Journal of Neuro-Ophthalmology, March 2015, Volume 35, Issue 1

Progressive MRI Findings in CreutzfeldtJakob Disease

Matthew J. Thurtell Department of Ophthalmology and Visual Sciences, University of Iowa; Department of Neurology, University of Iowa; Neurology Service, Iowa City VA Medical Center, Iowa City, Iowa The authors report no conflicts of interest. J. J. Chen and N. Singh are co-first authors. REFERENCES 1. Shaw HE Jr. Tigers and snakes in neuro-ophthalmology. J Neuroophthalmol. 2014;34:214-217. 2. Shields JA, Shields CL, Brotman HK, Carvalho C, Perez N, Eagle RC Jr. Cancer metastatic to the orbit: the 2000 Robert M. Curts Lecture. Ophthal Plast Reconstr Surg. 2001;17:346-354. 3. Tatsis E, Reinhold-Keller E, Steindorf K, Feller AC, Gross WL. Wegener granulomatosis associated with renal cell carcinoma. Arthritis Rheum. 1999;42:751-756. 4. Bumbasirevic U, Dragicevic D, Janicec A, Cemerikic- Martinovic V, Cekeravac M, Aleksic V, Tulic C. Renal cancer and Wegener granulomatosis: a case report. World J Surg Oncol. 2011;9:165. 5. Deger SM, Mutluay R, Ebinc FA, Arinsoy T, Sindel S. Renal cell carcinoma associated immunosuppressive therapy: a case report with Wegener granulomatosis. Rheumatol Intl. 2009;30:119-121. 6. Odeh M. Renal cell carcinoma associated with cyclophosphamide therapy for Wegener granulomatosis. Scand J Rheumatol. 1996;25:391-393. 7. Faurschou M, Sorensen IJ, Mellemkjaer L, Loft AG, Thomsen BS, Tvede N, Baslund B. Malignancies in Wegener granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. J Rheumatol. 2008;35:100-105. Progressive MRI Findings in Creutzfeldt-Jakob Disease Parker et al (1) recently reported characteristic magnetic resonance imaging (MRI) findings in 2 confirmed cases of the Heidenhain variant of Creutzfeldt-Jakob disease. The following is a similar case that demonstrates progressive neuroimaging abnormalities. An 89-year-old woman complained of dizziness, unsteadiness, disruption of her sleep pattern, forgetfulness, and gradually worsening vision for several months. She had fallen many times and recently stopped driving. She denied fever, head-aches, or other focal neurologic symptoms. She underwent a neurologic examination, which was reported as unremark-able, and MRI was reported to be normal except for age-related atrophy. Her symptoms were attributed to Alzheimer disease. Her dizziness was treated with meclizine with no relief. FIG. 1. A. Diffusion-weighted imaging shows subtle ribbon-like areas of restricted diffusion along the gyri of the right cerebral hemisphere. B. Repeat imaging 1 month later demonstrates progression of the disease and involvement of the left occipital cortex. 96 Letters to the Editor: J Neuro-Ophthalmol 2015; 35: 94-105 Letters to the Editor Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. One month later, the patient experienced a rapid decline with difficulty ambulating and performing activities of daily living. Her family noted emotional outbursts, startle myoclonus, and left-sided neglect. On neuro-ophthalmologic testing, she was oriented to person and place only. Visual acuity was counting fingers in both eyes. She could not read the Ishihara color plates and had spasm of fixation. Confrontation visual fields suggested bilateral homonymous hemianopias, denser on the left than the right. Pupils reacted normally to light. Ocular examination was otherwise unremarkable. She had mild rigidity of both upper extremities and increased deep tendon reflexes. Repeat brain MRI (Fig. 1B) showed ribbon-like areas of restricted diffusion along the gyri of the right cerebral hemi-sphere and left occipital lobe on diffusion-weighted imaging (DWI). In retrospect, these areas were visible, but more subtle, on the initial MRI (Fig. 1A). Cerebrospinal fluid (CSF) studies revealed a positive 14-3- 3 protein and positive t of 3872 pg/mL, as well as a positive real-time quaking-induced conversion assay (2). The remain-der of the CSF studies were normal. A 16-channel electroen-cephalogram showed periodic frontally dominant sharp wave discharges with periodicity of 1-2 Hz in the right hemisphere. The patient was discharged to hospice and died 2 weeks later. An autopsy specimen of the brain was sent to the National Prion Research Center at Case Western Reserve University in Cleveland, OH. Immunohistochemical analysis on the autopsy tissue with 3F4, the monoclonal antibody to the prion protein (PrP), revealed granular deposits typical of prion disease (Fig. 2). Western blot analysis revealed the presence of abnormal protease resistant PrP without a pathogenic mutation in the coding region of the PrP gene. Further historical information from the family revealed that the patient had exposure to raw undercooked meat in Germany in the 1980s, and she had lived with a friend at that time who died of "mad cow disease." Unlike other causes of dementia, prion disease may be associated with high signal in the basal ganglia, thalamus, or along the cortical ribbon on DWI, fluid-attenuated inversion recovery, or T2-weighted MRI sequences, with a sensitivity and specificity of .90% (3-5). However, these subtle changes are often missed. The cause for restricted diffusion is attributed to abnormal vacuoles in the cytoplasm and microvacuolation of neurons leading to spongiform degeneration, cell lysis, and membrane disrup-tion. We emphasize the importance of these neuroimaging findings, as they can aid in early and accurate diagnosis of this rapidly progressive and fatal condition. Kaushal M. Kulkarni, MD Department of Ophthalmology, Sharp Rees-Stealy Medical Group, San Diego, California The author reports no conflicts of interest. FIG. 2. Fine spongiform degeneration affecting the occipital cortex (A) and cerebellum (B) (hematoxylin & eosin). Diffuse and synaptic immunostaining for the prion protein (PrP), with foci of larger PrP granules surrounding vacuoles (inset) in the oc-cipital cortex (C) and "brush-like" PrP immunostaining in the molecular layer of the cerebellum (D) (immunostain with 3F4 monoclonal antibody to prion protein (PrP) residue 109-112). Letters to the Editor: J Neuro-Ophthalmol 2015; 35: 94-105 97 Letters to the Editor Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. REFERENCES 1. Parker SE, Gujrati M, Pula JH, Zallek SN, Kattah JC. The heidenhain variant of Creutzfeldt-Jakob disease-a case series. J Neuroophthalmol. 2014;34:4-9. 2. McGuire LI, Peden AH, Orrú CD, Wilham JM, Appleford NE, Mallinson G, Andrews M, Head MW, Caughey B, Will RG, Knight RS, Green AJ. Real time quaking-induced conversion analysis of cerebrospinal fluid in sporadic Creutzfeldt-Jakob disease. Ann Neurol. 2012;72:278-285. 3. Caobelli F, Cobelli M, Pizzocaro C, Pavia M, Magnaldi S, Guerra UP. The role of neuroimaging in evaluating patients affected by Creutzfeldt-Jakob disease: a systematic review of the literature. J Neuroimaging. [published ahead of print March 5, 2014] doi: 10.1111/jon.12098. 4. Young GS, Geschwind MD, Fischbein NJ, Martindale JL, Henry RG, Liu S, Lu Y, Wong S, Liu H, Miller BL, Dillon WP. Diffusion-weighted and fluid-attenuated inversion recovery imaging in Creutzfeldt-Jakob disease: high sensitivity and specificity for diagnosis. Am J Neuroradiol. 2005;26:1551-1562. 5. Carswell C, Thompson A, Lukic A, Stevens J, Rudge P, Mead S, Collinge J, Hyare H. MRI findings are often missed in the diagnosis of Creutzfeldt-Jakob disease. BMC Neurol. 2012;12:153. Autoimmune Acquired Rippling Muscle Disease and Myasthenia Gravis We present an intriguing postscript to a case published by Kosmorsky et al (1) in this journal in 1995. It con-cerned a 58-year-old man with intermittent diplopia, arm, and leg weakness, dysarthria, and muscle rippling. Examination demonstrated intermittent esotropia triggered by prolonged convergence. Creatine phosphokinase (CPK) was mildly ele-vated at 676 IU (normal range 293-378 IU). Electromyogra-phy (EMG) showed electrically silent percussion-induced muscle rippling. Muscle biopsy showed a nonspecific myopa-thy consisting of rare interstitial and perivascular lymphocytic infiltrates, scattered atrophic type I and II muscle fibers, and electron microscopic subsarcolemmal honeycomb structures. The authors interpreted these findings as consistent with rip-pling muscle disease (RMD). The patient was treated with calcium channel blocking agents without response. The same patient was reported the next year by Ansevin and Agamanolis (2), who had examined him 16 months before and 3 years after he was examined by Kosmorsky. The patient's first visit had been prompted by painful muscle rippling and cramping. Examination disclosed percussion-induced muscle rippling and mild proximal extremity weakness. EMG did not reveal myotonia. CPK was elevated. At the patient's second visit 5 years later, the muscle rippling had mostly resolved, his principal complaints now being bilateral ptosis, diplopia, dysphagia, and weakness. Examination revealed fatigable neck and proximal extremity weakness. Rest and edrophonium tests suggested myasthenia gravis (MG). EMG showed a decremental response on re-petitive stimulation without improvement with exercise and no myotonia. Acetylcholine receptor antibody was elevated at 64 nmol/L (normal ,0.02 nmol/L), and skeletal muscle antibody titer was elevated at 1:320 (normal ,1:60). Chest computed tomography revealed a thymic mass, and muscle biopsy showed a nonspecific myopathy, exactly as described by Kosmorsky. Ansevin and Agamanolis did not diagnose RMD but rather MG with muscle rippling. Thymectomy and treatment with pyridostigmine and plasmapheresis im-proved the clinical manifestations. Therefore, the same patient evaluated by 2 physicians at different times with similar EMG, and muscle biopsy findings was assigned completely different diagnoses. Which diagnosis is correct? We encountered a similar patient recently who led us to believe that both diagnoses are probably correct. Our patient was a 52-year-old former Olympic-level athlete who presented with cramping and stiffness of arms, legs, and chest for 4 years without weakness. He had been evaluated extensively by rheumatologists, the only abnormal laboratory test being a mildly elevated CPK. Our examination disclosed percussion-induced muscle rippling of the chest, arms, and thighs (See Supplemental Digital Content, Video 1, http://links.lww.com/WNO/A116). A paraneoplas-tic panel revealed an elevated striated muscle antibody titer of 1:61,440 (normal ,1:60) and an elevated acetylcholine receptor binding antibody at 4.35 nmol/L (normal ,0.02 nmol/L). EMG showed non-electrically silent muscle rippling without myotonia. There was no decrement on repetitive stimulation or clinical evidence of MG. We diagnosed RMD. Five months later, he developed binocular diplopia. Examination disclosed an exodeviation on right gaze, fatigable right upper lid ptosis, persistent muscle rippling, but no extremity or bulbar weakness (See Supplemental Digital Content, Video 2, http://links.lww.com/WNO/A117). CAV3 testing was negative. Now, we diagnosed a combina-tion of RMD and MG. Treatment with pyridostigmine was unhelpful, but ptosis, diplopia, and muscle rippling resolved after several weeks' treatment with mycophenolate 2000 mg/ d and prednisone 20 mg/d. There are now 14 reported cases of concurrent RMD and MG (1-7). The classic form of RMD is an autosomal dominant caveolinopathy associated with a CAV3 mutation (8). Other CAV3-related caveolinopathies include limb gir-dle muscular dystrophy-1C, distal myopathy, idiopathic creatine phosphokinase elevation, and familial hypertrophic cardiomyopathy (9). In the acquired autoimmune form, there is no family history of RMD, and CAV3 testing is negative. Clinical manifestations develop after the second decade of life, later than in hereditary RMD (10). Muscle rippling may not be electrically silent on EMG (5). Muscle biopsy discloses nonspecific myopathic findings and rare areas of inflammation (7), abnormalities that are not found in hereditary RMD or in MG. 98 Letters to the Editor: J Neuro-Ophthalmol 2015; 35: 94-105 Letters to the Editor Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.