Neuroradiology (1996) 38:226-231 �9 Springer-Verlag 1996 D I A G N O S T I C N E U R O R A D I O L O G Y

J. M. Garcla Santos J. A. L6pez Corbaldn J. E Mart/nez-Lage J. Sicilia Guill~n

CT and MRI in iatrogenic and sporadic Creutzfeldt-Jakob disease: as far as imaging perceives

Received: 10 November 1994 Accepted: 28 February 1995

Presented in part at the 6th annual meeting of the Sociedad Ibero-Latinoamericana de Neuroradiologfa Diagndstica y Terapdutica (SILAN) Madrid, June 1994

J. M. Garcfa Santos ( ~ ) Servicio de Radiodiagndstico, H.U. Dr. Morales Meseguer, c/Marqu6s de los V61ez s/n, E-30008 Murcia, Spain

J. M. Garcfa Santos �9 J. A. L6pez Corbalfn Section of Neuroradiology, HU Virgen de la Arrixaca, E-30120 E1 Palmar (Murcia), Spain

J. E Martfnez-Lage Service of Neurosurgery, HU Virgen de la Arrixaca, Murcia, Spain

J. Sicilia Guilldn Service of Neurology, HU Virgen de la Arrixaca, Murcia, Spain

Abstract Creutzfeldt-Jakob Dis- ease (CJD), an invariably fatal de- menting illness, affects patients in middle and old age (sporadic form). However, the association of CJD with certain treatments (iatrogenic form) has been described in younger patients. The clinical onset of the two forms seems to differ; in the ia- trogenic form a high frequency of the ataxic CJD variant has been re- ported. Nowadays, a definitive diag- nosis of CJD is exclusively histolog- ical. We present five cases of CJD, one sporadic and the others iatro- genic, following dura mater grafts and analyse their CT and MRI fea- tures. CT typically demonstrates brain atrophy, generally progressive, but in sporadic CJD midfield MRI also showed abnormal signal, with predominant deep grey mat ter in- volvement. The use of narrow win- dows with proton-density sequences

may reveal subtle cortical signal ab- normalities not clearly visible with conventional windows. The early demonstrat ion of these changes, in the appropriate clinical context, may suggest CJD and this supports the use of mid- or high magnetic fields in the diagnosis of CJD and other forms of dementia. In our cases of iatrogenic CJD, low-field MRI did not reveal more than the progressive atrophy displayed by CT, and raises the question on the one hand of possible differences, based on imaging, from the sporadic form, and on the other of the lack of sensitivity of tow-field magnets to signal changes in CJD.

Key words Computed tomography �9 Creutzfeldt-Jakob disease. Dement ia . Magnetic resonance imaging. Prion diseases

Introduction

Creutzfeldt-Jakob disease (CJD) can cause dementia. Although most cases are sporadic, there is sometimes a recognised means of transmission [1]. The causative agent is thought to be the "prion", which differs from a virus in not containing nuclei acid and not evoking an immune response [2]. These infective agents resist many conventional methods of disinfection [3]. CJD is one of the diseases in which dementia is a major clinical finding [4]; others are senile dementia of Alzheimer type, Pick's disease, vascular dementia and normal pressure hydro- cephalus (NPH). Many other diseases can cause de-

mentia, but other clinical aspects are generally more relevant. The importance of accurate diagnosis in de- mentia depends on the possibility of t reatment in cer- tain cases (for example NPH), on the need for preven- tion of a contagious spread, or on giving a prognosis (worse in the case of CJD). We had the opportunity of collaborating in the diagnosis of a case of CJD, by MRI. This was the starting point of the present study, aimed at analysing in retrospect our experience with five such cases.

227

T a b l e 1 Iatrogenic and sporadic Creutzfeldt-Jakob disease (CJD): clinical features

Case Age Transmission Initial EEG a CSF symptoms

1 19 Iatrogenic Unsteadiness, + / + + Normal blurred vision

2 57 Iatrogenic Unsteadiness, + / + + Elevated dysarthria proteins

3 17 Iatrogenic Unsteadiness, + + + Elevated dysarthria proteins

and white cells

Elevated IgA, IgG Elevated IgA, IgG

4 34 Iatrogenic Unsteadiness, + / + + dysarthria

5 50 Sporadic Behaviour + + + disturbances

a + slowing, + + slowing plus periodic waves, + + + triphasic waves

T a b l e 2 Iatrogenic and sporadic CJD: imaging

Case 1 28 3 a 4 b 5 b

Atrophy CT + MRI

Deep grey matter Low density High density Low signal High signal

Cortex Low density High density Low signal High signal

White matter Low density + High density Low signal High signal

Subdural fluid Bilateral

+ + + +

+ + + +

+ - _ _

_ _ ? -

_ _ ? +

i m

m m

.9 9 +

u

.9

.9

Unilateral

a Low-field b Midfield MRI

Materials and methods

Clinical features and imaging findings were retrospectively as- sessed. In all cases (4 men and 1 woman) the diagnosis was verified by brain biopsy, via a small right frontal burr-hole. The patients' age ranged from 17 to 57 years (average 35.8 years). The four pa- tients who constituted the iatrogenic group had received implants of cadaver dura mater during posterior cranial fossa surgery for astrocytomas (2) and Chiari malformations (2). The epidemiologi- cal and clinical characteristics of these cases have already been published [1, 5, 6], and these subjects have been included in a worldwide genetic study of iatrogenic CJD [7]. The fifth patient had no history of surgery, although he worked for years in a tan- nery.

All patients underwent several CT studies, and four were also investigated by MRI, two with low-field (0.16 and 0.2T) and two with midfield (0.5T) systems. MRI was carried out in all patients in the 2nd week after admission or later. In patient 5 (MRI 2 weeks after admission and 1 month since clinical onset), the proton-den- sity sequence was viewed with a very narrow window (width 6, le- vel 147), to analyse subtle differences in cortical signal between the hemispheres [this sequence was used instead of the T2-weighted sequence to avoid high signal from cerebrospinal fluid (CSF)]. The narrow-window findings in this patient were compared with those in 15 patients with diseases unrelated to cortical impairment. Pa- tient 5 underwent single-photon emission computed tomography (SPECT) the 2nd day after admission.

We analysed the following: development of cortical and sub- cortical cerebral atrophy, and whether it was progressive; varia- tions in cortical, basal ganglia and white matter density or inten- sity; and the presence and density/signal characteristics of subdural collections. The CT and MRI findings were compared.

Results

Clinical results

O u r four ia t rogenic cases (patients 1-4) had very var ied initial complaints , such as b lur red vision, dysarthria, dizziness, oscillopsia or somnolence . Howeve r , they all deve loped unsteadiness early in the course of the dis- ease, and examina t ion invariably displayed an ataxic gait. Clinical progress ion was very rapid and in 2 weeks f rom admiss ion they showed behav ioura l changes, de- ment ia and myoc lon ic jerks.

Pa t ien t 5 (sporadic CJD) was admi t ted due to be- havioura l changes, rapidly fo l lowed by left dystonia. Later , his r ight side b e c a m e dystonic, and this was ac- c o m p a n i e d by general ised myoc lonus and f rank de- mentia . Examina t i on also disclosed exaggera ted re- flexes, with clonus, m o r e evident on the left.

Initial symptoms, e l ec t roencepha lograph ic findings and CSF b iochemis t ry are summar i sed in Table 1.

Imag ing results (Table 2)

Computed tomography

All five pat ients showed cerebral atrophy, obviously progressive in three (patients 1, 3, 4) (Fig. 1). These pa- tients had vo lume loss in the cauda te nuclei, with p rominen t en l a rgemen t of the f rontal horns in two cases (patients 1, 4) (Fig. 2). They had the mos t striking corti- cal atrophy. All imaging studies showed variable vo lume loss in the white matter . Like cauda te nucleus atrophy, this was m o r e p r o m i n e n t in pat ients with m a r k e d corti- cal shrinkage.

In no case did we see any abnormal i ty of cortical density. Pat ient 2 had progress ive dense loci in bo th lent i form nuclei, suggestive of calcification (Fig.3).

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Fig.1 aNormal CTofa 10- year-old boy (patient 1) a few days after posterior cranial fos- sa surgery for cerebellar astro- cytoma. A dura mater graft was implanted, b After 8 years, the patient developed Creutzfeldt- Jakob disease (CJD). This study, done some months after the onset, shows striking corti- cal shrinkage and ventricular enlargement. The white matter is of low density, mainly in the peritrigonal regions, and there are bilateral subdural effusions, of higher density than CSE CT some months previously re- vealed less obvious atrophy and minimal subdural fluid collec- tions, without obvious white matter involvement

Fig.2 Axial CT of the same patient as in Fig. 1, showing marked caudate nucleus atro- phy and frontal horn enlarge- ment

Fig. 3 CT in a 56-year-old wo- man (patient 2) treated 3 years previously for a Chiari malfor- mation, with a dura mater graft. Note mild brain atrophy and lentiform nucleus calcification; the latter cannot be attributed to CJD and is probably a chance association

Another (patient 1) developed low density in periven- tricular white matter, more obvious close to the tri- gones and occipital horns in the last stages of the dis- ease (Fig. 1).

Two patients (nos. l , 4 ) developed subdural fluid collections during the evolution of the disease. Both had prominent brain atrophy. The density of the fluid collections was slightly higher than that of CSF (Fig.1 b).

Magnetic resonance imaging

The four patients studied by MRI showed cerebral at- rophy as on CT. No additional features were encoun- tered with regard to brain atrophy.

Midfield MRI (patients 4, 5), showed bilateral, sym- metrical abnormal high signal in caudate nuclei and

putamen on intermediate and T2-weighted images in patient 5 only (Fig. 4). The cortical signal was not obvi- ously abnormal, although some doubtful high signal was seen on proton density images (Fig. 5 a). The same im- age analysed with a narrow window showed a striking difference in cortical signal between the hemispheres (Fig. 5 b). None of the control group showed a similar asymmetry. SPECT, under taken 13 days previously, showed a clear flow defect in the same region (Fig. 5 c). White mat ter signal was interpreted as normal in this case. Intermediate and T2-weighted images of patient 4 were difficult to assess because of movement artefacts caused by the patient 's myoclonic jerks. Tl-weighted images were normal in both patients.

With low-field MRI (patients 2 and 3), no additional abnormality was discovered.

Patient 1, who had white mat ter density abnormali- ties on CT, did not undergo MRI.

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Fig.4 a Intermediate weight- ing MRI (TR 2000/TE 40) of a 51-year-old man with sporadic CJD (patient 5). Symmetrical high signal is seen in the head of both caudate nuclei, b T2- weighted image (TR 2000/ TE 100) in the same patient. The putamina also give high signal. There is no significant high signal from either globus pallidus or the thalamus

Fig. 5 a Proton-density weigh- ted MRI (TR 2000/TE 40), pa- tient 5. Only dubious high sig- nal may be seen in the right hemisphere, b The same image but with a very narrow window (width 6, level 147). Higher sig- nal is evident in the right cere- bral cortex, c SPECT show a paucity of flow coincident with the region of high signal in b

M R I of pat ient 4 showed a subdural fluid collection, which gave higher signal than CSF with all sequences. Patient 1, who also had a subdural collection, was not examined by MRI.

Discussion

Sporadic CJD begins clinically in middle-aged or prese- nile patients [8] and only exceptionally in patients tess than 33 years of age [9]. It is characterised by rapidly progressive dementia , associated later with myoclonus and a typical E E G pat te rn [8], but does not always fol- low the same course, and may present in several forms [10]. Ia t rogenic CJD tends to present in younger pa- tients. I t has been described following a t rea tments such

230

as the use of hormones obtained from pooled cadaver pituitary glands, surgery (mainly neurosurgery) and im- plantation of cadaver dura mater grafts [1]. Iatrogenic cases seem to foIlow a different clinical course, similar to the ataxic form of the disease [11]. These different clinical presentations, together with the variability of the EEG changes and the lack of specificity of the CSF results [8], give neuroimaging an important role in the diagnosis of these patients.

Macroscopically, CJD is characterised by cerebral atrophy, more prominent in advanced disease [8]. CT and MRI seem both to parallel this pathological finding [9, 12-17]. The atrophic process varies in individual cases, showing striking discrepancies in patients with similar disease duration, as in our patients 1 and 2. Nor- mality has even been reported as the most frequent finding [18]. In patients with extreme atrophy, subdural fluid collections have been described [16]. Our experi- ence differs in that both CT and MRI suggested that the subdural fluid, rather than being a hygroma, had a chronic haemorrhagic component.

Changes in CT density and MRI intensity character- istics may express the microscopic findings of the dis- ease: neuronal loss, astrocytosis, gliosis and spongiform neuronal degeneration [19]. Many reports indicate nor- mal CT densitometry in CJD [9, 12-16, 18], but recently bilateral occipital low signal [191, and diffuse periven- tricular low density in a case of a panencephalopathic CJD variant [20] have been described. As in the latter, the diffuse white matter low density seen in one of our patients might well represent the panencephalopathic type. However, secondary demyelinitation, due to neu- ronal damage in the final stages of the disease is much more frequent [8]. Without postmortem examination of the brain, we cannot distinguish the panencephalopathic form from secondary demyelinitation. Although proba- bly incidental even in a patient below the age at which basal ganglia calcification is common [21], lentiform nucleus calcification in one of our cases might possibly be related to CJD.

On MRI, brain atrophy has also been the only re- markable feature in some cases [14, 16], in which the magnetic field used in three patients was low (0.17T) [14], while in another case, its strength was not given [16]. Our finding only brain atrophy in patients studied with low-fieldmagnets is in keeping with previous re- ports. The latest MRI studies, with higher magnetic fields [17, 19, 22-28], have shown new features, consist- ing of signal abnormalities reflecting the histopatholog- icat findings. These include symmetrical high-signal ab- normalities on T2-weighting, of four types: in basal ganglia only [23-25], basal ganglia plus thalamus and cortex [22, 26], cortex with or without subcortical white matter [19, 27] and, in cases of the panencephalopathic variant, periventricular white matter with or without grey matter abnormalities [17, 28]. Changing the image

window width, we detected asymmetrical cortical in- volvement in one patient, The fact that our study was carried out at an early stage of the disease may explain unusual, subtle cortical findings, only visible using a very narrow window. Despite the frequency of deep grey matter changes, in all cases in which histology was spe- cifically reported, the absence of signs of cortical dam- age on MRI did not indicate pathological sparing of the cortex [24, 25, 29].

An interesting feature is the absence of abnormal signal in three of our iatrogenic patients and in reports of CJD in dural graft recipients [30-33]. In all these cases, MRI was normal or showed moderate cerebral and cerebellar atrophy only. In no case in the literature was the magnetic field strength reported. Our iatrogenic patients were examined with low field systems. The pathological descriptions of reported cases [32, 33] show marked grey matter involvement, as in classic CJD. It is therefore difficult to interpret the significance of the absence of abnormal signal, as we know neither if those patients did not have signal abnormalities at some stage, nor what magnetic field strength was used.

Based on previous reports and our own experience we may conclude that the clinical variability increases the value of imaging for the diagnosis of CJD and that MRI emerges as a more sensitive tool than CT for this purpose. Low-field magnets have not proved superior to CT in CJD; on the contrary, mid- and high-fields have been shown to be more sensitive, and must be preferred for the investigation of CJD In addition to the more usual bilateral high-signal changes in the basal ganglia in cases of diffuse grey matter disease [23-25], subtle cor- tical impairment might be demonstrated on early MRI if images are also assessed with very narrow windows, mainly when there is some laterality to the clinical manifestations. Mid- and high-field MRI might also contribute to identifying other clinical CJD variants in the early stages of the disease [17, 19, 28]. Although it has been suggested that MRI could help the neurosur- geon choose the target for cerebral biopsy [25], there is an apparent disproportion between imaging findings and the extent of the disease; for this reason it might be sufficient to take a frontal biopsy regardless of the site of changes on MRI. The possible imaging difference between sporadic and iatrogenic CJD is a question open to future investigation.

The only way to establish the diagnosis of CJD is by histological verification [4, 8]. CT and MRI are not de- finitive, although they may be highly suggestive of the diagnosis in the presence of the appropiate clinical fea- tures.

Acknowledgements We are very grateful to Mr. Luis Martfnez- Lozano Molina for reviewing our English.

231

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