The Open Neurology Journal




ISSN: 1874-205X ― Volume 13, 2019
CASE REPORT

E200k Familial Creutzfeldt-Jakob Disease Presenting with Subacute Multiple Cranial Neuropathy



C. Lapucci1, *, N. Romano2, G. Boffa1, 3, L. Saitta4, F. Nobili1, 3, G.L. Mancardi1, 3, P. Mandich1, M. Grandis1, 3
1 Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genoa, Italy
2 Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
3 Department of Neurology, Ospedale Policlinico San Martino IRCCS, Genoa, Italy
4 Department of Neuroradiology, Ospedale Policlinico San Martino IRCCS, Genoa, Italy

Abstract

Unusual clinical presentations in patients with E200K familial Creutzfeldt-Jakob Disease (fCJD) have been rarely reported. Herein, we described a case of E200K fCJD presenting with subacute cranial multiple neuropathy, initially suspected to be paraneoplastic or due to a leptomeningeal carcinomatosis, considering the neoplastic comorbidity of the patient. Surprisingly, brain MRI was highly suggestive of CJD. Brain histological examination confirmed the diagnosis. Genetic tests led to the definite diagnosis of E200K fCJD. To the best of our knowledge, the current case provides the first report of a histologically-confirmed E200K fCJD starting with cranial multiple neuropathy and may widen the spectrum of the clinical variability of CJD, also in its genetic variant. Unusual presentations may lead, as in this case, to incorrect diagnostic hypothesis and unuseful therapeutic attempts in the first phase of the diagnostic process. Also in the genetic variant of CJD, brain MRI demonstrated a very high sensitivity to detect the typical abnormalities since the earliest phases of the disease.

Keywords: Creutzfeldt Jacob disease, Familial, E200K, Multiple cranial neuropathy, MRI, 18F-fluoro-D-glucose positron emission tomography.


Article Information


Identifiers and Pagination:

Year: 2019
Volume: 13
First Page: 72
Last Page: 75
Publisher Id: TONEUJ-13-72
DOI: 10.2174/1874205X01913010072

Article History:

Received Date: 17/01/2019
Revision Received Date: 20/03/2019
Acceptance Date: 04/04/2019
Electronic publication date: 31/05/2019
Collection year: 2019

Article Metrics:

CrossRef Citations:
0

Total Statistics:

Full-Text HTML Views: 567
Abstract HTML Views: 344
PDF Downloads: 151
ePub Downloads: 113
Total Views/Downloads: 1175

Unique Statistics:

Full-Text HTML Views: 329
Abstract HTML Views: 216
PDF Downloads: 113
ePub Downloads: 79
Total Views/Downloads: 737
Geographical View

© 2019 Lapucci et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Ospedale Policlinico San Martino IRCCS, Largo P. Daneo, 3, 16132, Genoa, Italy; Tel: +39 0103537075; Fax +39 01035338751; Email: lapucci.caterina@alice.it




1. INTRODUCTION

Several unusual presentations in patients with E200K familial Creutzfeldt-Jakob Disease (fCJD) have been described in a recent review written by Cohen et al. [1Cohen OS, Kimiagar I, Korczyn AD, et al. Unusual presentations in patients with E200K familial Creutzfeldt-Jakob disease. Eur J Neurol 2016; 23(5): 871-7.
[http://dx.doi.org/10.1111/ene.12955] [PMID: 26806765]
]. Herein, we report the case of a histologically confirmed E200K fCJD presenting with a subacute multiple cranial neuropathy.

2. CASE REPORT

Here, we report the case of a 77-years old man with a metastatic colic cancer diagnosed two years before, who developed a multiple cranial neuropathy with a subacute onset, characterized by marked right eyelid ptosis, horizontal gaze palsy, left facial nerve palsy, hypophonia, dysarthria and dysphagia, associated to a left pyramidal-cerebellar syndrome. In particular, right eyelid ptosis and horizontal gaze palsy appeared one month before the admission in our department and had a rapid progressive course, becoming evident in one week. Two weeks later (thus, two weeks before the admission) the patient developed a left facial peripheral nerve palsy, followed by hypophonia, dysarthria and dysphagia that rapidly worsened, leading to the hospitalization. A mild left pyramidal-cerebellar syndrome characterized by limbs weakness and segmental dysmetria was detected at the neurological examination and not complained before by the patient. At the neuropsychological evaluation, Mini Mental Status Examination (MMSE) and Frontal Assessment Battery (FAB) revealed scores of 29/30 and 17/18 respectively, thus supporting preserved cognitive functions. A leptomeningeal carcinomatosis or a paraneoplastic multiple cranial neuropathy was initially suspected although total body TC/18F-fluoro-D-Glucose Positron Emission Tomography (FDG-PET) performed 3 months before the onset of neurological signs showed a steady neoplastic situation, with no increasing tumor size of both primitive cancer and pre-existing metastasis, nor detection of other sites of pathological tracer accumulation. The initial diagnostic work-up included electroencephalogram (EEG), to evaluate if the above mentioned left pyramidal syndrome, had a lateralized electroencephalographic correlate. Electroencephalogram revealed only mild and bilateral anterior slowing. Cerebrospinal Fluid (CSF) analysis included cytochemical analysis, that demonstrated the presence of 2 cell (lymphocytes)/mm3 (range 0-5 cells/mm3) with proteins and glucose levels within normal limits (30 mg/ml, normal range 15-45 mg/ml and 45 mg/dl, normal range 40-70 mg/dl respectively). Neither intrathecal synthesis of IgG nor oligoclonal bands were detected by immunochemical and immunoblot analysis respectively. Cytology showed normal mature lymphocytes with no nuclear and cytoplasmic abnormalities. Surprisingly, brain MRI showed FLAIR hyperintense signal involving right temporo-insular cortex, paramedian frontal cortex, putamen and caudate nuclei bilaterally with DWI hyperintensity seen at high b values in the same areas, with corresponding hypointensity on ADC map. The brainstem didn’t show signal abnormalities but appeared slightly atrophic (Fig. 1). Taken as a whole, MRI features were suggestive of CJD. Diagnostic work-up was completed with brain FDG-PET, that revealed cortical bilateral (but more pronounced on the right side) hypometabolism, involving temporopolar, fronto-polar, frontal dorso-ventrolateral, fronto-mesial and anterior cingulate cortices (Fig. 2). These features were associated with the evidence of bilateral putaminal hypermetabolism. Taking into account neurological features and the putaminal hypermetabolism, atypical for CJD, and the neoplastic comorbidity, a therapeutic attempt with Intravenous Immunoglobulins (IVIG, 0,4 mg/kg/die for 5 days totally) was performed, with no clinical improvement. Onconeural intracellular (anti-Hu, anti-Ri, anti-Yo, anti-Ma) and surface antigens (anti-NMDA, VGCK, GABA-a, GABA-b) antibodies were tested on CSF, with negative result. In the following month, the patient rapidly worsened and developed a severe cognitive impairment, finally evolving into mutism. Prominent oro-buccal dyskinesia also characterized this phase of the disease. Serial electroencephalograms were performed, with the final evidence of typical periodic waves. In keeping with the notion of massive neurodegeneration [2Zerr I, Zafar S, Schmitz M, Llorens F. Cerebrospinal fluid in Creutzfeldt-Jakob disease. Handb Clin Neurol 2017; 146: 115-24.
[http://dx.doi.org/10.1016/B978-0-12-804279-3.00008-3] [PMID: 291 10766]
], high tau (2269 pg/ml, normal range <400 pg/ml; ELISA, INNOTEST KIT, Fujirebio, Europe, Gent, Belgium) and mildly increased hyperphosphorylated-tau protein (69 pg/ml, normal range <40 pg/ml, ELISA, INNOTEST KIT, Fujirebio, Europe, Gent, Belgium) levels were detected in CSF, that turned positive also for 14-3-3 protein detection. The patient died one month later. Brain histological examination confirmed the diagnosis of CJD and PRNP gene sequencing revealed a Methionine-Methionine (MM) polymorphism on codon 129 and the E200K mutation, leading to the diagnosis of E200K fCJD. No evidence of metastatic involvement of cranial nerves and meninges was found at the histologic examination. Since, the patient was adopted after birth, data concerning his family history are not available.

Fig. (1)
MRI features. DWI (b1000) and ADC map: brainstem (A); basal ganglia (B); frontal paramedian cortex (C). No signal abnormalities are detectable in the brainstem. Note the marked DWI hyperintensity-ADC hypointensity involving putamen, caudate nuclei and right insular cortex (B), more subtle involving frontal paramedian cortex (C). Images are shown in radiological convention.


Fig. (2)
PET features. 18F-Fluoro-D-Glucose Positron Emission Tomography (FDG-PET): brainstem (A); basal ganglia (B); frontal paramedian cortex (C). No signal abnormalities are detectable in the brainstem. Note the bilateral putaminal hypermetabolism (B) associated to a bilateral hypometabolism involving the frontal paramedian cortex, particularly on the right side (C). Images are shown in radiological convention.


3. DISCUSSION

The wide phenotypic variability of fCJD clinical onset has been previously reported by Chapman et al. [3Chapman J, Brown P, Goldfarb LG, Arlazoroff A, Gajdusek DC, Korczyn AD. Clinical heterogeneity and unusual presentations of Creutzfeldt-Jakob disease in Jewish patients with the PRNP codon 200 mutation. J Neurol Neurosurg Psychiatry 1993; 56(10): 1109-12.
[http://dx.doi.org/10.1136/jnnp.56.10.1109] [PMID: 8105028]
] and Cohen et al. [1Cohen OS, Kimiagar I, Korczyn AD, et al. Unusual presentations in patients with E200K familial Creutzfeldt-Jakob disease. Eur J Neurol 2016; 23(5): 871-7.
[http://dx.doi.org/10.1111/ene.12955] [PMID: 26806765]
]. The risk of misdiagnosis and useless treatments comes down to unusual atypical presentations, particularly during the earliest stages of the disease. To the best of our knowledge, the current case provides the first report of a histologically-confirmed E200K fCJD starting with multiple cranial neuropathy. In our case, the neoplastic comorbidity and the initial lack of cognitive issues were misleading, while the typical cortical, putaminal and caudate restricted diffusion prompted us to investigate and identify this genetic variant of CJD. As previously reported, atrophic changes in the cerebellum and brainstem may cause elevated diffusivity leading to low, rather than high, signal in Diffusion Weighted Images (DWI) sequences and high Apparent Diffusion Coefficient (ADC) values. Moreover, DWI scans, set specifically to detect diffusion restriction may miss brainstem and posterior fossa changes [4Cohen OS, Hoffmann C, Lee H, Chapman J, Fulbright RK, Prohovnik I. MRI detection of the cerebellar syndrome in Creutzfeldt-Jakob disease. Cerebellum 2009; 8(3): 373-81.
[http://dx.doi.org/10.1007/s12311-009-0106-8] [PMID: 19408064]
]. Further, the absence of signal abnormalities in the brainstem on T2-FLAIR and T1SE sequences may be related to the low spatial resolution of these MRI sequences, not able to detect the pathological involvement of cranial nerves and/or brainstem nuclei.

The involvement of peripheral nervous system in human prion disease has not been widely investigated. In one paper [5Niewiadomska M, Kulczycki J, Wochnik-Dyjas D, et al. Impairment of the peripheral nervous system in Creutzfeldt-Jakob disease. Arch Neurol 2002; 59(9): 1430-6.
[http://dx.doi.org/10.1001/archneur.59.9.1430] [PMID: 12223030]
], electrophysiologic examinations confirmed peripheral nervous system damage in patients with sporadic CJD and revealed also preclinical peripheral nervous system impairment. Furthermore, in another report [1Cohen OS, Kimiagar I, Korczyn AD, et al. Unusual presentations in patients with E200K familial Creutzfeldt-Jakob disease. Eur J Neurol 2016; 23(5): 871-7.
[http://dx.doi.org/10.1111/ene.12955] [PMID: 26806765]
] neuronal loss, gliosis and Prionic Protein (PrP) deposits were observed in the vestibular and cochlear nuclei of a patients presenting with sesnorineural hearing loss. Similarly, cranial nerves involvement in our patient could be explained by the direct deposition of PrP in oculomotor, VII, IX and X brainstem cranial nerves nuclei. Unfortunately, no specific histo pathological examinations for Prp deposition in the cranial nerves and nuclei has been performed in our patient. Never theless, the absence of hystologic abnormalities suggestive of metastatic involvement of cranial nerves and meninges allows us to formally exclude a metastatic spreading in the brainstem as cause of the cranial multiple neuropathy.

18F-FDG-PET have been studied in prion disease although there are few studies with autopsy-confirmed cases and currently it is not routinely used in the diagnostic evaluation. Cortical hypometabolism in human prion diseases represents a well-known phenomenon, neuropathologically related to neuronal loss, astrocytosis and/or spongiosis. Conversely, hypermetabolism in 18F-FDG-PET seems to be related with microglial activation and neuroinflammation, as demonstrated in sporadic CJD [6Wojtera M, Sobów T, Kłoszewska I, Liberski PP, Brown DR, Sikorska B. Expression of immunohistochemical markers on microglia in Creutzfeldt-Jakob disease and Alzheimer’s disease: Morphometric study and review of the literature. Folia Neuropathol 2012; 50(1): 74-84.
[PMID: 22505366]
]. This pattern has been recently described in limbic and mesolimbic structures [7Mente KP, O’Donnell JK, Jones SE, et al. Fluorodeoxyglucose positron emission tomography (FDG-PET) correlation of histopathology and MRI in prion disease. Alzheimer Dis Assoc Disord 2017; 31(1): 1-7.
[http://dx.doi.org/10.1097/WAD.0000000000000188] [PMID: 2812 1634]
] but no cases of putaminal hypermetabolism, as shown in our patient, have been currently reported.

CONCLUSION

This case widens the broad phenotypic variability of fCJD, potentially leading to misdiagnosis and unuseful therapeutic attempts. Furthermore, it confirmed MRI highest sensibility and specificity for an early diagnosis, also when clinical features at the onset are atypical for prion disease.

LIST OF ABBREVIATIONS

fCJD = familial Creutzfeldt Jacob disease;
CSF = Cerebrospinal Fluid;
18F-FDG-PET = 18F-fluoro-D-Glucose Positron Emission Tomography;
DWI = Diffusion Weighted Images;
ADC = Apparent Diffusion Coefficient;
MM = Methionine-Methionine.

AUTHORS CONTRIBUTION

All authors (Lapucci C., Romano N., Boffa G., Saitta L., Nobili F., Mancardi G.L., Mandich P., Grandis M.) made a substantial contribution to the design, data collection and analysis of the research and the drafting of the manuscript and reviewed and accepted the contents of the manuscript prior to its submission.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Not applicable.

HUMAN AND ANIMAL RIGHTS

No animals/humans were used for studies that are the basis of this research.

CONSENT FOR PUBLICATION

Informed consent for publication was obtained by a next-of-kin of the patient after his death.

AVAILABILITY OF DATA AND MATERIALS

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

[1] Cohen OS, Kimiagar I, Korczyn AD, et al. Unusual presentations in patients with E200K familial Creutzfeldt-Jakob disease. Eur J Neurol 2016; 23(5): 871-7.
[http://dx.doi.org/10.1111/ene.12955] [PMID: 26806765]
[2] Zerr I, Zafar S, Schmitz M, Llorens F. Cerebrospinal fluid in Creutzfeldt-Jakob disease. Handb Clin Neurol 2017; 146: 115-24.
[http://dx.doi.org/10.1016/B978-0-12-804279-3.00008-3] [PMID: 291 10766]
[3] Chapman J, Brown P, Goldfarb LG, Arlazoroff A, Gajdusek DC, Korczyn AD. Clinical heterogeneity and unusual presentations of Creutzfeldt-Jakob disease in Jewish patients with the PRNP codon 200 mutation. J Neurol Neurosurg Psychiatry 1993; 56(10): 1109-12.
[http://dx.doi.org/10.1136/jnnp.56.10.1109] [PMID: 8105028]
[4] Cohen OS, Hoffmann C, Lee H, Chapman J, Fulbright RK, Prohovnik I. MRI detection of the cerebellar syndrome in Creutzfeldt-Jakob disease. Cerebellum 2009; 8(3): 373-81.
[http://dx.doi.org/10.1007/s12311-009-0106-8] [PMID: 19408064]
[5] Niewiadomska M, Kulczycki J, Wochnik-Dyjas D, et al. Impairment of the peripheral nervous system in Creutzfeldt-Jakob disease. Arch Neurol 2002; 59(9): 1430-6.
[http://dx.doi.org/10.1001/archneur.59.9.1430] [PMID: 12223030]
[6] Wojtera M, Sobów T, Kłoszewska I, Liberski PP, Brown DR, Sikorska B. Expression of immunohistochemical markers on microglia in Creutzfeldt-Jakob disease and Alzheimer’s disease: Morphometric study and review of the literature. Folia Neuropathol 2012; 50(1): 74-84.
[PMID: 22505366]
[7] Mente KP, O’Donnell JK, Jones SE, et al. Fluorodeoxyglucose positron emission tomography (FDG-PET) correlation of histopathology and MRI in prion disease. Alzheimer Dis Assoc Disord 2017; 31(1): 1-7.
[http://dx.doi.org/10.1097/WAD.0000000000000188] [PMID: 2812 1634]

Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


Browse Contents



Webmaster Contact: info@benthamopen.net
Copyright © 2019 Bentham Open