Seven of the 15 patients were women; the median patient age was 69 years. The median serum VGKC autoantibody level was 1.24 nmol/L (range, 0.16–51.9 nmol/L; reference range, ≤0.02 nmol/L). The clinical presentations, EEG and MRI findings, VGKC autoantibody titers, and treatment responses of the 7 patients evaluated directly by us are summarized in the .
Clinical Characteristics of 7 VGKC Ab–Positive Patients With Suspected CJD, Evaluated Directly by the Authors
In all cases, neurologic symptoms were subacute in onset. The median time from neurologic symptom onset to serologic diagnosis was 5 months (range, 0–13 months); median follow-up from onset was 9 months (range, 1–88 months). All of the patients had short-term memory impairment, 12 had myoclonus, 12 had seizures, 10 had behavioral or affective disturbance, 8 had dyssomnia, 6 had extrapyramidal dysfunction, 5 had autonomic dysfunction, 5 had gait ataxia, and 5 had visual hallucinations. Nine patients (60%) satisfied the World Health Organization diagnostic criteria for sporadic CJD18
: 3 probable and 6 possible. Nine patients had hyponatremia (presumed to reflect hypothalamic involvement), including 2 with hyperphagia.
Five patients had documented coexisting organ-specific autoimmune disease: 3 with thyroiditis (1 with vitiligo) and 2 with diabetes mellitus. Two patients had a remote history of neoplasia in remission. Active neoplasia was confirmed histologically in 3 patients (2 had colonic adenocarcinoma and 1 had renal oncocytoma) and was suspected in 5 others (1 had a prostatic nodule and a serum prostate-specific antigen level elevation and 4 had mass lesions on thoracic or abdominal computed tomography).
Comprehensive serologic evaluation19
documented coexisting organ-specific autoantibodies in 8 patients. Six patients had autoantibody markers of thyrogastric autoimmunity: 4 had striated muscle autoantibodies, 3 had glutamic acid decarboxylase (65-kDa isoform) autoantibodies, and 2 had thyroid peroxidase autoantibodies. Three patients had autoantibodies that frequently accompany cancer: Purkinje cell cytoplasmic autoantibody type 2,20
neuronal ganglionic acetylcholine receptor autoantibody,21
and N-type voltage-gated calcium channel autoantibody.22
Brain MRI abnormalities, noted in 9 of 13 patients in whom images or reports were available, included cerebral cortical diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) abnormalities in 2 ( and ), T2-weighted or FLAIR hyperintensities in 5 (all involving hippocampi and 2 involving additional cerebral foci), and generalized atrophy in 2. Both patients with apparent DWI abnormalities had normal attenuation diffusion coefficient maps.
Figure 1 Brain magnetic resonance images of a patient with immunotherapy-responsive voltage-gated potassium channel (VGKC) autoimmunity and renal oncocytoma illustrate increased signal in the left anterior cingulate gyrus and insular cortex on diffusion-weighted (more ...)
Figure 2 Diffusion-weighted magnetic resonance images in a patient with immunotherapy-responsive voltage-gated potassium channel autoimmunity illustrate increased signal in the left temporo-occipital cortex (A and C, arrows) and the bilateral mesial frontal cortex (more ...)
The CSF analysis in 10 patients revealed elevated protein levels in 3 (0.057–0.112 g/dL; range, 0.014–0.045 g/dL [to convert to grams per liter, multiply by 10.0]), lymphocytosis in 2 (white blood cell counts, 6 and 28/μL [to convert to × 109 per liter, multiply by 0.001]), and supernumerary (4) oligoclonal bands in 1. The CSF markers of neuronal injury were elevated in 5 of 8 patients tested: 14-3-3 protein (National Prion Disease Pathology Surveillance Unit, Cleveland, Ohio) was positive in 4 and neuron-specific enolase (Mayo Medical Laboratories, Rochester) was positive in 2.
The EEG findings were abnormal in 9 of 13 patients with available data. All 9 patients had diffuse slowing, 1 had frontal intermittent rhythmic delta activity, and 3 had focal epileptogenic activity (1 temporal, 1 frontal, and 1 frontotemporal). None had periodic sharp wave complexes.
Information about initial treatment and outcome was available for 13 patients: 9 received corticosteroids, 2 received intravenous immunoglobulin, and 2 received plasmapheresis and corticosteroids combined. Clinical improvement was reported by the treating physician in 12 patients (92%; 5 dramatic, 6 moderate, and 1 mild). Of those 12 patients, 8 experienced relapses that required continued or repeated immunomodulatory therapy: corticosteroids (7 patients), immunoglobulin (2 patients), plasmapheresis (1 patient), mycophenolate mofetil (2 patients), rituximab (1 patient), or azathioprine (1 patient).
ILLUSTRATIVE PATIENT 1
A 73-year-old woman (patient 1 in the ) presented to the UCSF Memory and Aging Center with an 8-month history of involuntary movements of the right upper extremity and face and a 4-month history of rapidly progressive cognitive decline, abulia, insomnia, and frequent falls. Examination revealed fluctuating alertness, a Folstein Mini-Mental State Examination score of 18 (maximum possible score is 30) (impairment across multiple domains), myoclonus and spasms of the right upper extremity and face, mild generalized bradykinesia, right upper extremity rigidity, and gait ataxia.
Laboratory evaluation revealed hyponatremia (sodium, 127 mEq/L [to convert to millimoles per liter, multiply by 1.0]) and 4 CSF-unique oligoclonal bands. The CSF 14-3-3 protein level was mildly elevated initially (considered “ambiguous” for CJD) but was normal on 2 subsequent spinal taps. Brain MRIs were considered suggestive of CJD, showing increased DWI and FLAIR signal in the left anterior cingulate gyrus and insula (); however, the attenuation diffusion coefficient map was normal. Biopsy of the left frontal lobe revealed microgliomatosis and neuronophagia without inflammation and astrocytic gliosis without vacuolation or prion deposition. During serologic evaluation for paraneoplastic autoantibodies, indirect immunofluorescence screening suggested the presence of VGKC specific IgG (). Reflex radioimmunoprecipitation assay confirmed the presence of VGKC autoantibodies (51.9 nmol/L; reference range, ≤0.02 nmol/L). N-type voltage-gated calcium channel autoantibody was also detected (0.17 nmol/L; reference range, ≤0.03 nmol/L). Computed tomography revealed a renal mass suggestive of adenoma.
After 3 days of intravenous methylprednisolone therapy, alertness, verbal output, and cognitive performance (a Mini-Mental State Examination score of 30) improved remarkably. Subsequent brain MRI showed reduced DWI and FLAIR hyperintensity in the left insula and cingulate gyri but new T2 hyperintensity involving the left caudate and putamen (data not shown). Repeated pulsed corticosteroid therapy was required in the ensuing 18 months for recurrent generalized tonicclonic seizures and cognitive impairment; intravenous immunoglobulin therapy, plasmapheresis, mycophenolate therapy, and partial nephrectomy (confirming a renal oncocytoma) did not seem to provide additional benefit. Rituximab therapy commenced 23 months after onset was followed by considerable clinical improvement, comparable with that seen previously with pulsed corticosteroid therapy.
ILLUSTRATIVE PATIENT 2
A 75-year-old man (patient 4 in the ) with a 50–pack-year history of smoking and a past diagnosis of colonic adenoma presented to Mayo Clinic with a 5-month history of cognitive impairment and a 3-month history of startle myoclonus, hypnagogic jerks, urinary and fecal incontinence, shuffling gait, and a presumed rapid eye movement sleep behavior disorder characterized by episodic screaming and thrashing. He scored 30 (maximum possible score is 38) on the Kokmen short test of mental status; short-term recall and abstract thinking were most impaired. Myoclonic jerks of both upper extremities and the face were observed, with hypomimia, hypophonia, and parkinsonian gait.
Brain MRI showed mild global atrophy. The CSF protein level was mildly elevated (0.057 g/dL; reference range, 0.014–0.045 g/dL), without lymphocytosis or oligoclonal bands. The EEG documented diffuse slowing during wakefulness and focal rhythmic theta activity (consistent with a frontal lobe seizure) during a typical sleep episode of abrupt yelling, right arm jerking, and stiffening. Movement laboratory evaluation documented spontaneous multifocal cortical myoclonus, and serologic evaluation revealed VGKC autoantibody (0.16 nmol/L) and striated muscle autoantibody (1:30 720; reference range, ≤1:60). Chest computed tomography revealed mediastinal lymphadenopathy; subsequent biopsy revealed hyalinized granulomata but no neoplasm.
Treatment with intravenous methylprednisolone led to complete resolution of all deficits (including a Kokmen score of 38), but pulsed corticosteroid treatment was required intermittently for 12 months because of neurologic relapse. In the following 18 months, he remained in remission without further treatment.