Isolated language impairment as the primary presentation ...



Title:

Isolated language impairment as the primary presentation of sporadic Creutzfeldt Jakob Disease

Authors:

• Salwa El Tawil, MD

E mail: Salwa_eltawil@

National CJD Research & Surveillance Unit, University of Edinburgh, Edinburgh, UK

• Gurjit Chohan, MD

E-mail: gurj21@

National CJD Research & Surveillance Unit, University of Edinburgh, Edinburgh, UK

• Jan Mckenzie

E mail: jan.mackenzie@ed.ac.uk

National CJD Research & Surveillance Unit, University of Edinburgh, Edinburgh, UK

• Anne Rowe

E-mail: Anne.Rowe@nhslothian.scot.nhs.uk

Department of Clinical Neurosciences, Western General Hospital, Edinburgh, UK

• Belinda Weller

E mail: B.Weller@ed.ac.uk

Department of Clinical Neurosciences, Western General Hospital, Edinburgh, UK

• Robert G. Will, FRCP

E-mail: r.g.will@ed.ac.uk

National CJD Research & Surveillance Unit, University of Edinburgh, Edinburgh, UK

• Richard Knight, FRCP

E mail: R.Knight@ed.ac.uk

National CJD Research & Surveillance Unit, University of Edinburgh, Edinburgh, UK

Corresponding Author

Professor Richard Knight

E-mail:

R.Knight@ed.ac.uk

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

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

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

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 (1). There is significant clinico-pathological heterogeneity in sCJD and atypical presentations exist, complicating early diagnosis (2, 3). 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) (4-6) and the Heidenhain form (pure visual onset) (7) (8), but other forms of focal presentation such as deafness, (9) (10) or monoparesis (11) 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 (6, 7).

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.

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 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 into definite, possible and probable sporadic CJD according to WHO criteria (12). The methodology of the unit has been described in detail elsewhere (13).

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 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 (14). 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 (2)).

DISCUSSION

Aphasia is a common symptom in sporadic CJD, occurring at some point in the illness in 40 to 60% of cases (15, 16). Aphasia at disease onset is much less common, occurring in 3-8 % of cases in series where initial symptoms were reported (15-18) . 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 (17, 19).

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 (20, 21). 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 (22-27) (28) 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 (29). 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(24, 30), 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 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 (23, 27, 31)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 (32). A good correlation between focal neurological abnormalities and lateralized EEG changes was previously shown in patients with sporadic CJD (33). 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 (22).

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.

Acknowledgements

Conflict of interest: none

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