isolated language impairment as the primary presentation ... · web viewisolated language...

Title:

Isolated language impairment as the primary presentation of sporadic Creutzfeldt

Jakob Disease

Authors:

Salwa El Tawil, MD

E mail: [email protected]

National CJD Research & Surveillance Unit, University of Edinburgh,

Edinburgh, UK

Gurjit Chohan, MD

E-mail: [email protected]


Edinburgh, UK

Jan Mckenzie



Edinburgh, UK

Anne Rowe


Department of Clinical Neurosciences, Western General Hospital, Edinburgh,

UK

Belinda Weller


1

Department of Clinical Neurosciences, Western General Hospital, Edinburgh,

UK

Robert G. Will, FRCP



Edinburgh, UK

Richard Knight, FRCP



Edinburgh, UK

Corresponding Author

Professor Richard Knight

E-mail:

[email protected]

Address:

National Creutzfeldt-Jakob disease Research and Surveillance Unit

Western General Hospital

Edinburgh

EH4 2XU

UK

Phone: +44 (0)131 537 3104

Fax: +44 (0)131 343 1404

2

Running Head: sCJD presenting as isolated dysphasia

Sources of Funding:

THE NCJDRSU is funded by the UK Department of Health and the Scottish Government Health

Department.

Conflict of interest: none

Word Count: 2545

Tables: 2

Figures: 0

3

ABSTRACT

Objectives:

Sporadic Creutzfeldt Jakob Disease (sCJD) is a neurodegenerative disorder that presents with

rapidly progressive encephalopathy associated with various neurological features, culminating in

akinetic mutism and death. Atypical cases, may cause diagnostic confusion. We described a series

of patients with sCJD presenting with isolated language impairment

Materials & methods:

We reported a patient with sCJD referred to the NCJDRSU, who presented with isolated language

impairment and subsequently identified all cases of sporadic CJD on the NCJDRSU database

(covering the years 1990-2012) with an isolated language impairment presentation.

Results:

Nineteen patients (11 females) with sCJD ( 1.19%of all patients) had an isolated language disorder

of at least 2 weeks duration as the first neurological symptom pattern. Mean age at onset was

68.28 years. No specific pattern of language affection was seen in these patients. Further

progression usually affected more than one neurological domain, with all patients eventually

developing cognitive decline and myoclonic jerks. The median duration of illness was four months.

CSF 14.3.3 was positive and S100b level was elevated in all patients in whom it was performed.

EEG and MRI showed typical features of sCJD in 6 patients each. Most patients showed MM

genotype of PRNP codon 129.

Conclusion

This study highlights the fact that isolated aphasia can be the first neurological symptom

approximately in 1% of patients with sCJD. The diagnosis is usually made with appearance of other

clinical features and investigation result, but in a small minority these may not be apparent for

relatively long periods.

Key words: sporadic CJD, rapidly progressive dementia, dysphasia

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INTRODUCTION

Sporadic Creutzfeldt Jakob Disease (sCJD) is an invariably fatal neurodegenerative disorder that

typically presents as a rapidly progressive encephalopathy with prominent cognitive impairment,

associated with various other neurological features, most characteristically cerebellar ataxia, visual

disturbance and myoclonus, culminating in akinetic mutism and death with a median disease

duration of around 5 months . There is significant clinico-pathological heterogeneity in sCJD and

atypical presentations exist, complicating early diagnosis . One particular diagnostic difficulty

concerns presentation with an isolated, or virtually isolated, focal clinical feature. The two best

documented such presentations of sCJD are the Brownell Oppenheimer form (pure cerebellar onset)

and the Heidenhain form (pure visual onset) , but other forms of focal presentation such as

deafness, or monoparesis have been reported. The typical onset in sCJD may involve prominence

of some focal features, for example, cerebellar, but these atypical cases present with such features in

isolation; there is no absolute definition of the period over which these features should be present in

isolation, but a period of at least two weeks has been used in previous publications .

In this study we report a patient with sCJD referred to the UK National CJD Research and

Surveillance Unit (NCJDRSU), who presented with an isolated language impairment. The

presentation of sCJD with focal language disturbance is insufficiently recognized. We subsequently

identified all cases of sporadic CJD on the NCJDRSU database (covering the years 1990-2012) with

an isolated language impairment presentation and here report their clinical features, investigation

results and neuropathological data. We determined the frequency in the UK of this unusual

presentation of sCJD and discuss its diagnosis.

5

CASE REPORT

The patient, a 65 years old man with unremarkable past medical history, presented shortly after

retirement with severe headaches concentrating around the right eye. At the same time the family

noticed minor speech problems such as using the wrong word, or saying something that seemed out

of context. This grew more noticeable over the following week. The patient knew what they wanted

to say, but could not get the words out. There did not seem to be any difficulties understanding

conversations and the patient could still read, although slower than normal. Writing was not

affected at this stage, and there was no clear evidence of memory problems or other cognitive or

behavioural disturbances. The headache resolved with no specific treatment. About 6-7 weeks later,

the patient started to have difficulty with balance, walking with a wide based gait, and had some

difficulties using hands in everyday tasks. At around 8 weeks of the illness, the patient was admitted

to hospital. The patient looked generally well with appropriate behaviour except for being slightly

less engaged with the examination and history taking than expected. The patient was well orientated

in time and place and the two main clinical features were a mainly expressive dysphasia and a

cerebellar disturbance (unsteady, wide-based gait, finger-nose ataxia and horizontal nystagmus).

Detailed language assessment, done 2 days after admission showed a marked expressive dysphasia

with occasional neologisms and perseverations. Phonemic errors were noted in spontaneous speech,

repetition and naming. The patient could count from one to 20 with prompting, reversing order at

times, and used one sentence “The son fall stool” for description of the cookie theft scene.

Comprehension was less severely affected; patient was able to follow verbal 2 step but not 3 step

commands. The patient could follow written 3 stage commands but showed phonemic errors in

reading aloud, could write single words, including naming pictures and writing the year, but showed

grammatical errors when attempting to write full sentences. The patient seemed frustrated by this

communication defect and tried to use other means to communicate. When reviewed again 10 days

later the patient could only follow single commands and could not follow simple conversations. The

patient responded to greeting but verbal output was largely non comprehensible sentences with only 6

a few clear words and there was repetition and perseveration. The patient was unable to name single

objects but could communicate through gestures.

Communication and mobility continued to deteriorate and the patient would sit in a chair for long

periods with eyes open but showed no response to the environment. Occasional myoclonic jerks

were noticed in the limbs as well as an excessive startle response to noise. About one month later,

the patient was bed bound and mute with increased tone in the limbs and positive grasp reflex.

Breathing was irregular. The patient died one week later, less than four months after onset of the

illness, as a result of acute bilateral bronchopneumonia.

Routine blood investigations during hospital stay were unremarkable, MRI of the brain showed

small old lacunar infarcts in the right basal ganglia and internal capsule regions but no other

abnormalities. EEG showed nonspecific diffuse slowing. Routine CSF analysis was normal but

showed a positive 14.3.3 test. Post mortem examination showed widespread spongioform

encephalopathy predominnalty of microvacuolar type, associated with significant neuronal loss and

gliosis. Immunohistiochemistry showed a poisitive reaction to prion protein, and Western blot

analysis showed protease resistant prion protein of type 1 isoform. The pathological findings

confirmed the diagnosis of sporadic CJD. PRNP analysis showed no pathogenic mutations and an

MM codon 129 genotype. There was no history of iatrogenic exposure relevant to CJD

DATABASE REVIEW

Methods:

The NCJDRSU was established in 1990 to monitor the incidence and pattern of CJD in the UK.

Cases are identified mainly by direct referral from neurologists. Whenever possible, suspected

patients are visited and examined by a neurologist from the unit. A detailed clinical history is

obtained from the patients relatives and supplemented by perusal of the primary and secondary

health care records, where available. All investigations including EEG, MRI, CSF, PRNP codon

129 and neuropathology are reviewed by NCJDRSU staff where possible. Patients are classified 7

into definite, possible and probable sporadic CJD according to WHO criteria . The methodology of

the unit has been described in detail elsewhere .

The database of referrals to the unit between May 1990 and 31 December of 2012 was searched for

patients with a diagnosis sporadic CJD (definite, probable or possible) in whom a language related

problem was documented as the first symptom. The unit records of these patients were then

reviewed to identify those in whom a language problem was the only neurological deficit for at least

the first two weeks of the illness. The study was approved by Ethics of Medical Research Sub-

Committee for Medicine and Clinical Oncology, Lothian Health Board.

Results:

The unit received 3017 referrals between May 1990 and December 2012. Of these 1506 were

diagnosed as sporadic CJD (1010 definite, 386 probable and 110 possible). Only 18 (1.19% ) had an

isolated language disorder of at least 2 weeks duration as the first neurological symptom 14 were

classified as definite, 4 as probable sCJD. Eleven were female and 7 male, with a mean age at onset

of 68.28(+/-5.08) years. The mean age of onset for all sporadic cases referred to the unit was 66.8

years.

The clinical features of these patients are summarized in table 1. The language problem was most

commonly described as word finding difficulties (11/18). Formal language assessment is reported in

the notes for only 6 of the 18 patients, and in all of them language was assessed after other

symptoms have appeared. In patients where detailed language assessment was performed, one

language domain such as receptive or expressive functions, reading or writing was more severely

affected.

The average duration from onset to the appearance of another symptom was 7.78 weeks (range 2 to

21 weeks). Despite the well-defined onset, further progression usually affected more than one

neurological domain. In 14 patients other disturbances in cortical functions followed including

memory disturbances, apraxia, visospatial disorientation and confusion. In three patients this was 8

associated with appearance of balance problems. In the remaining 4 patients the following

symptoms were right sided weakness (2 patients), left sided weakness (1 patients), and right sided

myoclonic jerks (1 patient).

All patients eventually developed cognitive decline and myoclonic jerks during the course of the

illness. Other manifestations included ataxia (12/18), pyramidal signs (extensor plantar responses

and/or lateralised weakness with asymmetrical tendon reflexes) (11/18), and rigidity (6/18). Visual

symptoms occurred in only 3. Six patients developed akinetic mutism. The total duration of illness

ranged from 12 to 124 weeks, with a median duration of 17 weeks (4 months) which is the same as

median duration of illness in all definite and probable sCJD cases referred to the unit. Four patients

(cases 1, 11, 16 and 18) had a disease duration that is significantly longer than median of all

patients, lasting more than 52 weeks.

CSF 14.3.3 was analysed thirteen patients, being positive in all with elevated S100b levels, ranging

from 0.62 to 5.79 ng/ml, in all 13 patients. An EEG was available in 16 of the 18 patients and

was reported to show periodic sharp wave complexes characteristic of sCJD in 8 patients. In cases

2 and 7, background slowing was noticed in the left hemisphere only in earlier EEG records, done 3

weeks and 5 weeks after onset respectively. Brain MRI was available for review by the NJCDSU

neuroradiologist in the unit in 13 of the 18 patients Of these, six patients showed the high signal on

basal ganglia or cortex in FLAIR and DWI sequences previously described in sporadic CJD .

FLAIR and DWI sequences were not available in four patients. MRI changes could not be clearly

correlated to symptoms, with no preferential affection of left frontal or temporal areas. PRNP codon

129 analysis was carried in 14 of the 18 patients: 12/14 were MM, and 2/ 14 were MV. No

pathogenic mutations were found. . PrPSc subtype was available in 8 cases (type 1 in 6 cases and

type 2A in two cases) In pathologically confirmed cases, the pathological features in our cases

were consistent with those expected based on PRNP codon 129 genotype and protein subtype ).

9

DISCUSSION

Aphasia is a common symptom in sporadic CJD, occurring at some point in the illness in 40 to 60%

of cases . Aphasia at disease onset is much less common, occurring in 3-8 % of cases in series

where initial symptoms were reported . The mean age of onset and median duration of illness for

the patients in the current study is comparable to that of the overall sCJD cases referred to the unit

and to previously reported figures .

Ten cases with isolated aphasic onset have been previously reported (summarized in Table 2). Two

further cases were reported, but with a family history suggestive of familial prion disease, although

PRNP mutation analysis was not available . The previously described cases are younger (mean age=

56.7+/-12.33, t=0.002), with a longer disease duration (median duration of 58 weeks) than our

cases, although the difference was not statistically significant. Difficulties with individual words

were the initial symptom in seven of the previous literature cases similar to our cases. Word

finding difficulty, however, is a nonspecific symptom and can reflect abnormalities in different

language related domains, as well as other cognitive problems such as agnosia or memory problems

. The progression of language defect is very variable and a specific pattern for CJD cases could not

be deduced from either the previously reported or our cases. Unfortunately, very detailed language

assessment was not always undertaken in our cases; this was an analysis of clinical data obtained

from routine clinical practice and UK CJD surveillance, not a study designed specifically to explore

language characteristics.

Illness progression usually involved more than one aspect of language and other cortical functions

before appearance of other features such as ataxia or myoclonus. Asymmetrical limb symptoms,

with earlier affection of the right side was seen in three of our cases (cases 6,10 and 12) and two of

the patients in literature, supporting earlier affection of the left hemisphere in these patients.

In most cases, rapid appearance of more global cognitive decline, other clinical manifestations and

investigation results led to the diagnosis of sCJD. However, some cases had a prolonged course in

which language disturbance was the predominant clinical manifestation. These are represented by 10

cases 1, 11, 16 and 18 in the our series. Two of these patients showed suggestive MRI changes and

CSF 14.3.3 was positive in the three cases were it was tested highlighting the value of these

investigations in the diagnosis of sCJD.

Three of the cases described in literature showed changes on brain imaging that were limited to or

more prominent in left frontal or temporal regions, but such correlation was not seen in our cases.

However, this may reflect the timing of MRI investigation in relationship to symptom onset, and the

quality of the scan, as some MRIs lacked FLAIR and DWI sequences . EEG changes appeared

earlier in the left hemisphere in cases 2 and 7 in this series as well as 7 of the cases reported in

literature. In the case reported by Cohen and co-workers focal EEG changes were consistent with

non-convulsive status epilepticus . A good correlation between focal neurological abnormalities

and lateralized EEG changes was previously shown in patients with sporadic CJD . In the current

group of patients changes were mostly nonspecific and were not helpful in establishing the

diagnosis at an earlier stage.

At autopsy, pathological changes were generalized in all studied cases, which is not unexpected as

pathological studies reflect terminal changes. One of the literature cases had pathological changes

limited to the left hemisphere, but this is highly exceptional .

This study highlights the fact that isolated aphasia can be the first clearly neurological symptom in

approximately 1% of patients with sporadic CJD . The later appearance of other clinical features

and investigation results facilitate the diagnosis of sporadic CJD in most cases, but in a small

minority these may not be apparent for relatively long periods. These patients pose a particular

diagnostic difficulty and a definitive diagnosis might not be reached in life.

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Acknowledgements

Conflict of interest: none

12

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