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Cerebral and cerebellar atrophy on serial magnetic resonance imaging in an initially symptom free subject at risk of familial prion disease

BMJ 1997; 315 doi: https://doi.org/10.1136/bmj.315.7112.856 (Published 04 October 1997) Cite this as: BMJ 1997;315:856
  1. N C Fox (n.fox{at}ion.bpmf.ac.uk), research fellowa,
  2. P A Freeborough, physicista,
  3. K F Mekkaoui, research assistanta,
  4. J M Stevens, consultant neuroradiologista,
  5. M N Rossor, consultant neurologista
  1. a Dementia Research Group, National Hospital for Neurology and Neurosurgery, London WC1N 3BG
  1. Correspondence to:Dr Fox
  • Accepted 3 February 1997

Introduction

Prion diseases are transmissible neurodegenerative conditions which occur in sporadic, acquired, or inherited forms. Sporadic Creutzfeldt-Jakob disease presents as a rapidly progressive dementia with myoclonus, most patients showing characteristic pseudoperiodic complexes on electroencephalography. A new variant of Creutzfeldt-Jakob is characterised by a younger age at onset, longer survival, and non-specific initial symptoms including behavioural changes, dysaesthesias, and ataxia but without the expected electroencephalographic changes.1 Some of these features are also found in 5-15% of all cases of the inherited forms of Creutzfeldt-Jakob disease and are associated with mutations in the prion protein gene.2 We report the case of a woman with a family history of prion disease in whom progressive cerebral and cerebellar atrophy was seen when two magnetic resonance scans were compared using registration.

Case report

A 42 year old woman from a family with histologically confirmed prion disease entered a study of symptom free subjects. She had no complaints of physical or cognitive problems and her lack of symptoms was confirmed by her family. Neurological examination and neuropsychometry gave normal results. She scored 29/30 on the mini-mental state examination. Her magnetic resonance scan was interpreted, by a neuroradiologist (JMS) blind to clinical details, as showing widening of cortical sulci, particularly those of the parietal lobes. In T2 weighted images there were no obvious abnormalities.

Nine months later she reported that her balance was not normal and that her legs felt stiff. Over the next six months her balance deteriorated and her family noticed that she was emotionally labile. She was referred for neurological evaluation after a fall. She had a broad based ataxic gait, dysarthria, and jerky pursuit eye movements. No myoclonus was observed; tone, power, and tendon reflexes were normal. She scored 29/30 on the mini-mental state examination. Neuropsychometry showed a decline only in verbal recognition memory and comprehension of abstract words. Laboratory investigations and electroencephalography gave normal results. A magnetic resonance scan showed diffuse atrophy of all elements of the brain including the caudate nucleus, the thalamus, cerebellum, and pons. There was again no detectable signal change in the basal ganglia. A diagnosis of hereditary prion dementia was confirmed by finding a point mutation at codon 102 of the prion protein gene (PrP Leu 102).

The first two magnetic resonance scans were registered and atrophy was detected by subtraction of the second scan from the first.3 The figure shows points of signal loss >20% of the mean (atrophy) in red and points of signal gain in green. Atrophy was widespread, with a total loss of cerebral tissue of 45 ml (4.3% of total brain) and of cerebellar tissue of 9 ml (7.9%).

Figure1

Coronal slice from initial magnetic resonance scan overlaid in red to show tissue loss that had occurred in second scan. Green overlay shows points of signal gain in second scan

Comment

Neuroimaging may show atrophy in established prion disease, but magnetic resonance imaging gives normal results in almost 50% of cases.4 Signal changes in the basal ganglia on T2 weighted imaging may be a distinctive early sign of Creutzfeldt-Jakob disease,5 but in one study such signal abnormalities were reported in only 4 out of 96 cases.4

Presymptomatic parietal atrophy was seen in our patient's first magnetic resonance scan, but the appearance of the parietal sulci generally varies widely. In contrast, rapidly progressive cortical and cerebellar atrophy was seen when the scans were compared using registration. The rate of brain atrophy was much greater than that in normal aging and rapid even for Alzheimer's disease. The pattern of atrophy, affecting the cerebellum and sparing medial temporal structures, differed from that in Alzheimer's disease, in which the cerebellum is usually unaffected.3 The rapid cerebellar atrophy was consistent with the clinical symptoms which included ataxia—often an early feature in familial prion disease associated with the leucine 102 mutation of the prion protein gene. It is also common in iatrogenic and new variant Creutzfeldt-Jakob disease. The technique of registration of serial volumetric magnetic resonance images may prove helpful in diagnosing neurodegenerative disorders.

Acknowledgments

We thank the family members who generously participated in the longitudinal studies.

Funding: NCF holds an Alzheimer's Disease Society research fellowship; PAF and KFM are supported by the Charles Wolfson Charitable Trust.

Conflict of interest: None.

References

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