Journal of Neuro-Ophthalmology, June 2000, Volume 20, Issue 2

Selective Loss of the Electroretinogram B-wave in a Patient with Creutzfeldt-Jakob Disease

Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disease characterized by movement abnormalities and dementia that inevitably progress to death. Familial, infectious, and sporadic forms of the disease are recognized. The worldwide incidence of CJD is estimated at 1:1,000,000 per year, and it affects middle-aged men and women in roughly equal proportions. The disease is caused by a unique infectious vector, the prion, which is a mutant form of a normally occurring cell surface protein found predominantly in the central nervous system. A significant proportion of patients with CJD will have visual disturbances at some point in their illness and may therefore consult a neuro-ophthalmologist. The case of a woman in whom the diagnosis of CJD was not known until autopsy is reported. Early in the course of her disease, she sought ophthalmic consultation because of vision problems.

Journal of Neuro- Ophthalmology 20( 2): 116- 118, 2000. © 2000 Lippincott Williams & Wilkins, Inc., Philadelphia Selective Loss of the Electroretinogram B- wave in a Patient With Creutzfeldt- Jakob Disease Bradley J. Katz, MD, PhD, Judith E. A. Warner, MD, Kathleen B. Digre, MD, and Donnell J. Creel, PhD Creutzfeldt- Jakob disease ( CJD) is a neurodegenerative disease characterized by movement abnormalities and dementia that inevitably progress to death. Familial, infectious, and sporadic forms of the disease are recognized. The worldwide incidence of CJD is estimated at 1: 1,000,000 per year, and it affects middle- aged men and women in roughly equal proportions. The disease is caused by a unique infectious vector, the prion, which is a mutant form of a normally occurring cell surface protein found predominantly in the central nervous system. A significant proportion of patients with CJD will have visual disturbances at some point in their illness and may therefore consult a neuro- ophthalmologist. The case of a woman in whom the diagnosis of CJD was not known until autopsy is reported. Early in the course of her disease, she sought oph­thalmic consultation because of vision problems. Key Words: Creutzfeldt- Jakob- Electroretinogram- Spongiform Encephalopathy- Prion. CASE REPORT A 44- year- old woman was referred because of dizzi­ness and difficulty tracking moving objects. Her family reported memory difficulties, diminished reasoning abili­ties, and personality changes. The patient had no signifi­cant medical history or risk factors for contracting Creutzfeldt- Jakob disease ( CJD). Visual acuity was 20/ 20 OU. There was no afferent pupillary defect. Fields were full by confrontation. Mo­tility was full, but saccades were hypometric, left- beating nystagmus was present, and vestibulo- ocular response Manuscript received November 19, 1999; accepted February 2, 2000. From the Departments of Ophthalmology ( BJK, JEAW, KBD, DJC) and Neurology ( JEAW, KBD) and the John A. Moran Eye Center ( BJK, JEAW, KBD, DJC), University of Utah Health Sciences Center, Salt Lake City, Utah. Supported in part by a grant from Research to Prevent Blindness, Inc., New York, New York, to the Department of Ophthalmology, University of Utah, Salt Lake City, Utah. Presented at the 25th annual meeting of the North American Neuro- Ophthalmology Society, March 15, 1999, Snowmass, Colorado. Address correspondence and reprint requests to Bradley J. Katz, MD, PhD, John A. Moran Eye Center, University of Utah, 50 N. Medical Drive, Salt Lake City, UT 84132. suppression was absent. Anterior segments, intraocular pressure, and fundi were normal. The patient was unable to perform serial 7' s and had poor recall. Motor strength was full with a kinetic tremor. She had a wide- based gait, dysmetria, and was unable to tandem walk. An electrore­tinogram ( ERG) revealed selective loss of the b- wave ( Fig. 1). Results of magnetic resonance imaging ( MRI), an electroencephalogram, a lumbar puncture, small bowel and muscle biopsies, and an extensive serological evalu­ation were not diagnostic. A follow- up MRI showed T2 hyperintensity of the basal ganglia ( Fig. 2). The patient experienced progressive neurologic dete­rioration. She died of pneumonia at home, 6 months after presentation. At autopsy, extensive vacuolar degeneration and glio­sis of the brain were found to be most marked in the basal ganglia and brainstem, and kuru plaques were present in the cerebellum, consistent with a diagnosis of CJD ( Fig. 3). Immunohistochemistry confirmed the presence of a protease- resistant, mutant prion protein \**\ f\ „ \ , ^ J W W ^ i . WW - A, ^ ^ M l ^ * ^ ^ ^ ^ FIG. 1. Electroretinogram. For comparison, the left column con­tains responses from a normal eye. The right column contains responses from the patient's right eye. The a- wave is of normal amplitude. The b- wave is markedly diminished under both pho-topic and scotopic conditions. Time epoch is 200 ms for the scotopic blue response. 116 CREUTZFELDT- JAKOB DISEASE 117 FIG. 2. Coronal MRI fluid attenuated inversion recovery ( FLAIR) image through the optic chiasm demonstrates hyperintensity of the caudate and putamen ( arrows). ( PRPrcs Type 2). Genetic analyses performed in the labo­ratory of Dr. Pierluigi Gambetti revealed that the patient was heterozygous for a methionine/ valine polymorphism at codon 129 of the prion protein gene ( 129M/ V), but there were no mutations in the gene. The patient was therefore classified as having sporadic CJD ( 1). DISCUSSION Neuro- ophthalmologic abnormalities associated with CJD include nystagmus ( 2), homonymous field defects ( 3), palinopsia ( 4), diplopia ( 5), and optic atrophy ( 6). In a review of 232 patients with sporadic CJD, 19% had visual symptoms at disease onset, 32% had signs at their first examination, and 42% had signs or symptoms at some point in the course of their illness ( 7). Neuro-ophthalmologists may therefore play a critical role in establishing a diagnosis for this infectious and fatal dis­ease. In addition to the above clinical observations, Richard et al. ( 5) and De Seze et al. ( 8) reported a reduction in b- wave amplitude in patients with CJD. Both of these groups noted a progressive decline in b- wave voltage in TABLE 1. Entities with selective or predominant decrease in b- wave amplitude Siderosis Central retinal artery or vein occlusion X- linked juvenile retinoschisis Congenital stationary night blindness Oguchi disease Myotonic dystrophy Lipopigment storage disorders ( neuronal ceroid lipofuscinosis, Batten disease) Coat disease Quinine intoxication Methanol intoxication From Fishman GA, Sokol S. Electrophysiologic testing in disorders of the retina, optic nerve, and visual pathway. San Francisco: American Academy of Ophthalmology, 1990: 52. patients in whom serial measurements were performed, with some patients manifesting nonrecordable ERGs late in their illness. We also observed a nonrecordable ERG in a patient less than 2 days before she died of compli­cations of CJD. Both Richard et al. ( 5) and others ( 3,9) have recorded normal ERGs in patients with CJD. Be­cause CJD diffusely and variably affects the central ner­vous system, it is not surprising to find evidence that the prion may also affect retinal electrophysiology in many of these patients and that these abnormalities may vary from patient to patient. Histopathologic abnormalities of the photoreceptor synapses, outer plexiform layer, and Miiller cells ( 5) are particularly interesting because the ERG b- wave is gen­erated by bipolar cells and Miiller cells ( 10). Selective loss of the b- wave is an uncommon finding, and diseases characterized by selective loss of the b- wave comprise a relatively short list ( Table 1). These diseases are all thought to affect photoreceptor endplates, the outer plexiform layer, bipolar cells, or Miiller cells. We con­clude that in our patient, the disease had a specific effect on one or more of these outer retinal structures. Currently, noninvasive tests for CJD lack sensitivity. The usefulness of obtaining an ERG in patients sus­pected to have CJD remains to be determined. From the work of de Seze et al. ( 8), loss or diminution of the ERG b- wave in patients with a neurodegenerative illness ap­pear to be relatively sensitive and specific for CJD. We conclude that if there is a clinical suspicion of CJD, obtaining an ERG may be helpful. In such cases, the finding of an abnormal ERG should prompt a work- up for toxic and metabolic diseases, as well as consideration FIG. 3. A: A gross coronal section through the brain shows only minimal atrophy. The plane of section is just rostral to the plane of the MRI in Figure 2. B: The vacuoles in this specimen represent spongiform degenera­tion of cortex. A Kuru plaque is present ( ar­row). Hemotoxylin and eosin staining; origi­nal magnification, x200. J Neuro- Oplithalnwl, Vol. 20. No. 2, 2000 118 B. J. KATZETAL. of a brain biopsy. 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