- Email: [email protected]
Phenotypic similarities causing clinical misdiagnosis of pathologically-confirmed sporadic Creutzfeldt-Jakob disease as dementia with Lewy bodies
Clinical Neurology and Neurosurgery 110 (2008) 194–197
Case report
Phenotypic similarities causing clinical misdiagnosis of pathologically-confirmed sporadic Creutzfeldt-Jakob disease as dementia with Lewy bodies D.G. du Plessis a , A.J. Larner b,∗ b
a Greater Manchester Neurosciences Centre, Humphrey Booth Building, Hope Hospital, Salford M6 8HD, UK Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazakerley, Liverpool L9 7LJ, UK
Received 24 July 2007; received in revised form 18 September 2007; accepted 20 September 2007
Abstract A patient fulfilling central, core and supportive clinical diagnostic criteria for dementia with Lewy bodies deteriorated rapidly in the absence of neuroleptic drug treatment, prompting suspicion of a diagnosis of sporadic Creutzfeldt-Jakob disease. At postmortem examination, the brain showed features typical of Creutzfeldt-Jakob disease of the MV1 subtype. We review the phenotypic overlap between dementia with Lewy bodies and Creutzfeldt-Jakob disease which may cause clinical misdiagnosis. © 2007 Elsevier B.V. All rights reserved. Keywords: Creutzfeldt-Jakob disease; Dementia with Lewy bodies; Diagnosis
1. Introduction
2. Case report
The differential diagnosis of dementia with Lewy bodies (DLB) and sporadic Creutzfeldt-Jakob disease (sCJD) may be challenging. “Possible” cases of sCJD referred to national prion disease surveillance units occasionally prove to have a pathological diagnosis of DLB [1–5]. This may result from the overlap of clinical features, or from investigation findings such as EEG periodic sharp wave complexes (PSWC) which, though highly sensitive and specific for the diagnosis of pathologically-confirmed sCJD [6], are not pathognomonic, occurring on occasion in pathologically confirmed DLB [2,3,7–9]. Conversely, cases have been reported in which the presentation fulfilled clinical diagnostic criteria for DLB but in which subsequent clinical course, radiological and CSF findings necessitated diagnostic revision to sCJD, though without neuropathological confirmation [10]. We report a patient presenting with a phenotype suggestive of DLB but who at postmortem proved to have sCJD of the MV1 subtype.
A 74 year-old right-handed man was referred to the neurology clinic by an ophthalmologist with a complaint of seeing colours for which no ophthalmological explanation could be found (normal corrected visual acuities, peripheral visual fields). If he closed his eyes, he reported “seeing” a colour, often red, which would fade over about 30 s when he opened his eyes. This simple visual hallucination interfered with watching television and shopping. He also complained of feeling unsteady on his legs but without any falls. He commented that sometimes he had the feeling that someone was standing beside him and he would say hello although no one was there. On clinical examination he had a mild bradykinesia, slightly stooped posture, hesitant gait, and hypophonic speech, but there was no tremor or rigidity and eye movements were intact. The signs were consistent with mild motor features of parkinsonism. There was no family history of neurodegenerative disease. Although there was no initial complaint of cognitive decline, the patient was requiring increased assistance with some instrumental activities of daily living and within six weeks of outpatient assessment he was admitted to hospital with increasing episodic confusion. MR brain imaging showed generalized atrophy
∗
Corresponding author. Fax: +44 151 529 8552. E-mail address: [email protected] (A.J. Larner).
0303-8467/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2007.09.017
D.G. du Plessis, A.J. Larner / Clinical Neurology and Neurosurgery 110 (2008) 194–197
with periventricular ischaemic changes, particularly in the occipital regions. Around 18 months earlier the patient had developed lightheadedness on standing from sitting or lying. Investigations showed a 20–40 mmHg systolic blood pressure postural drop which had been diagnosed as orthostatic hypotension and treated with fludrocortisone 0.1–0.2 mg/day with some clinical benefit. Formal autonomic studies had not been undertaken (tilt table, noradrenaline levels) but biochemical studies had excluded Addison’s disease. A working diagnosis of dementia with Lewy bodies was made based on widely-accepted clinical diagnostic criteria [11]: central (progressive cognitive decline interfering with activities of daily living), core (visual hallucinations; spontaneous motor features of parkinsonism), and supportive features (orthostatic hypotension) were deemed to be present. Over the next two months the patient deteriorated progressively and rapidly to an encephalopathic state. At no time were neuroleptic medications administered. Because of the rapid and unanticipated decline the diagnosis of sporadic CJD was considered, but clinically no myoclonus was observed. CSF was normal aside from slightly elevated protein (0.67 g/l; normal range 0.15–0.45 g/l; sample was insufficient for 14-33 estimation). The patient was too unwell for hospital transfer for EEG. Palliative care was instituted and he died of a bronchopneumonia six weeks after admission, just over three months after the initial neurological consultation, and one year from the onset of his visual symptoms. Macroscopically, the brain showed generalized mild atrophy with relative sparing of the occipital lobes. Mild atrophy of the cerebellar vermis was also apparent. Normal pigmentation of the substantia nigra and locus coeruleus was observed on sectioning the brainstem. The spinal cord was not available for examination. Histological examination of the brain showed striking, focally confluent, spongiform change with background gliosis and neuronal loss in the occipital lobe neocortex (Fig. 1a). Less advanced, more microvacuolar, spongiform change was apparent in the neocortex elsewhere, in the molecular layer of the cerebellar cortex, in the basal ganglia and the thalamus, with preferential involvement of the medial nucleus of the latter. Limited spongiform change was found in the midbrain tectum/periaqueductal grey matter and entorhinal cortex with relative sparing of the hippocampus. The substantia nigra showed somewhat equivocal spongiform change without significant neuronal loss or Lewy bodies. A predominantly synaptic pattern of staining for PrP was seen with KG9 and 3F4 immunostaining, with additionally perivacuolar and focal perineuronal staining in the occipital cortex (Fig. 1b). PrP plaques were not evident. The substantia nigra was spared of PrP staining apart from very rare neurones showing fine punctuate perineuronal staining. Immunostaining for tau and ␣-synuclein showed no evidence for tauopathy or synucleinopathy. Biochemical analysis of frozen brain tissue by Western blot showed protease-resistant PrP with Type 1 isoform. The patient was a methionine-valine heterozygote
195
Fig. 1. (a) Occipital cortex showing marked spongiform change with confluent vacuolation in the deeper layers associated with astrocytic gliosis and neuronal loss (H&E, original magnification ×400). (b) Excessive, mainly synaptic, pattern of PrP immunostaining in the medial occipital cortex with focal perineuronal staining (KG9 antibody, original magnification ×630).
at codon 129 (M129V). Hence the diagnosis, according to the molecular and phenotypic classification of CJD devised by Parchi et al. [12], was sporadic CJD consistent with the MV1 subtype. 3. Discussion The initial working diagnosis in this patient was DLB because of the clinical presentation with progressive cognitive decline (central diagnostic criterion), visual hallucinations and motor features of parkinsonism (core criteria), with a prior history of symptomatic orthostatic hypotension (supportive criterion) [11]. With respect to the latter criterion, cases of pure autonomic failure evolving to DLB have been reported [13,14]. Although patients with DLB may decline rapidly following administration of neuroleptic medications [15], this disease course is unusual in drug-na¨ıve patients [16]. The very rapid clinical progression in this case in the absence of neuroleptic use prompted consideration of sCJD as the diagnosis [17]: abrupt decline into stupor or coma after
196
D.G. du Plessis, A.J. Larner / Clinical Neurology and Neurosurgery 110 (2008) 194–197
showing neurological signs without dementia is reported in MM1 and MV1 sCJD subtypes [12]. A patient with a PRNP gene mutation (M232R) but with the neuropathological phenotype of DLB has been reported [18], as has an atypical case of CJD with Parkinson’s disease [19]. Variants of Gerstmann–Str¨aussler–Scheinker disease (GSS) may exhibit Lewy body pathology: the F198S129V genotype was associated with numerous neocortical ␣-synuclein immunopositive Lewy bodies in members of one family [20]. Lewy bodies may also be found in the substantia nigra in the Q217R-129V genotype [21]. Both genotypic variants develop dementia and may be characterized by parkinsonian symptoms. Neuropathological studies show that spongiform change, which is typically but not invariably [22] a feature of prion diseases, is common in DLB, resembling the microvacuolation found in CJD [23]. This feature is most notable in cortical layers 1, 2 and 3 [23], but may be transcortical as in CJD. It is usually localized to the medial temporal lobe, but has been described in the occipital cortex with gliosis [24]. The presence of parkinsonism and fluctuations in “possible” CJD cases is said to point to a diagnosis of DLB [4]. The atypical findings in our MV1 sCJD patient are reflected by the fact that parkinsonism was not observed in this subtype by Parchi et al. [12] but they found myoclonus, not observed in our patient, to be a virtually invariable feature. We are not aware of accounts of autonomic dysfunction causing orthostatic hypotension in sCJD, although dysautonomia is a prominent feature of fatal familial insomnia [25]. The visual hallucinations in this case were atypical for DLB, being simple colours rather than complex images of people or animals, although the sensation of a presence, someone standing beside the patient (anwesenheit), is relatively common in parkinsonian syndromes [26]. The Heidenhain variant of sCJD, accounting for perhaps 20% of sCJD cases, is characterized by visual disorders which persist throughout the disease course. These may include blurred vision, diplopia, visual field restriction, metamorphopsia, cortical blindness, and visual hallucinations [27,28]. These symptoms typically cause the patient to give up reading or watching television although there are no conspicuous findings on ophthalmological examination. Visual hallucinations have been reported as the presenting feature of CJD [29]. The clinical features which might possibly have alerted us to the correct diagnosis at an earlier stage in this case were the simple, rather than complex, nature of the visual hallucinations, and the absence of marked cognitive fluctuations, both typical features of DLB [11], although memory impairment does not necessarily occur in the early stages. We endorse the recommendation that sCJD Heidenhain variant should enter the differential diagnosis in visual disorders of uncertain origin [27]. However, we are not aware of any prior report of the gestalt of visual hallucinations, motor features of parkinsonism, and symptomatic orthostatic hypotension in a pathologically-confirmed case of sCJD.
Acknowledgement The authors thank the UK National CJD Surveillance Unit for confirming the diagnosis and providing genotypic and biochemical data. References [1] Ha¨ık S, Brandel J-P, Sazdovitch V, et al. Dementia with Lewy bodies in a neuropathologic series of suspected Creutzfeldt-Jakob disease. Neurology 2000;55:1401–4. [2] Tschampa HJ, Neumann M, Zerr I, et al. Patients with Alzheimer’s disease and dementia with Lewy bodies mistaken for Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry 2001;71:33–9. [3] Mollenhauer B, Zerr I, Varges D, et al. Dementia with Lewy bodies as differential diagnosis of Creutzfeldt-Jakob disease. J Neurol 2002;249(Suppl. 1):I76 [Abstract P277]. [4] Van Everbroeck B, Dobbeleir I, De Waele M, De Deyn P, Martin J-J, Cras P. Differential diagnosis of 201 possible Creutzfeldt-Jakob disease patients. J Neurol 2004;251:298–304. [5] Larner AJ, Doran M. Prion disease at a regional neuroscience centre: a retrospective audit. J Neurol Neurosurg Psychiatry 2004;75:1789–90. [6] Zerr I, Pocchiari M, Collins S, et al. Analysis of EEG and CSF 14-3-3 proteins as aids to the diagnosis of Creutzfeldt-Jakob disease. Neurology 2000;55:811–5. [7] Burkhardt CR, Filley CM, Kleinschmidt-DeMasters BK, de la Monte S, Norenberg MD, Schneck SA. Diffuse Lewy body disease and progressive dementia. Neurology 1988;38:1520–8. [8] Yamamoto T, Imai T. A case of diffuse Lewy body disease and Alzheimer’s disease with periodic synchronous discharges. J Neuropathol Exp Neurol 1988;47:536–48. [9] Doran M, Larner AJ. EEG findings in dementia with Lewy bodies causing diagnostic confusion with sporadic Creutzfeldt-Jakob disease. Eur J Neurol 2004;11:838–41. [10] Kraemer C, Lang K, Weckesser M, Evers S. Creutzfeldt-Jacob [sic] disease misdiagnosed as dementia with Lewy bodies. J Neurol 2005;252:861–2. [11] McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005;65:1863–72. [12] Parchi P, Giese A, Capellari S, et al. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999;46:224–33. [13] Larner AJ, Mathias CJ, Rossor MN. Autonomic failure preceding dementia with Lewy bodies. J Neurol 2000;247:229– 31. [14] Kaufmann H, Nahm K, Purohit D, Wolfe D. Autonomic failure as the initial presentation of Parkinson disease and dementia with Lewy bodies. Neurology 2004;63:1093–5. [15] McKeith I, Fairbairn A, Perry R, Thompson P, Perry E. Neuroleptic sensitivity in patients with senile dementia of Lewy body type. BMJ 1992;305:673–8. [16] Armstrong TP, Hansen LA, Salmon DP, et al. Rapidly progressive dementia in a patient with the Lewy body variant of Alzheimer’s disease. Neurology 1991;41:1178–80. [17] Lemstra AW, Schoenmaker N, Rozemuller-Kwakkel AJM, van Gool WA. The association of neuroleptic sensitivity in Lewy body disease with a false positive clinical diagnosis of Creutzfeldt-Jakob disease. Int J Geriatr Psychiatry 2006;21:1031–5. [18] Koide T, Ohtake H, Nakajima T, et al. A patient with dementia with Lewy bodies and codon 232 mutation of PRNP. Neurology 2002;59:1619–21. [19] Iida T, Doh-ura K, Kawashima T, Abe H, Iwaki T. An atypical case of sporadic Creutzfeldt-Jakob disease with Parkinson’s disease. Neuropathology 2001;21:294–7.
D.G. du Plessis, A.J. Larner / Clinical Neurology and Neurosurgery 110 (2008) 194–197 [20] Ghetti B, Gambetti P. Human prion diseases. In: Mattson MP, editor. Advances in cell aging and gerontology, vol. 3: Genetic aberrancies and neurodegenerative disorders. Greenwich, CT: Jai Press, 1999. p. 135–87. [21] Ghetti B, Bugiani O, Tagliavini F, Piccardo P. Gerstmann–Str¨aussler –Scheinker disease. In: Dickson D, editor. Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders. Basel: ISN Neuropath Press; 2003. p. 318–25. [22] Collinge J, Owen F, Poulter M, et al. Prion dementia without characteristic pathology. Lancet 1990;336:7–9. [23] Hansen LA, Masliah E, Terry RD, Mirra SS. A neuropathological subset of Alzheimer’s disease with concomitant Lewy body disease and spongiform change. Acta Neuropathol (Berl) 1989;78:194–201. [24] Higuchi M, Tashiro M, Arai H, et al. Glucose hypometabolism and neuropathological correlates in brains of dementia with Lewy bodies. Exp Neurol 2000;162:247–56.
197
[25] Lugaresi E, Medori R, Montagna P, et al. Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. N Engl J Med 1986;315:997–1003. [26] F´en´elon G, Mahieux F, Huon R, Ziegler M. Hallucinations in Parkinson’s disease: prevalence, phenomenology and risk factors. Brain 2000;123:733–45. [27] Kropp S, Schulz-Schaeffer WJ, Finkenstaedt M, et al. The Heidenhain variant of Creutzfeldt-Jakob disease. Arch Neurol 1999;56:55– 61. [28] Armstrong RA. Creutzfeldt-Jakob disease and vision. Clin Exp Optom 2006;89:3–9. [29] Heinz A, Schmidt LG, Winterer G, Gerhard L, Przuntek H. Optical and tactile hallucinosis as clinical onset of Creutzfeld-Jakob disease. Nervenarzt 1995;66:712–6 [in German].
Case report
Phenotypic similarities causing clinical misdiagnosis of pathologically-confirmed sporadic Creutzfeldt-Jakob disease as dementia with Lewy bodies D.G. du Plessis a , A.J. Larner b,∗ b
a Greater Manchester Neurosciences Centre, Humphrey Booth Building, Hope Hospital, Salford M6 8HD, UK Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazakerley, Liverpool L9 7LJ, UK
Received 24 July 2007; received in revised form 18 September 2007; accepted 20 September 2007
Abstract A patient fulfilling central, core and supportive clinical diagnostic criteria for dementia with Lewy bodies deteriorated rapidly in the absence of neuroleptic drug treatment, prompting suspicion of a diagnosis of sporadic Creutzfeldt-Jakob disease. At postmortem examination, the brain showed features typical of Creutzfeldt-Jakob disease of the MV1 subtype. We review the phenotypic overlap between dementia with Lewy bodies and Creutzfeldt-Jakob disease which may cause clinical misdiagnosis. © 2007 Elsevier B.V. All rights reserved. Keywords: Creutzfeldt-Jakob disease; Dementia with Lewy bodies; Diagnosis
1. Introduction
2. Case report
The differential diagnosis of dementia with Lewy bodies (DLB) and sporadic Creutzfeldt-Jakob disease (sCJD) may be challenging. “Possible” cases of sCJD referred to national prion disease surveillance units occasionally prove to have a pathological diagnosis of DLB [1–5]. This may result from the overlap of clinical features, or from investigation findings such as EEG periodic sharp wave complexes (PSWC) which, though highly sensitive and specific for the diagnosis of pathologically-confirmed sCJD [6], are not pathognomonic, occurring on occasion in pathologically confirmed DLB [2,3,7–9]. Conversely, cases have been reported in which the presentation fulfilled clinical diagnostic criteria for DLB but in which subsequent clinical course, radiological and CSF findings necessitated diagnostic revision to sCJD, though without neuropathological confirmation [10]. We report a patient presenting with a phenotype suggestive of DLB but who at postmortem proved to have sCJD of the MV1 subtype.
A 74 year-old right-handed man was referred to the neurology clinic by an ophthalmologist with a complaint of seeing colours for which no ophthalmological explanation could be found (normal corrected visual acuities, peripheral visual fields). If he closed his eyes, he reported “seeing” a colour, often red, which would fade over about 30 s when he opened his eyes. This simple visual hallucination interfered with watching television and shopping. He also complained of feeling unsteady on his legs but without any falls. He commented that sometimes he had the feeling that someone was standing beside him and he would say hello although no one was there. On clinical examination he had a mild bradykinesia, slightly stooped posture, hesitant gait, and hypophonic speech, but there was no tremor or rigidity and eye movements were intact. The signs were consistent with mild motor features of parkinsonism. There was no family history of neurodegenerative disease. Although there was no initial complaint of cognitive decline, the patient was requiring increased assistance with some instrumental activities of daily living and within six weeks of outpatient assessment he was admitted to hospital with increasing episodic confusion. MR brain imaging showed generalized atrophy
∗
Corresponding author. Fax: +44 151 529 8552. E-mail address: [email protected] (A.J. Larner).
0303-8467/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2007.09.017
D.G. du Plessis, A.J. Larner / Clinical Neurology and Neurosurgery 110 (2008) 194–197
with periventricular ischaemic changes, particularly in the occipital regions. Around 18 months earlier the patient had developed lightheadedness on standing from sitting or lying. Investigations showed a 20–40 mmHg systolic blood pressure postural drop which had been diagnosed as orthostatic hypotension and treated with fludrocortisone 0.1–0.2 mg/day with some clinical benefit. Formal autonomic studies had not been undertaken (tilt table, noradrenaline levels) but biochemical studies had excluded Addison’s disease. A working diagnosis of dementia with Lewy bodies was made based on widely-accepted clinical diagnostic criteria [11]: central (progressive cognitive decline interfering with activities of daily living), core (visual hallucinations; spontaneous motor features of parkinsonism), and supportive features (orthostatic hypotension) were deemed to be present. Over the next two months the patient deteriorated progressively and rapidly to an encephalopathic state. At no time were neuroleptic medications administered. Because of the rapid and unanticipated decline the diagnosis of sporadic CJD was considered, but clinically no myoclonus was observed. CSF was normal aside from slightly elevated protein (0.67 g/l; normal range 0.15–0.45 g/l; sample was insufficient for 14-33 estimation). The patient was too unwell for hospital transfer for EEG. Palliative care was instituted and he died of a bronchopneumonia six weeks after admission, just over three months after the initial neurological consultation, and one year from the onset of his visual symptoms. Macroscopically, the brain showed generalized mild atrophy with relative sparing of the occipital lobes. Mild atrophy of the cerebellar vermis was also apparent. Normal pigmentation of the substantia nigra and locus coeruleus was observed on sectioning the brainstem. The spinal cord was not available for examination. Histological examination of the brain showed striking, focally confluent, spongiform change with background gliosis and neuronal loss in the occipital lobe neocortex (Fig. 1a). Less advanced, more microvacuolar, spongiform change was apparent in the neocortex elsewhere, in the molecular layer of the cerebellar cortex, in the basal ganglia and the thalamus, with preferential involvement of the medial nucleus of the latter. Limited spongiform change was found in the midbrain tectum/periaqueductal grey matter and entorhinal cortex with relative sparing of the hippocampus. The substantia nigra showed somewhat equivocal spongiform change without significant neuronal loss or Lewy bodies. A predominantly synaptic pattern of staining for PrP was seen with KG9 and 3F4 immunostaining, with additionally perivacuolar and focal perineuronal staining in the occipital cortex (Fig. 1b). PrP plaques were not evident. The substantia nigra was spared of PrP staining apart from very rare neurones showing fine punctuate perineuronal staining. Immunostaining for tau and ␣-synuclein showed no evidence for tauopathy or synucleinopathy. Biochemical analysis of frozen brain tissue by Western blot showed protease-resistant PrP with Type 1 isoform. The patient was a methionine-valine heterozygote
195
Fig. 1. (a) Occipital cortex showing marked spongiform change with confluent vacuolation in the deeper layers associated with astrocytic gliosis and neuronal loss (H&E, original magnification ×400). (b) Excessive, mainly synaptic, pattern of PrP immunostaining in the medial occipital cortex with focal perineuronal staining (KG9 antibody, original magnification ×630).
at codon 129 (M129V). Hence the diagnosis, according to the molecular and phenotypic classification of CJD devised by Parchi et al. [12], was sporadic CJD consistent with the MV1 subtype. 3. Discussion The initial working diagnosis in this patient was DLB because of the clinical presentation with progressive cognitive decline (central diagnostic criterion), visual hallucinations and motor features of parkinsonism (core criteria), with a prior history of symptomatic orthostatic hypotension (supportive criterion) [11]. With respect to the latter criterion, cases of pure autonomic failure evolving to DLB have been reported [13,14]. Although patients with DLB may decline rapidly following administration of neuroleptic medications [15], this disease course is unusual in drug-na¨ıve patients [16]. The very rapid clinical progression in this case in the absence of neuroleptic use prompted consideration of sCJD as the diagnosis [17]: abrupt decline into stupor or coma after
196
D.G. du Plessis, A.J. Larner / Clinical Neurology and Neurosurgery 110 (2008) 194–197
showing neurological signs without dementia is reported in MM1 and MV1 sCJD subtypes [12]. A patient with a PRNP gene mutation (M232R) but with the neuropathological phenotype of DLB has been reported [18], as has an atypical case of CJD with Parkinson’s disease [19]. Variants of Gerstmann–Str¨aussler–Scheinker disease (GSS) may exhibit Lewy body pathology: the F198S129V genotype was associated with numerous neocortical ␣-synuclein immunopositive Lewy bodies in members of one family [20]. Lewy bodies may also be found in the substantia nigra in the Q217R-129V genotype [21]. Both genotypic variants develop dementia and may be characterized by parkinsonian symptoms. Neuropathological studies show that spongiform change, which is typically but not invariably [22] a feature of prion diseases, is common in DLB, resembling the microvacuolation found in CJD [23]. This feature is most notable in cortical layers 1, 2 and 3 [23], but may be transcortical as in CJD. It is usually localized to the medial temporal lobe, but has been described in the occipital cortex with gliosis [24]. The presence of parkinsonism and fluctuations in “possible” CJD cases is said to point to a diagnosis of DLB [4]. The atypical findings in our MV1 sCJD patient are reflected by the fact that parkinsonism was not observed in this subtype by Parchi et al. [12] but they found myoclonus, not observed in our patient, to be a virtually invariable feature. We are not aware of accounts of autonomic dysfunction causing orthostatic hypotension in sCJD, although dysautonomia is a prominent feature of fatal familial insomnia [25]. The visual hallucinations in this case were atypical for DLB, being simple colours rather than complex images of people or animals, although the sensation of a presence, someone standing beside the patient (anwesenheit), is relatively common in parkinsonian syndromes [26]. The Heidenhain variant of sCJD, accounting for perhaps 20% of sCJD cases, is characterized by visual disorders which persist throughout the disease course. These may include blurred vision, diplopia, visual field restriction, metamorphopsia, cortical blindness, and visual hallucinations [27,28]. These symptoms typically cause the patient to give up reading or watching television although there are no conspicuous findings on ophthalmological examination. Visual hallucinations have been reported as the presenting feature of CJD [29]. The clinical features which might possibly have alerted us to the correct diagnosis at an earlier stage in this case were the simple, rather than complex, nature of the visual hallucinations, and the absence of marked cognitive fluctuations, both typical features of DLB [11], although memory impairment does not necessarily occur in the early stages. We endorse the recommendation that sCJD Heidenhain variant should enter the differential diagnosis in visual disorders of uncertain origin [27]. However, we are not aware of any prior report of the gestalt of visual hallucinations, motor features of parkinsonism, and symptomatic orthostatic hypotension in a pathologically-confirmed case of sCJD.
Acknowledgement The authors thank the UK National CJD Surveillance Unit for confirming the diagnosis and providing genotypic and biochemical data. References [1] Ha¨ık S, Brandel J-P, Sazdovitch V, et al. Dementia with Lewy bodies in a neuropathologic series of suspected Creutzfeldt-Jakob disease. Neurology 2000;55:1401–4. [2] Tschampa HJ, Neumann M, Zerr I, et al. Patients with Alzheimer’s disease and dementia with Lewy bodies mistaken for Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry 2001;71:33–9. [3] Mollenhauer B, Zerr I, Varges D, et al. Dementia with Lewy bodies as differential diagnosis of Creutzfeldt-Jakob disease. J Neurol 2002;249(Suppl. 1):I76 [Abstract P277]. [4] Van Everbroeck B, Dobbeleir I, De Waele M, De Deyn P, Martin J-J, Cras P. Differential diagnosis of 201 possible Creutzfeldt-Jakob disease patients. J Neurol 2004;251:298–304. [5] Larner AJ, Doran M. Prion disease at a regional neuroscience centre: a retrospective audit. J Neurol Neurosurg Psychiatry 2004;75:1789–90. [6] Zerr I, Pocchiari M, Collins S, et al. Analysis of EEG and CSF 14-3-3 proteins as aids to the diagnosis of Creutzfeldt-Jakob disease. Neurology 2000;55:811–5. [7] Burkhardt CR, Filley CM, Kleinschmidt-DeMasters BK, de la Monte S, Norenberg MD, Schneck SA. Diffuse Lewy body disease and progressive dementia. Neurology 1988;38:1520–8. [8] Yamamoto T, Imai T. A case of diffuse Lewy body disease and Alzheimer’s disease with periodic synchronous discharges. J Neuropathol Exp Neurol 1988;47:536–48. [9] Doran M, Larner AJ. EEG findings in dementia with Lewy bodies causing diagnostic confusion with sporadic Creutzfeldt-Jakob disease. Eur J Neurol 2004;11:838–41. [10] Kraemer C, Lang K, Weckesser M, Evers S. Creutzfeldt-Jacob [sic] disease misdiagnosed as dementia with Lewy bodies. J Neurol 2005;252:861–2. [11] McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005;65:1863–72. [12] Parchi P, Giese A, Capellari S, et al. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999;46:224–33. [13] Larner AJ, Mathias CJ, Rossor MN. Autonomic failure preceding dementia with Lewy bodies. J Neurol 2000;247:229– 31. [14] Kaufmann H, Nahm K, Purohit D, Wolfe D. Autonomic failure as the initial presentation of Parkinson disease and dementia with Lewy bodies. Neurology 2004;63:1093–5. [15] McKeith I, Fairbairn A, Perry R, Thompson P, Perry E. Neuroleptic sensitivity in patients with senile dementia of Lewy body type. BMJ 1992;305:673–8. [16] Armstrong TP, Hansen LA, Salmon DP, et al. Rapidly progressive dementia in a patient with the Lewy body variant of Alzheimer’s disease. Neurology 1991;41:1178–80. [17] Lemstra AW, Schoenmaker N, Rozemuller-Kwakkel AJM, van Gool WA. The association of neuroleptic sensitivity in Lewy body disease with a false positive clinical diagnosis of Creutzfeldt-Jakob disease. Int J Geriatr Psychiatry 2006;21:1031–5. [18] Koide T, Ohtake H, Nakajima T, et al. A patient with dementia with Lewy bodies and codon 232 mutation of PRNP. Neurology 2002;59:1619–21. [19] Iida T, Doh-ura K, Kawashima T, Abe H, Iwaki T. An atypical case of sporadic Creutzfeldt-Jakob disease with Parkinson’s disease. Neuropathology 2001;21:294–7.
D.G. du Plessis, A.J. Larner / Clinical Neurology and Neurosurgery 110 (2008) 194–197 [20] Ghetti B, Gambetti P. Human prion diseases. In: Mattson MP, editor. Advances in cell aging and gerontology, vol. 3: Genetic aberrancies and neurodegenerative disorders. Greenwich, CT: Jai Press, 1999. p. 135–87. [21] Ghetti B, Bugiani O, Tagliavini F, Piccardo P. Gerstmann–Str¨aussler –Scheinker disease. In: Dickson D, editor. Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders. Basel: ISN Neuropath Press; 2003. p. 318–25. [22] Collinge J, Owen F, Poulter M, et al. Prion dementia without characteristic pathology. Lancet 1990;336:7–9. [23] Hansen LA, Masliah E, Terry RD, Mirra SS. A neuropathological subset of Alzheimer’s disease with concomitant Lewy body disease and spongiform change. Acta Neuropathol (Berl) 1989;78:194–201. [24] Higuchi M, Tashiro M, Arai H, et al. Glucose hypometabolism and neuropathological correlates in brains of dementia with Lewy bodies. Exp Neurol 2000;162:247–56.
197
[25] Lugaresi E, Medori R, Montagna P, et al. Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. N Engl J Med 1986;315:997–1003. [26] F´en´elon G, Mahieux F, Huon R, Ziegler M. Hallucinations in Parkinson’s disease: prevalence, phenomenology and risk factors. Brain 2000;123:733–45. [27] Kropp S, Schulz-Schaeffer WJ, Finkenstaedt M, et al. The Heidenhain variant of Creutzfeldt-Jakob disease. Arch Neurol 1999;56:55– 61. [28] Armstrong RA. Creutzfeldt-Jakob disease and vision. Clin Exp Optom 2006;89:3–9. [29] Heinz A, Schmidt LG, Winterer G, Gerhard L, Przuntek H. Optical and tactile hallucinosis as clinical onset of Creutzfeld-Jakob disease. Nervenarzt 1995;66:712–6 [in German].