VGKC autoantibodies mimicking CJD

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


VGKC antibodies have been described in a variety of patient types, and may present with a symptom c0mplex including cognitive impairment and myoclonus, mimicking Creutzfeld-Jacob disease, which is untreatable. Some cases of VGKC may be treatable with IVIG or other anti-immune strategies.

Paraneoplastic VGKC have been identified as paraneoplastic antibodies in neuroendocrine tumors (including small cell lung cancer), retinoblastoma, oligodendroglioma, melanoma, leiomyosarcoma, and hematologic malignancies. They are also seen as markers of neuromyotonia, Morvan's, epilepsy, limbic encephalits, and dysautonomia with hyperhidrosis and GI dysmotility. Animal passive transfer experiments suggest pathogenicitiy. IVIG and plasma exchange are beneficial.

Among 80 patients in this Mayo Clinic series, was usually an inflammatory or neurodegenerative disease. 11 were correctly thought to have autoimmune encephalopathy, 10 with CJD, 5 with viral encephalitis, 3 with recurrent TGA, 4 with psychiatric (anxiety disorder/panic attacks/ conversion disorder). Examination showed frontosubcortical involvement, pesonality change, executive dysfunction, disinhibition, visual hallucinations (10%), agitation or depression. Short term memory impairment, with 58 % having some form of seizure disorder (all types seen) . Cranial nerve involvement was seen in 19 % including diplopia (not MG associated), dysarthria, dysphagia, vision loss, hemifacial spasm, hyperphagia, hyponatremia, EPS, cerebellar ataxia, recurrent ON without NMO antibodies, myoclonus, hypersomnia, autonomic dysfunction. MRI's showed abnormalities in bilateral hippocampi, CN head, splenium , frontal lobe, or multifocal suspicious for CJD. MRI improved partly or wholly. SPECT, EEG, CSF generally or often abnormal. 47% had documented neoplasia, of whom 76 % were smokers, and VGKC preceded diagnosis by five or more months.

Coexisting antibodies included ANNA-1, PCA2, amphiphysin IgG, CRMP 5 IgG with ultimate diagnosis of 5 small cell lung CA, three thymic CA, four prostate adenoCA, Becelllymphoma, CLL, mycosis fungoides, 3 head and neck CA, one colonic adenoca. There also were benign neoplasia including 5 pituitary adenoca, one adrenal, one colonic, one parathyroid, one renal oncocytoma, one gastric leiomyoma. Other AI disorders were Hashimoto titers in 15, endocrine pancreas in 8, and pernicious anemia. 89 % improved with treatment, half dramatically so, including 8 of 10 with initial misdiagnosis of CJD. These included six patients with increased 14,3,3 or NSE, 5 of whom improved remarkably.

Changing the trajectory of cognitive decline?

Albert, MS. Clinical implications of basic research. NEJM 2007; 357:502-503.

This brief article describes recent findings in mouse models of cognitive loss. An enriched environment, containing many objects a mouse can explore, enhances learning and memory. Hippocampal neurogenesis is increased but not olfactory bulb. A model described by Fischer et al (Nature 2007) correlates with histone acetylation. Histone deacetylase (HDAC) inhibitor injections also facilitates memory. Histone acetylation is associated with synaptic plasticity.

Capgras syndrome and its relationship to neurodegenerative disease

Joseph KA. Arch Neurol 2007;64:1762-1766.
Capgras s is delusional belief that a person has been removed and replaced by an impostor (husband, wife, etc.) In a review of 57 instances (Mayo Minnesota) 38 had neurodegenerative disease usually Lewy body disease. 100 % of those with LBD had visual hallucinations too compared to only one with AD. In younger patients CS occurred in the context of paranoid schizophrenia, schizoaffective disorder, methamphetamine abuse, and immediately after massive infarctions not in any one distinctive area.

Antiinflammatories, APOE status and dementia risk

Szekely CA, Breitner JCS, Fitzpatrick AL et al. NSAID use and dementia risk in the cardiovascular health study. Role of APOE and NSAID type. Neurology 2008; 70:17-24.

3229 subjects aged 65+, free of dementia were analyzed. Use of NSAID's led to lower dementia risk (did not matter which AED). Acetominophen did not prevent dementia. Risk reduction was present only among subjects having an APOE4 allele . A contoversy exists regarding the use of particular NSAID's (ie ibuprofen but not naproxen due to AB 42 lowering effect) but there was not advantage seen in this study.

Blogger comment:
Back to screening first degree relatives of Alz patients to prevent their risk of developing disease and advising them. We have a rationale for measuring APOE status in these patients (which has been missing for 15 years). Mechanisms, counselling, etc. needs to be put into place first.

The natural history of cognitive dysfunction in late onset GM2 gangliosidosis

Frey LC, Ringel SP, Filley CM. Arch Neurol 2005;62:989-994

Comment-- As one my mentors warned, pediatric diseases show up in adults and we need to diagnose them. This is the "adult form" of Tay Sachs disease. Late onset GM2 gangliosidosis (LGG)has late onset (adolescents and young adults), has a prolonged disease course, comparably late onset of neurologic dysfunction, and affects a significant minority of patients who are not of Ashkenazi Jewish descent.

Case one was a 46 year old Ahkenazi Jewish woman who had required special tutoring and was "emotionally immature." She showed emotional lability, aggressiveness and visual hallucinations. She had dysarthria, poor recall on memory tests, muscle atrophy and fasciculations, appendicular ataxia, and dysmetria, diffusely brisk reflexes and upgoing toes. EMG/ muscle biopsy done at age 13 showed diffuse denervation. She had a FSIQ of 93 at age 10, and 70 at age 20. CT showed cerebellar atrophy. Hex A level at age 20 showed partial deficiency (20.3 % residual WBC hex A).

Case 2 was sister of case one. She was learning disabled, weakness and ataxia, multiple psychiatric hospitalizations for psychoses, responsive to phenothiazines and lithium. She had partial hex A deficiency (20 %). She had supranuclear gaze palsy, tongue fasciculations, diffuse weakness, brisk reflexes, and flexor plantar responses. She had abnormal executive function, as detailed in Trailmaking Tests A and B and memory.

Case 3 was a 30 yo woman who had come to attention with deteriorating schoolwork in second grade. At age 25 she had a confusional state and profound abulia. She was briefly given AED's. MMSE was 27/30. She had limited upgaze, mild neck flexor weakness, diffuse limb weakness, brisk reflexes with bilateral Babinski signs, mild CT atrophy, slow RAM's, EMG showed abnormal spontaneous activity and decreased motor unit amplitude.

Review of 62 patients-- 2/3 were Ashknenazi Jews, 82 % LMN signs, and 69 % cerebellar signs, were seen. Mean hex A ranged from 0-48 %. 44 % were described as having cognitive dysfunction. 38 % of patients were cognitively stable, and 62 % had progressive cognitive loss.

Cognitive impairment in familial ALS

Wheaton MW, Salamone AR, Mosnik DM et al. Cognitive impairment in familial ALS. Neurology 2007; 69:1411-1417.

Background. 51 % of patients with sALS have mild cognitive impairment, esp. executive function and memory. A subset, 15 % have more sever impairments with features of FTD. Over 60 % of patients had some cognitive impairment, either moderate or severe, generally unrelated to motor variables.

Binge eating in FTLD

Neurology 2007; 69: 1424-33 and editorial 1389-1390. Article by Wooley et al, editorial by Murray Grossman

FTLD patients binge eat, especially sweets, even when stated that they are full. Investigators found significant atrophy in ventral insula, rostral orbital frontal, and striatum of right hemisphere among six binge eaters. Interestingly other frontal lobe abnormalities on neuropsychological tests were not found. Also they did not gain weight, leading Grossman to question whether the eating was a form of L'Hermitte's environmental dependency.