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Show Journal ofNeuro- Ophthalmology 21( 2): 99- 102, 2001. © 2001 Lippincott Williams & Wilkins, Inc., Philadelphia The Heidenhain Variant of Creutzfeldt- Jakob Disease: Clinical, Pathologic, and Neuroimaging Findings Dina A. Jacobs, MD, Robert L. Lesser, MD, Zissimos Mourelatos, MD, Steven L. Galetta, MD, and Laura J. Balcer, MD, MSCE We report two patients who developed isolated visual symptoms and signs as initial manifestations of Creutzfeldt- Jakob disease ( CJD). Both patients had normal conventional T l - and T2- weighted brain magnetic resonance ( MR) images; in one patient, early cortical abnormalities were detected by diffusion-weighted and fluid attenuated inversion recovery ( FLAIR) magnetic resonance imaging ( MRI). Results from the cerebrospinal fluid assay for the 14- 3- 3 brain protein were also negative in one patient, despite pathologic confirmation of CJD at autopsy. The Heidenhain variant of CJD should be considered in all patients who present with isolated visual manifestations, including homonymous hemianopsia and normal conventional brain MRI. Diffusion- weighted and FLAIR MRI may demonstrate early cortical abnormalities in patients with CJD. The CSF assay for the 14- 3- 3 protein may be normal, even in pathologically confirmed cases. Key Words: Heidenhain variant- Creutzfeldt- Jakob disease- MRI- Cerebrospinal fluid- Homonymous hemianopsia. Creutzfeldt- Jakob disease ( CJD) is a rapidly progressive neurodegenerative disease typically characterized by dementia, myoclonus, and periodic electroencephalogram ( EEG) complexes ( 1- 4). CJD is a transmissible spongiform encephalopathy caused by prions ( protein-aceous infectious particles) ( 3- 8). Although CJD may be transmitted iatrogenically or genetically, its occurrence is most often sporadic ( 3,5- 8). In iatrogenic cases, the most frequent modes of transmission have included corneal transplantation, dural grafts, and human growth hormone injection ( 9). Independent of the mode of transmission, all cases of CJD are caused by abnormalities of a single neuronal membrane protein, the prion protein ( PrP) ( 8). According to the prion hypothesis, there is a posttrans- Manuscript received December 6, 2000; accepted April 10, 2001. From the Departments of Neurology ( DAJ, SLG, LJB), Ophthalmology ( SLG, LJB), and Pathology and Laboratory Medicine ( ZM), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and the Department of Ophthalmology and Visual Science ( RLL), Yale University School of Medicine, New Haven, Connecticut. Address correspondence and reprint requests to Laura J. Balcer, MD, MSCE, Department of Neurology, 3 East Gates, 3400 Spruce Street, Philadelphia, PA 19104; e- mail: lbalcer@ mail. med. upenn. edu. lational recruitment reaction of the normal prion protein PrP to the abnormal form PrPCJD ( 5- 8). This event leads to conversion of the protein conformation from an alpha-helical to a beta- pleated sheet structure ( 5- 8). The abnormal prion protein PrPCJD then serves as the template for the conversion of more PrP° to PrPCID, thus creating a self- perpetuating process within the brains of affected patients ( 8). Patients with the Heidenhain ( occipitoparietal) variant of CJD present with isolated homonymous hemianopsia or other visual disturbances, often in the absence of specific magnetic resonance imaging ( MRI), EEG, or laboratory abnormalities ( 1,2). Visual loss in such patients is frequently attributed initially to ischemia or to other ophthalmic disorders that may be coincidentally present. We report the neuro- ophthalmologic, neuroimaging, pathologic, and laboratory findings for two patients with the Heidenhain variant of CJD. Both patients had visual loss and homonymous field defects as initial manifestations of their disease. MRI, EEG, and cerebrospinal fluid ( CSF) findings were non- specific; the second patient had an incidental pituitary adenoma whose anatomic location could not completely explain the pattern and extent of his visual loss. Diagnostic issues for patients with the Heidenhain variant of CJD, including the use of the CSF 14- 3- 3 protein assay, MRI techniques, and electroretin-ography ( ERG) are also discussed. CASE REPORTS Case 1 In October 1997, a 79- year- old woman noted the onset of episodic colored spots in her right hemifield. The spots were described as purple in color, lasting for seconds, and initially appearing only with her eyes closed. There was no history of headache or other neurologic symptoms. The patient had recently undergone surgery for a hip fracture and since that time had begun to feel " nervous." Neuro- ophthalmologic examination and computed tomograph ( CT) scan results of the brain, performed in December 1997, were normal. In January 1998, the patient experienced two episodes of word- finding difficulty, each lasting several minutes. 99 100 D. A. JACOBS ETAL. She also noted that objects appeared to " shimmer" when she looked to the right. A psychiatrist had recently started the patient on sertraline for depression. Her past medical history was remarkable for hypertension. A neuro- ophthalmologic examination, performed within days after the episodes of word- finding difficulty, revealed visual acuities of 20/ 25 OU. The pupils and fundi were normal. Right beating nystagmus was noted, and a right homonymous hemianopsia was present on confrontation testing. She had normal mental status, including speech, language, and memory. Mild left pronator drift, bilateral finger- to- nose dysmetria, and extensor plantar responses were noted. A MRI of the brain revealed normal Tl- and T2- weighted images ( Fig. 1A); however, increased signal intensity was demonstrated in the left parietal cortex on fluid attenuated inversion recovery ( FLAIR) and diffusion- weighted images ( Fig. 1B, C). Results from a carotid ultrasound and echocardiogram were within normal limits. Electroencephalogram results revealed left temporal slowing with absence of the normal alpha rhythm over the left hemisphere. Frontal intermittent rhythmic delta activity ( FIRDA) was also seen. Cerebrospinal fluid ( CSF) examination was unremarkable, with the exception of mildly elevated protein ( 60 mg/ dL); CSF assay results for the 14- 3- 3 protein were negative. A positron-emission tomography ( PET) scan of the brain revealed diffuse hypometabolism within the cerebral cortex, with an area of focal hypometabolism in the left occipital cortex ( Fig. ID). By February 1998, the patient had experienced a rapid decline in her mental status. Myoclonus and ataxia had also developed. She frequently perseverated and had difficulty remembering her children's names. The right homonymous hemianopsia had persisted, and visual field testing now demonstrated a left inferior quadrantanopsia. An EEG showed diffuse slowing, and the patient's neurologic status continued to decline. The patient died at home several weeks later. Gross pathology of the brain at autopsy was normal. Microscopic examination revealed the classic triad of histopathologic findings for CJD, including marked neuronal loss, prominent gliosis, and spongioform vacuolization within the cortical gray matter ( Fig. 2). These findings were most prominently seen within the occipital cortex and to a lesser degree within the temporal lobes. A Western blot analysis of homogenized brain tissue revealed the presence of the proteinase- resistant prion protein PrPCID, confirming the diagnosis of CJD. Case 2 A 69- year- old man presented in April 1994 with a chief complaint of " not seeing well." He reported difficulty in seeing objects to his left side and problems with depth perception. These symptoms had progressively worsened during the preceding 6 months. There was no other history of progressive neurologic symptoms. His past medical history was significant for hypertension, which was managed with hydrochlorothiazide. A neuro- ophthalmologic examination in April 1994 revealed visual acuities of 20/ 60 OD and 20/ 50 OS. Color vision was abnormal OU. The pupils were normal. Funduscopic examination revealed temporal pallor of the right optic disc. Goldmann visual field testing demonstrated a dense left homonymous hemianopsia; an incongruous right homonymous hemianopsia was also noted. Neurologic examination was remarkable for left hand clumsiness, mild finger- to- nose dysmetria, and left- sided hyperreflexia. Results from the MRI of the brain were normal, whereas sellar images demonstrated enlargement of the pituitary gland. Suprasellar extension of the pituitary mass was to the left side; therefore, it was thought that this finding alone could not entirely account for the patient's visual loss, particularly the left homonymous hemianopsia. CSF examination results were normal with negative cytology. During the next 10 days, the patient noted further loss of vision to the right OU. Examination revealed visual acuities of 20/ 80. He had also developed confusion and short- term memory difficulty. Biopsy of the right frontal lobe revealed spongioform vacuolization within the cortical gray matter. An EEG revealed moderate to severe slowing with bilateral occipital epileptiform discharges. The patient became progressively more confused and developed myoclonus; he died in June 1994. Gross examination of the brain at autopsy was normal. Diffuse spongioform vacuolization, neuronal loss, and gliosis were demonstrated on microscopic pathology, similar to that demonstrated in Figure 2. Microscopic examination of the pituitary mass was consistent with a pituitary adenoma. DISCUSSION Although dementia, myoclonus, and ataxia are the most common clinical manifestations of CJD, our patients presented initially with isolated visual symptoms, consistent with the Heidenhain variant ( 1,2,10). Presenting signs and symptoms in patients with the Heidenhain variant of CJD may include visual field defects, visual hallucinations, visual agnosia, cortical blindness, and abnormal color or visuospatial perception ( 1,2,10). Isolated eye movement disturbances may also occur ( 1,11). Patients may initially complain of vague visual disturbances, and may give up reading or watching television. Purvin et al. ( 12) described a patient who presented with palinopsia as a presenting manifestation of CJD. Ophthalmologic examinations early in the course of CJD are often unrevealing, and patients may try new eyeglasses without resolution of symptoms ( 10). Despite isolated early visual symptoms, a rapid progression to dementia and death follows. Histopathologic changes characteristic of CJD, including spongioform degeneration, neuronal loss, and astrocytic gliosis, are most pronounced in the occipital lobes of patients with the Heidenhain variant ( 10). The characteristic triad of dementia, myoclonus, and abnormal EEG may be lacking in as many as 25% of patients with the Heidenhain variant of CJD ( 13- 15). / Neuro- Ophthalmol, Vol. 21, No. 2, 2001 HEIDENHAIN VARIANT OF CREUTZFELDT- JAKOB DISEASE 101 FIG. 1. Case 1. A: Axial T2- weighted MRI demonstrating normal cerebral cortex. B: Axial FLAIR image showing abnormal signal intensity in the left parietal cortex ( arrows). C: Diffusion- weighted MRI demonstrating abnormal increased signal intensity in the left parietal cortex ( arrow). D: Axial PET scan of the brain showing diffuse hypometabolism throughout the cerebral cortex and an area of focal hypo-metabolism in the left occipital cortex ( arrows). V i * • FIG. 2. Case 1. A: Microscopic pathology of occipital cortex ( hematoxylin and eosin stain, x100) demonstrating diffuse spongioform vacuolization, marked neuronal loss, and prominent gliosis ( reactive astrocytes with clear nuclei [ arrow]). Note the coalescence and septation of the vacuoles; these findings distinguish the spongioform changes of Creutzfeldt- Jakob disease from those found in hypoxic cerebral edema and other neurologic disorders. Also note the presence of small vacuoles in the neuropil. B: Glial fibrillary acidic protein stain ( x200) for astrocytes demonstrating prominent gliosis and reactive astrocytes ( arrow) in the occipital cortex. J Neuro- Ophthalmol, Vol. 21, No. 2, 2001 102 D. A. JACOBS ETAL. The classic EEG finding of 1 cycle/ second triphasic waves may not be present until late in the disease. Short of brain biopsy, testing to confirm the diagnosis of CJD with certainty before death is lacking. The spinal fluid assay for the 14- 3- 3 protein may be a useful marker for the disease ( 16) but may be negative in some patients with pathologically confirmed CJD ( as in case 1). The 14- 3- 3 assay also lacks specificity for CJD and may be positive in patients with other conditions causing neuronal death, such as stroke, hypoxic- ischemic injury, and herpes encephalitis ( 16). In addition, a recent report of three cases indicates that there may be false- negative results ( consistent with case 1) and false- positive results for the 14- 3- 3 assay in patients with CJD ( 17). Our cases emphasize the need for suspicion of CJD ( Heidenhain variant) in patients with apparently isolated visual symptoms or field defects and normal conventional neuroimaging studies, or in cases in which MRI abnormalities ( as in case 2) do not completely explain the extent of visual loss. The brain parenchyma of both patients in this series appeared normal by conventional Tl- and T2- weighted MRI. Early cortical abnormalities were detected in patient 1 by diffusion- weighted and FLAIR imaging. A recent study has shown that diffusion- weighted MRI may indeed be helpful in confirming early suspicion of CJD based on the demonstration of cortical lesions ( 13). Although conventional MRI may show cortical and basal ganglia abnormalities on T2- and proton density- weighted images, such scans may be normal in as many as 21% of patients in the early course of CJD ( 15). Gadolinium enhancement is most often absent ( 15). Diffusion- weighted imaging may be abnormal secondary to cell lysis and membrane disruption ( 13). Diffusion- weighted imaging and FLAIR sequences should therefore be included in MRI protocols for patients with unexplained visual loss and normal Tl- and T2- weighted images. Recent reports have suggested that the ERG may also provide a useful adjunct in cases of suspected CJD ( 18,19). Patients with CJD have been demonstrated to have a decrease in the b- wave amplitude of the ERG ( 18,19). This abnormality most likely relates to degenerative changes in the outer plexiform layer and Mueller cells ( 18- 20). Whereas a decrease in the b- wave amplitude is not specific for CJD, the magnitude of this finding may correlate with disease progression ( 18). Richard et al. ( 21) reported progressive reduction in the b- wave amplitude in two patients with CJD during the course of their disease ( 21). ERG abnormalities may appear before the emergence of characteristic EEG findings in CJD ( 21), particularly among patients with visual symptoms. The Heidenhain variant of CJD must be considered in all patients who present with isolated visual complaints and either normal conventional brain neuroimaging or findings that do not completely correlate with signs and symptoms. In such patients, diffusion- weighted and FLAIR MRI may reveal early cortical changes ( 13,15). CSF assay for the 14- 3- 3 protein, if positive, may also aid in the diagnosis for patients in whom the degree of suspicion for CJD is high ( 16). REFERENCES 1. Vargas ME, Kupersmith MJ, Savino PJ, et al. 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