Neurological Autoimmune Disorders' and SRI is co-applicant on the patent and may receive royalties from VGKC-complex antibody testing. The patent has been licensed to Euroimmun AG for the development of assays for Lgi1 and other VGKC-complex antibodies. SRI was supported by the National Institute for Health Research (NIHR), Department of Health, UK.
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