Creutzfeldt-Jakob Disease in the Hospital Setting a Case Report and Review

Clinical AND Health Affairs

Creutzfeldt-Jakob Disease in the Hospital Setting A Case Report and Review

BY PEZHMAN ROOHANI, M.D., MANISH K. SAHA, M.D., AND MICHAEL ROSENBLOOM, M.D.

Rapidly progressive dementia is a neurological condition that results in subacute deterioration in cognitive, behavioral and motor function. The most serious diagnosis for a patient with rapidly progressive dementia is Creutzfeldt-Jakob Disease (CJD), a prion-related illness that typically results in death within one year. However, there are numerous autoimmune, infectious and toxic-metabolic causes of rapidly progressive dementia that are potentially reversible with treatment. Thus, the differential diagnosis for a rapidly progressive dementia is critically important. In this article, the authors discuss a case of CJD diagnosed at a St. Paul hospital to illustrate the differential diagnosis of rapidly progressive dementia and highlight the role of neuroimaging.

apidly progressive dementia describes history of dizziness and cognitive changes. screen, HIV, copper, thyroglobulin anti- progressive deterioration in cognitive, Initially, her symptoms consisted of light- body, thyroid peroxidase antibody, thyroid Rbehavioral and motor functions that headedness upon standing or walking. stimulating hormone, vitamin B12, eryth- occurs over a period ranging from weeks This was followed by progressive cogni- rocyte sedimentation rate, C-reactive pro- to months.1 Unlike Alzheimer’s disease, tive decline, characterized by difficulty tein, anti-nuclear antibody, paraneoplastic Lewy body dementia, vascular dementia transferring telephone numbers between panel and voltage-gated potassium chan- and frontotemporal dementia, rapidly pro- mobile phones, following familiar reci- nel complex antibody (VGKC-Ab). Cere- gressive dementia is subacute rather than pes, misplacing objects and remembering brospinal fluid analysis (CSF) was non- chronic. There are numerous autoimmune, television programs she watched the night inflammatory with two nucleated cells/ infectious and toxic-metabolic causes of before. She also experienced difficulty uL and normal glucose levels and protein rapidly progressive dementia, some of speaking. Her vital signs were within nor- concentration. Studies for herpes simplex which are treatable. Thus, correctly iden- mal limits without evidence of fever, and virus polymerase chain reaction, coccidioi- tifying the etiology of the condition is es- her general exam was unremarkable. Her des Ab, oligoclonal bands, Whipple disease sential. neurological exam showed disorientation PCR and West Nile encephalitis (IgG/IgM Creutzfeldt-Jakob disease (CJD) is the to time with expressive aphasia. She was antibody tests in CSF) were all negative. A most serious diagnosis for a patient with unable to follow three-step commands and full-body positron emission tomography such a dementia, as it leads to death within could not draw intersecting pentagons. She (PET) scan failed to demonstrate hypermet- one year. In this article, we present the case demonstrated ideomotor apraxia of both abolic lesions suggestive of neoplasm. of a patient who was diagnosed with spo- hands, increased left upper-extremity tone Brain magnetic resonance imaging radic (having no known cause) CJD, after with spontaneous choreiform movements (MRI) showed abnormal findings on fluid- presenting with subacute onset of cogni- on the left side, bilateral upper-limb ataxia attenuated inversion recovery (FLAIR) tive impairment, behavior changes, ataxia on finger-nose-finger testing and bilateral and diffusion-weighted imaging (DWI) and dizziness. We use the case to discuss grasp reflexes with intact deep tendon sequences. (In general, FLAIR images key aspects in the differential diagnosis of reflexes. Her gait was wide-based and are ideal for showing such conditions as a rapidly progressive dementia. unsteady. Within one week of admission, abnormal central nervous system lesions she became less conversational and experi- resulting from stroke, demyelination, Case enced difficulty recognizing her husband. tumor and infection. And DWI sequences A 53-year-old, right-handed woman with Laboratory studies, all of which were are specific for showing acute cytoxic a past medical history significant for within normal limits, included complete brain injuries such as those resulting from otosclerosis with right-ear stapedectomy blood count, electrolytes, liver and renal stroke.) The FLAIR sequences revealed presented to our hospital with a two-week function tests, urinalysis, urine drug hyperintensities involving the right cau-

46 | MINNESOTA MEDICINE | MAY 2013 Clinical AND Health Affairs date nucleus, right parietal cortex and Obtaining an accurate, comprehensive FIGURE 1 bilateral frontal cortices (Figure 1). There medical history is essential. In addition to Fluid-Attenuated Inversion was restricted diffusion on DWI involv- interviewing the patient, clinicians should Recovery Image ing the same regions (Figure 2) but with a talk to family members and caregivers to greater intensity as compared with FLAIR identify symptom onset and obtain spe- sequences. Apparent diffusion coefficient cific details relating to cognitive, behav- sequences showed hypointense regions ioral and motor deficits. As observed in that corresponded to areas of restricted this case, patients frequently have overlap- diffusion (confirming that the lesion was ping memory, language, motor and con- not artifactual). stitutional symptoms within a period of Electroencephalogram (EEG) revealed weeks to months. In fact, in 20% of cases, polymorphic theta-delta slowing and constitutional symptoms may be the first triphasic waves without epileptiform dis- manifestations of CJD.2 charges. Cerebrospinal prion biomarkers Regardless of presentation, all patients were elevated, including neuron-specific warrant basic serum labs to rule out enolase (175ng/mL [reference range <15 reversible causes of subacute dementia. ng/mL]) and tau (19023 pg/mL [decision These can include hepatic and uremic point: 1200 pg/mL]), and 14-3-3 protein encephalopathy, electrolyte imbalance, was positive. (It should be noted that all vitamin B12 deficiency, hypothyroidism, of these proteins, which are released from human immunodeficiency virus encepha- MRI fluid-attenuated inversion recovery (FLAIR) neurons upon cell death and are most lopathy and neurosyphilis. If laboratory sequence demonstrates hyperintensities involving commonly associated with CJD, may also tests fail to result in a diagnosis, a more the right caudate nucleus, right parietal cortex, and bilateral frontal cortices. be elevated in Alzheimer’s disease, vascu- extensive evaluation, including lumbar lar dementia, multiple sclerosis, stroke and puncture, EEG and brain MRI studies, FIGURE 2 other CNS-related conditions.) should be performed. The patient was administered empiric Given that 38% of cases referred to Diffusion-Weighted Image high-dose intravenous methylpredniso- tertiary care centers for suspected CJD in- lone for five days with no cognitive, be- volve a non-prion-related illness,3 address- havioral or motor improvement. She was ing potential non-CJD-related etiologies is diagnosed with sporadic CJD and eventu- critical. Chronic neurodegenerative pro- ally discharged to a nursing home, where cesses including frontotemporal dementia, her health continued to decline. She died Alzheimer’s disease and Lewy body de- within three months of symptom onset. mentia may present in a rapidly progres- The family declined autopsy and brain sive manner in rare instances.4 However, biopsy. our experience shows that the majority of patients are misdiagnosed as having Identifying Causes of Rapidly rapidly progressive dementia because of Progressive Dementia a poor delineation of the disease timeline Rapidly progressive dementia is distin- during the history. guished by its subacute time course—hav- Various autoimmune conditions may ing an accelerated rate of decline that mimic CJD both clinically and radio- affects cognitive, behavioral and/or motor graphically. Paraneoplastic neurological function. The differential diagnosis for syndromes are caused by an inflammatory MRI diffusion-weighted imaging shows restricted rapidly progressive dementia is extensive, response directed against the central and diffusion involving the right caudate nucleus, right parietal cortex, and bilateral frontal cortices with encompassing neurodegenerative, auto- peripheral nervous system in patients with greater intensity compared with FLAIR sequences. immune, infectious and toxic-metabolic cancers (commonly involving the lung, etiologies. It is important to use a systemic thymus, breast, testicles and ovaries).5 pocampus, are frequently vulnerable, and approach to rule out potentially reversible They result from antigenic response to patients present with a limbic encephalitis conditions. Creutzfeldt-Jakob disease is the nervous system by antibodies; the characterized by acute-onset cognitive an irreversible neurodegenerative process antibodies recognize not only the anti- dysfunction and emotional liability, with that should always be considered in the gens expressed ectopically in a tumor but or without seizures.6 Typical paraneo- differential diagnosis of rapidly progres- also those found in the nervous system. plastic syndromes that may present with sive dementia. The limbic structures, including the hip- limbic encephalitis include anti-Hu, CV2,

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Ma2 and voltage-gated potassium channel encephalitis may infect the limbic system, Recognizing antibodies (VGKC).5 Recently described and patients may present with acute con- Creutzfeldt-Jakob Disease syndromes resulting in rapidly progress- fusion and seizure. In addition, Lyme dis- In cases where the aforementioned auto- ing dementia have also been associated ease and syphilis are both great mimickers immune, infectious and toxic-metabolic with antibodies against NMDA, GABA, and may be the cause of cognitive and be- work-ups are unremarkable, prion-related amphiphysin and AMPA channels.7 All havioral changes. Whipple’s disease, which illness should be considered. The most of these conditions involve autoantibod- typically involves the small intestine, also common presentation of CJD is rapidly ies expressed against cell surface proteins, may cause rapidly progressive dementia.10 progressive dementia along with myoc- namely neuronal ion channels within In general, infectious conditions resulting lonus. The disease is also associated with cortical and limbic brain structures. Con- in rapidly progressive dementia may be ataxia and extrapyramidal abnormalities sequently, patients with these syndromes distinguished from CJD by the presence (tremor, rigidity, chorea, etc.). In addition, often present with cognitive and behav- of fever, elevated serum white count and patients may present with a subacute pro- ioral changes. inflammatory CSF. gressive focal cortical syndrome such as Sometimes, encephalopathy related to Toxic-metabolic conditions also may cortical blindness and primary progressive antibodies against cell surface proteins (eg, present as rapidly progressive dementia. aphasia. anti-VGKC) may present in the absence Wilson’s disease, vitamin B12 deficiency, Creutzfeldt-Jakob Disease is caused by of an underlying tumor. Many of these Wernicke-Korsakoff syndrome (or thia- misfolded prion proteins and may be clas- conditions may be treated either by ad- mine deficiency) and hepatic encephalo- sified as sporadic, acquired and familial. dressing the underlying tumor or using pathy should all be considered and ruled The sporadic type accounts for 85% of all immunotherapy (eg, IVIG, plasmapha- out in patients with rapidly progressive CJD presentations.16 resis, steroids). Another autoimmune dementia. Brain MRI may demonstrate The World Health Organization encephalopathy associated with antibodies hyperintensities involving the globus palli- (WHO) criteria (the most commonly used is Hashimoto’s encephalopathy, a steroid- dus/putamen in Wilson’s disease11 and me- CJD classification) requires that the fol- responsive encephalopathy presenting diodorsal thalamus in Wernicke-Korsakoff lowing be met for sporadic CJD: with either stroke-like episodes or seizures syndrome.12 In both cases, these may be • Progressive dementia and anti-thyroid antibodies (anti-TPO and confused with prion disease both clinically • At least two of the following four clinical thyroglobulin antibodies).8 Often, diagno- and radiographically. features: myoclonus, visual or cerebellar sis depends on assessing clinical response Neoplastic conditions such as intravas- abnormalities, akinetic mutism, pyrami- to empirical steroids. cular lymphoma, a rare non-Hodgkin-type dal/extrapyramidal movements Central nervous system vasculitis is a lymphoma associated with neoplastic • Atypical EEG during an illness of any cell-mediated condition that may present growth of lymphoid cells within the lumen duration and/or positive 14-3-3 CSF with rapid cognitive, behavioral or motor of small and medium-sized cerebral ves- assay with clinical duration to death in deterioration and should be evaluated with sels, may result in rapid cognitive, be- less than two years conventional cerebral angiography and havioral and motor decline through the • Routine investigation not suggestive of spinal fluid analysis. In addition, Sjogren’s development of subcortical strokes.13 Neu- an alternative diagnosis.17 syndrome, a chronic inflammatory disor- roimaging (MRI) is helpful in identifying Although EEG and CSF studies for der resulting in lymphocytic inflammation the strokes. Since adrenal infiltration is 14-3-3 have traditionally been used to of exocrine organs and sicca symptoms, present in 60% of cases, it is recommended confirm the diagnosis of probable CJD has been shown to mimic CJD in both the that patients suspected of having this based on the WHO criteria, recent inves- rapidly progressive presentation and the diagnosis undergo abdominal CT, but a tigations have shown brain MRI to have radiological appearance on MRI FLAIR/ definitive diagnosis can only be made with a higher sensitivity and specificity for DWI sequences. 9 This condition can be visceral tissue or through brain biopsy.14 sporadic CJD. Typical MRI findings in diagnosed by checking SSA/SSB autoan- Finally, it should be noted that complex sporadic CJD demonstrate DWI>FLAIR tibodies and is typically responsive to ste- partial status epilepticus may result in hyperintensities involving the cortical roid treatment. subacute altered mental status and confu- and subcortical structures (thalamus and Several infectious diseases have a predi- sion. Brain MRI may also reveal restriction striatum, particularly putamen and cau- lection for involving CNS structures and diffusion localized to the hippocampus date). A study of 23 patients showed that should be considered if the patient has and the thalamus (pulvinar nucleus on detection of DWI hyperintensities within elevated white count and fever. In addi- DWI sequences).15 An EEG is essential to the cortical and subcortical gray matter tion, these processes often result in an in- ruling out this condition during the eva- was 92.3% sensitive and 93.8% specific and flammatory CSF, whereas the CSF in CJD luation of rapidly progressive dementia. considered superior to both EEG and CSF would be expected to have normal cell biomarkers, including 14-3-3 protein.18 counts, protein and glucose levels. HSV Another study of 40 patients with probable

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3. Geschwind MD, Shu H, Haman A, Sejvar JJ, or definite CJD showed that the com- Minnesota Department of Health. The Miller BL. Rapidly progressive dementia. Ann Neurol. bined use of DWI and FLAIR sequences National Prion Disease Pathology Surveil- 2008;64(1):97-108. 4. Josephs KA, Ahlskog JE, Parisi JE, et al. Rapidly was 91% sensitive and 95% specific for lance Center at Case Western Reserve progressive neurodegenerative dementias. Arch sporadic CJD.19 More recent studies have University provides a free autopsy service Neurol. 2009;66(2):201-7. 5. Dalmau J, Rosenfeld MR. Paraneoplastic syndromes shown that the addition of apparent dif- for confirmation of prion disease. More of the CNS. Lancet Neurol. 2008;7(4):327-40. fusion coefficient sequences increases the information on this service can be found 6. Lee R, Buckley C, Irani SR, Vincent A. sensitivity and specificity of MRI for spo- on the National Prion Disease Pathology Autoantibody testing in encephalopathies. Pract Neurol. 2012;12(1):4-13. radic CJD to 96% and 93%, respectively.20 Surveillance Center website, www.cjdsur- 7. Lancaster E, Martinez-Hernandez E, Dalmau J. Additionally, MRI is helpful in identifying veillance.com. Encephalitis and antibodies to synaptic and neuronal potential inflammatory, infectious and cell surface proteins. Neurology. 2011;77(2):179-89. 8. Chong JY, Rowland LP, Utiger RD. Hashimoto toxic-metabolic causes of RPD that may Conclusion encephalopathy: syndrome or myth? Arch Neurol. mimic CJD. Sporadic CJD is a rare, fatal disease with 2003;60(2):164-71. Other tools for diagnosing sporadic clinical and radiological presentation 9. Matsuo K, Saburi M, Ishikawa H, et al. Sjogren syndrome presenting with encephalopathy mimicking CJD include EEG and spinal fluid analysis. that occasionally may overlap with other Creutzfeldt-Jakob disease. J. Neurol. Sci. 2013;326(1- The most common EEG finding is dif- disease processes that are potentially treat- 2):100-3. 10. Louis ED, Lynch T, Kaufmann P, Fahn S, Odel fuse slowing, yet the periodic sharp wave able. For this reason, it is important to rule J. Diagnostic guidelines in central nervous system complex, which is present in later stages of out potential reversible causes of rapidly Whipple’s disease. Ann Neurol. 1996;40(4):561-8. the disease, has a specificity for sporadic progressive dementia (autoimmune, in- 11. Sinha S, Taly AB, Ravishankar S, et al. Wilson’s disease: cranial MRI observations and clinical correla- 21, 22 CJD ranging from 66% to 91%. Protein fectious and toxic-metabolic etiologies) tion. Neuroradiology. 2006;48(9):613-21. 14-3-3 is the test of choice with a positive before making the final diagnosis of prion 12. Sechi G, Serra A. Wernicke’s encephalopathy: new clinical settings and recent advances in diagnosis predictive value of 93% to 95%, but more disease. and management. Lancet Neurol. 2007;6(5):442-55. recent studies have shown that the sensi- Although MRI is highly accurate in 13. Sumer M, Ozon AO, Bakar B, Cila A, Ruacan S. 23 Intravascular lymphoma masquerading as multiem- tivity is lower than expected. Along with identifying sporadic CJD, it does not re- bolic stroke developing after coronary artery by-pass 14-3-3 protein, tau, and neuron-specific place biopsy. Nevertheless, at some local surgery. Neurologist. 2009;15(2):98-101. enolase may be elevated in CJD, but these hospitals, biopsy may not be available 14. Baumann TP, Hurwitz N, Karamitopolou- Diamantis E, Probst A, Herrmann R, Steck AJ. proteins are also general markers of neu- and the prolonged turnaround time for Diagnosis and treatment of intravascular lymphoma- ronal injury and therefore nonspecific.1 lab tests such as VGKC-AB and paraneo- tosis. Arch Neurol. 2000;57(3):374-7. 15. Szabo K, Poepel A, Pohlmann-Eden B, et al. Treatment for prion disease is limited plastic panels make it impossible to rule Diffusion-weighted and perfusion MRI demonstrates to supportive therapy and palliative care, out reversible causes of rapidly progres- parenchymal changes in complex partial status epilep- although antiepileptic drugs such as val- sive dementia. Therefore, after ruling out ticus. Brain. 2005;128(Pt 6):1369-76. 16. Will RG, Alperovitch A, Poser S, et al. proic acid may be used for myoclonic certain potential infectious etiologies, it is Descriptive epidemiology of Creutzfeldt-Jakob symptoms. Patients need not be isolated our practice to administer an empiric dose disease in six European countries, 1993-1995. EU Collaborative Study Group for CJD. Ann Neurol. Jun because the disease is not transferrable by of methylprednisolone (1 g IV for three 1998;43(6):763-7. touch or contact. to five days) to treat possible underlying 17. Miller BL, Boeve BF, eds. The Behavioral Neurology of Dementia. 1st ed. Cambridge, UK: Our patient met WHO criteria for autoimmune encephalopathy. This treat- Cambridge University Press; 2009. probable sporadic CJD and presented with ment may be considered for patients who 18. Shiga Y, Miyazawa K, Sato S, et al. Diffusion- rapid decline of language, behavior and have elevated CSF protein or a personal weighted MRI abnormalities as an early diagnostic marker for Creutzfeldt-Jakob disease. Neurology. motor function (choreiform movements). or family history of autoimmune disease. 2004;63(3):443-9. Interestingly, her initial symptoms were It must be noted, however, that there is no 19. Young GS, Geschwind MD, Fischbein NJ, et al. Diffusion-weighted and fluid-attenuated inversion nonspecific and constitutional, character- literature to support the use of steroids as recovery imaging in Creutzfeldt-Jakob disease: high ized by positional-dependent dizziness. As a routine treatment in rapidly progressive sensitivity and specificity for diagnosis. AJNR Am J Neuroradiol. 2005;26(6):1551-62. mentioned earlier, she died within three dementia. MM 20. Vitali P, Maccagnano E, Caverzasi E, et al. months of symptom onset, which was Pezhman Roohani is a neurology resident Diffusion-weighted MRI hyperintensity patterns differ- entiate CJD from other rapid dementias. Neurology. consistent with epidemiological studies at the University of Minnesota, Manish 2011;76(20):1711-9. Saha is a hospitalist at HealthPartners and showing an 85% mortality rate within one 21. Steinhoff BJ, Racker S, Herrendorf G, et al. 3 Michael Rosenbloom is clinical director of the year. Her diagnosis was largely dependent HealthPartners Center for Memory and Aging. Accuracy and reliability of periodic sharp wave complexes in Creutzfeldt-Jakob disease. Arch Neurol. on neuroimaging. The utility of MRI in 1996;53(2):162-6. CJD diagnosis cannot be overestimated; 22. Steinhoff BJ, Zerr I, Glatting M, Schulz-Schaeffer REFERENCES W, Poser S, Kretzschmar HA. Diagnostic value of it offers greater sensitivity and specificity periodic complexes in Creutzfeldt-Jakob disease. Ann compared with more traditional methods 1. Rosenbloom MH, Atri A. The evaluation of Neurol. 2004;56(5):702-8. rapidly progressive dementia. Neurologist. Mar such as CSF biomarkers and EEG. 2011;17(2):67-74. 23. Geschwind MD, Martindale J, Miller D, et al. Challenging the clinical utility of the 14-3-3 protein In Minnesota, cases of CJD and other 2. Rabinovici GD, Wang PN, Levin J, et al. First symp- for the diagnosis of sporadic Creutzfeldt-Jakob dis- tom in sporadic Creutzfeldt-Jakob disease. Neurology. ease. Arch Neurol. 2003;60(6):813-6. prion diseases are reportable to the 2006;66(2):286-7.

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