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Case 1

57 year old right handed man. Family history negative for neurological or cognitive disorder.
Birth and early development were unremarkable. He was schooled until the age of 15 and
trained as an electrician. He had always worked as an electrician, most recently in a printing
works. He has not worked for several months because of the difficulties with memory and
job performance.

He is previously fit and well with no vascular risk factors.

Cognitive problems date back less than 9 months according to him and his brother in law. He
describes difficulties with remembering how to carry out tasks, like fixing printing machines.
He described an instance where he wired up a printing machine in the wrong way. Previously
he would be able to carry out jobs in the plant without any form of prompt, but recently has
had to write everything down. He has also developed a tendency to lose things, particularly
tools. There was no suggestion of particular problems with language function or praxis. He
became more hesitant in his manner according to his brother in law, without any more marked
behavioural changes. His mood had been low, and he had lost some weight. He would sleep
more during the day and sleep normally at night. There were no psychotic features.

Neurological examination was unremarkable.

• What is the diagnosis?

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NEUROPSYCHOMETRY

Cambridge score 72/100 MMSE 27/30 (0/3 one minute recall)

NART estimate of premorbid FSIQ: XX

WAIS: FSIQ XX VIQ XX PIQ XX

WAIS scaled subtest scores

Information XX Picture completion XX


Digit Span XX Picture Arrangement XX
Vocabulary XX Block Design XX
Arithmetic XX Object Assembly XX
Comprehension XX Digit symbol XX
Similarities XX

WMS indices

Verbal memory XX
Visual memory XX
General memory XX
Attention/concentration XX
Delayed recall XX

• Does the neuropsychometry help?

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Investigations

• MRI. Essentially normal. Minimal possible cortical atrophy with preservation


of hippocampal volumes and no signal change.

• EEG normal

• Screening blood tests normal

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Discussion

1. This patient has an early organic dementia with symptomatic deficits in new
learning and anterograde memory.

2. Notice that the MMSE exam score is above the cut off score typically used to
identify cognitive disorder (24) whilst the Cambridge assessment yields a score that is
below the cut off used to predict cognitive disorder (84). The Cambridge assessment
incorporates additional tests of verbal fluency, new learning and delayed recall that
are useful in helping to pick up early dementia. The Cambridge assessment is
therefore more sensitive than the MMSE. Both MMSE and Cambridge assessment
have sensitivities of 96% but the sensitivity of the two tests is 52% and 82%
respectively (based on the cut offs above and a population of patients referred to the
Cognitive Clinic in Cambridge.

3. XXX Neuropsychology discussion

4. He has clinically probably AD according to NINCDS-ADRDA criteria with deficits


in memory and at least one other domain.

5. The NINCDS-ADRDA criteria are rather broad research criteria and also often
apply to other forms of dementia, especially Lewy Body dementia. In this case there
are no operational criteria to support that diagnosis. There are no features to suggest
the multi infarct form of vascular dementia although the distinction between vascular
dementia and AD can be very difficult clinically, radiological and pathologically.

6. In terms of imaging for early-onset dementia I think all patients should have at least
a CT scan, primarily to exclude a structural lesion such as frontal meningioma. In AD,
MRI research studies using volumetric analyses demonstrate hippocampal atrophy
followed by atrophy of other areas, but in early cases the MRI is often normal based
on a standard qualitative report. I do not think that SPECT is needed in most early-
onset cases of dementia and I reserve it for cases where 1) I am not sure if there is an
organic dementia or not and 2) when I want evidence as to whether the patient has a
frontotemporal dementia as opposed to one of the other types (when the distribution
of perfusion deficit is helpful).

7. The main use of the EEG in early-onset dementia is to provide supportive evidence
for the presence of an organic dementia, when slow wave changes will be present.
These are not specific, being present in most forms of dementia, and follow treatment
with a number of drugs. There is argument about whether the EEG can help
distinguish AD and other forms of dementia. I am not enthusiastic, especially in
clinical practice where you want single-subject inference rather than group
differences. The EEG can be normal in many cases of early-onset dementia. The
periodic complexes in CJD are specific, but often not present. Do not forget to tell the
EEG department if this is an issue as they will need to use disposable electrodes.

8. I do not think there is a role for routinely assessing mutations of Amyloid Precursor
Protein (APP), Presinilin (PrS), or ApoE ε4 in clinically probable early-onset
Alzheimers disease. I carry out occasional assays for APP and PrS if there is good
evidence for an autosomal dominant family history. In that case I only carry out the

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assessment after consultation with the genetics service who are able to counsel and
screen families after identification of index cases.

9. The definitive diagnosis of AD can only be made at autopsy. The hit rate using
current criteria during life is about the same as in idiopathic Parkinson’s disease,
about 80%.

Refs

Hodges JR and Graham NL. Vascular dementias. Chapter 14 in: Early-onset


dementia. A multidisciplinary approach. (Editor Hodges). Oxford: OUP, 2001.
Mathuranath PS, Nestor PJ, Berrios MD, Rakowicz W, Hodges JR. A brief cognitive
test battery to differentiate Alzheimer's disease and frontotemporal dementia.
Neurology 2000; 55: 1613-1620.
McKeith IG, Perry RH, Fairburn AF, Jabeen S, Perry EK. Operational criteria for
senile dementia of Lewy body type (SDLT). Psychol Med 1992; 22: 911-922.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical
diagnosis of Alzheimers disease: report of the NINCDS-ADRDA Work Group under
the auspices of Department of Health and Human Services Task Force on
Alzheimers's Disease. Neurology 1984: 939-944.

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Case 2

58 year old right handed man. Family history negative for cognitive or other
neurological disorders. Premature birth with no clear index neurological event
otherwise. Degree in civil engineering and work as an engineer until just before
assessment. Previously fit and well and moderate alcohol drinker.

Cognitive symptoms noticed over 10 - 12 months before presentation with


progression according to the patient and his wife. He noticed a deficit in memory so
that he found it difficult to remember what he has to do over the course of the day
unless he wrote it down. There was also a tendency to misplace things. He has found
it increasingly difficult to manage at work, for example losing simple computer skills
and failing to acquire new ones. Word finding difficulty was a particular problem for
him and he noticed that the speed of his reading slowed down and that he had
difficulty with writing in addition. No history to suggest difficulty with arithmetic, left
right disorientation or apraxia. Planning abilities for simple domestic tasks were also
affected.

The main problem that his wife had noticed was the progressive difficulty with speech
with agrammatic non-fluent effortful output. No change in his behaviour noticed by
his wife. He did not describe any depression or biological features of depression. The
pattern was of clear-cut progressive deterioration in clear consciousness with no
diurnal or other variation. No accompanying neurological symptoms, hallucinosis or
psychotic features.

Screening cognitive assessment including the Cambridge assessment revealed striking


abnormalities in memory and in several cognitive domains. He was fully oriented
with poor working memory (digit span forwards four) and short-term memory.
Language comprehension was impaired for two and three step commands whilst
repetition was also impaired and he had a non-fluent agrammatic output. Naming was
preserved. Reading was intact and writing of a single sentence normal, but detailed
assessment of writing did demonstrate agrammatism. His drawing was strikingly
impaired with him being unable to copy even simple figures.

Neurological examination revealed no abnormality in the cranial nerves. In the limbs


he had symmetrically rather brisk reflexes with downgoing plantar responses. There
were bilateral palmomental reflexes with no other frontal release signs. There were no
extrapyramidal features or myoclonus.

• What is the diagnosis?

6
NEUROPSYCHOMETRY

Cambridge score 57/100 MMSE 20/30

NART estimate of premorbid FSIQ: 120

WAIS: FSIQ 87 VIQ 95 PIQ 77

WAIS-R scaled subtest scores

Information 15 Picture completion 8


Digit Span 5 Picture Arrangement
Vocabulary 13 Block Design 7
Arithmetic 8 Object Assembly
Comprehension 10 Digit symbol 3
Similarities 6

WMS indices

Verbal memory 65
Visual memory <50
General memory <50
Attention/concentration <50
Delayed recall 51

• Does the neuropsychometry help?

7
Investigations

• CT and MRI showed diffuse atrophy affecting frontal temporal and parietal
lobes particularly

Coronal T1 weighted section through parietal cortex showing parietal and temporal atrophy (latter
more marked on left) and slight ventricular enlargement

• EEG showed intermittent slow wave activity

• CSF and screening blood tests normal

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Discussion

1. This patient has a more aggressive organic dementia than case 1. He has a decrease
in VIQ and PIQ compared to his premorbid achievement and estimated premorbid IQ
(likely to be higher than the estimate because he has presented rather late with a
moderate dementia). The decreased performance compared to verbal index (even
despite the symptomatic and observed language deficit) is typical of Alzheimer’s
disease (AD) and a number of other types of dementia. The WMS shows striking
difficulties in memory and attention.

2. He has clinically probably AD according to NINCDS-ADRDA criteria with deficits


in memory and at least one other domain (in his case there is evidence of an effect on
multiple domains including language and visiospatial skills). The deficit in new
learning and anterograde memory come first in AD (learning of the name and address
and five minute recall in the Cambridge schedule) and working memory (digit span
which is affected here) is not affected until a later stage.

3. The rapidity of progression and presentation with predominant language symptoms


here are atypical for AD. Twenty percent of cases of Primary Progressive Aphasia
(defined on the basis of a non-fluent output aphasia in the absence of accompanying
cognitive deficits for at least two years) turn out to have AD pathology. He does not
meet criteria for Primary Progressive Aphasia due to the early prominent memory and
visiospatial symptoms.

7. I do not carry out lumbar puncture on all patients presenting to the cognitive clinic,
but did so here because of the atypical features and rapid progression. This is mainly
to seek evidence for an inflammatory basis or vasculitis, and to allow 14-3-3 protein
testing in a small number of patients where there is a strong suspicion of CJD.

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Case 3

Transfer from one of the local hospitals two months after admission there. 59 year old
right handed man with no family history of cognitive or neurological disorder and no
index neurological event. He previously worked as an RAF flight sergeant. There was
a background of hypertension and a question about his previous alcohol intake. This
was recorded in the notes as being at a level of 70 or 80 units per week at one time but
this was not corroborated with his family.

He had a stroke two years before assessment when he was found to have a
haemorrhagic right frontal and temporal infarction from which he recovered well. He
had a single blackout of unclear cause one year before assessment shortly after return
from a trip to Goa, with no events after that to suggest generalised or partial seizures.
The current admission followed presentation to his local hospital in a confused state
after return from another trip to India. His money and credit cards had been stolen
and he had no recollection of the events whilst he was in India. He was disoriented
and had nystagmus on admission to the referring hospital.

During his admission to the referring hospital he had been agitated and restless and
exhibited repetitive motor behaviour such as pacing and repeatedly going to the toilet.
He had been disoriented in place, thinking that he was at his friend’s house and he
repeatedly tried to leave the ward. He needed to be prompted about meal times and
would forget that he had had a meal within one hour. His memory of events from one
day to the next was very poor. There were reports of auditory and visual
hallucinations and he expressed a number of abnormal beliefs including the belief that
he was still in the RAF. According to his care assistant his conscious level had not
shown any marked fluctuation over time over the last month and there had been little
change in his memory capacity.

Cognitive assessment at transfer revealed him to be disoriented as to the date, day,


and month. He knew he was in hospital but thought that he was still in the referring
hospital. Testing of verbal working memory revealed a normal forward digit span of 6
and a reverse span of 4. One-minute recall of three objects was 0 without cueing and 2
out of 3 with cueing and his five-minute recall of an address was 0. He thought the
current Prime Minister was Attlee, and when told that this was in fact Tony Blair he
claimed that he had met him and that Tony Blair was an Ophthalmologist. He thought
that the current President of the USA was Kennedy. Verbal and category fluency over
one minute were 10 and 8 respectively with some perseveration. Language
comprehension and repetition was normal though he made 2 out of 10 bizarre errors
on testing of naming, saying that a pig and a barrel were a polar bear and a car
respectively. Drawing was adequate. Proverb interpretation was markedly concrete
and he failed on tests of sequencing including the Luria 3-step and Oszeretski.

Neurological examination on initial assessment by our service revealed nystagmus on


right and left lateral gaze with a lateral and horizontal component. Lower cranial
nerve testing and limb examination were normal and there were no frontal release
signs.

• What is the diagnosis?


• What is the prognosis?

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Investigations

• MRI showed changes consistent with the old right frontotemporal infarction

• EEG normal

• Lumbar puncture showed raised protein on two occasions two months apart
(0.98 g/L and 0.74 g/L). Sample as acellular and negative for oligoclonal
bands

• FBC normal and MCV consistently less than 95 during admission

• Liver function tests normal during this admission

• Other normal or negative screening blood tests included HIV serology,


Malaria thick films, Lyme and syphilis serology, autoantibodies

• CXR normal

• Urinary screen for cannabis negative

• serum B12, red cell folate, red cell transketolase levels not available prior to
receiving a month of B vitamin supplements

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Discussion

1. Detailed neuropsychometry is not really needed here, and has not been supplied.
The striking confabulation actually made formal neuropsychometry extremely
difficult.

2. This patient has marked anterograde and retrograde memory disturbance


accompanied by confabulation with some historical psychotic features. This is
accompanied by historical and examination findings consistent with frontal lobe
dysfunction, without striking deficits in other cognitive domains. This syndrome is
entirely consistent with Korsakoffs Syndrome, and the raised csf protein is also
consistent with that. There was a question about whether the known previous right
frontal and temporal damage would be an adequate explanation for his current state; it
is not. We also considered a limbic encephalitis, which can produce a marked
disturbance of recent memory; there were no supportive features like affective
disturbance or positive oligoclonal bands and a screen for cancer was negative. There
was no evidence on the MRI of a dienecephalic stroke, which can also produce an
amnesic syndrome, and the findings do not suggest any other form of metabolic or
toxic disturbance.

3. In terms of recovery this is still possible in such cases after several months. In
studies by Victor a quarter recovered completely on thiamine, a half showed partial
recovery and the rest showed no recovery. Recovery can be delayed for months and
can take up to two years if it does occur.

4. The aetiology of Korsakoff’s is likely to be more complex than classical


explanations based on pathology in basal brain structures including the mamillary
bodies. Structural imaging of alcoholics with and without an amnesic syndrome
suggests more widespread lesions in the former. In terms of confabulation, studies of
(non-alcoholic) patients with lesions suggest the importance of the involvement of
medial frontal structures (see Schnider and Ptak study). This patient’s lesion is
actually placed laterally in right frontal cortex, but his confabulation is so striking I
just wonder if the frontal lesion may have contributed. There is also functional
imaging work on normal subjects that might be relevant, suggesting a role for the
right prefrontal cortex in episodic memory retrieval.

Refs

Jacobsen RR, Lishman WA. Cortical and diencephalic lesions in Korsakoff's


syndrome: a clinical and CT scan study. Pyschol Med 1990; 20:63-75.
Schnider A, Ptak R. Spontaneous confabulators fail to suppress currently irrelevant
memory traces. Nature Neurosci 1999; 2: 677-681.
Victor M, Adams RD. The alcoholic dementias. In: Vinken PJ, Bruyn GW and
Klawans HL, editors. Handbook of clinical neurology, Series 2. Vol 46. Amsterdam:
Elselvier, 1985.

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Case 4

Initial assessement: 49 year old fully right-hand dominant woman with normal birth
and early history and no index neurological event. Schooling to the age of 16 after
which she has worked as a librarian, shop assistant and housewife. Family history
negative for neurological disorder or vascular disease. Non-smoker and occasional
drinker.

Her husband described a four-year history of cognitive symptoms before initial


assessment with no preceding neurological or cognitive symptoms. She has had a
difficulty with word finding over this time although it was very difficult to get a clear
idea of the pattern of progression from her or her husband. In addition she had a two-
year history of difficulty walking and one or two falls. She was apparently managing
the family accounts and going to the bank until three months before assessment and
also doing the shopping and keeping the house well. Her ability to carry out these
tasks deteriorated and her husband took them over. Her speech comprehension was
said to be good and her speech output had not noticeably changed according to her
husband. Her reading was slow but she has apparently always been a slow reader.
There have been no episodes of losing things and getting lost herself and no
aggressive outbursts. She was sleeping at night when first assessed but rather more
tired in the day and she had recent visual and auditory hallucinations in the early
morning. There was no fluctuation in her conscious level reported or reactions to
drugs (she had only had a short trial of a benzodiazepine before assessment).

Apart from a tendency to walk with a shuffling gait she had no other neurological
symptoms and she was systemically well.

Screening cognitive testing using the Cambridge schedule yielded a mini-mental state
examination score of 15 out of 30. She was disoriented with poor registration and
recall. New learning of a seven-item address was poor and she showed perseverative
errors, a tendency to mix items and phonemic paraphrasias. Language comprehension
and reading were good and her repetition for single words was normal but impaired
for phrases. Naming testing yielded a score of 7 out of 10 and her verbal fluency was
strikingly abnormal at zero. Her drawing was very poor.

Neurological examination revealed normal fields, fundi and eye movements. Lower
cranial nerve testing was normal. In the limbs she had normal tone with symmetrical
slightly depressed reflexes and bilateral downgoing plantar responses. There was no
finger nose dysmetria or gait ataxia. There were no primitive reflexes. She walked
with a shuffling gait which was not broad based with decreased arm swing. There
were no abnormal movements.

Assessment after 6 months of Rivastigmine treatment: Initial response to drug


described by her husband as ‘like a light being switched on’ meaning she had became
much more alert and showed more initiative to do things. Her motor symptoms had
progressed with the development of extrapyramidal tremor, decreased arm swing
bilaterally and extra-pyramidal rigidity of the arms. Her gait initiation was slow and
mild impairment of postural reflexes.

• What is the diagnosis?

13
NEUROPSYCHOMETRY

Cambridge score 44/100 MMSE 14/30

NART estimate of premorbid FSIQ: 95

WAIS: FSIQ 62 VIQ 64 PIQ 65

WAIS-R scaled subtest scores

Information 2 Picture completion 8


Digit Span 5 Picture Arrangement 3
Vocabulary 3 Block Design 2
Arithmetic 4 Object Assembly
Comprehension 3 Digit symbol 2
Similarities 5

WMS indices

Verbal memory 65
Visual memory <50
General memory <50
Attention/concentration <50
Delayed recall 51

• Does the neuropsychometry help?

14
Investigations

• MRI scan showed central and cortical atrophy with one or two small areas of
white matter signal change

Axial T2 weighted MRI section

• EEG showed slow wave activity

• Screening blood tests normal and negative tandem repeat for Huntington
mutation.

• csf examination showed minor excess of protein in the CSF (0.58g/l), negative
14-3-3 protein and s100b.

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Discussion

1. This patient has a moderately severe dementia and meets operational criteria for
Dementia with Lewy Bodies (DLB). She exhibits fluctuation in conscious level,
hallucinosis, and extrapyramidal symptoms and signs. There is a particular sensitivity
to neuroleptic medication in this group and increased incidence of neuroleptic
malignant syndrome (not relevant here).

2. In terms of the neuropsychometry she shows poorer WMS-R indices than the VIQ
and PIQ as might be present in a patient with AD of comparable severity.
Comparisons of groups of subjects with AD and DLB show poorer attention and
working memory in the latter. They also show poorer visiospatial skills. It is
important to point out that these cognitive features are based on group studies and it is
very difficult to point out in any subject, on the basis of the psychology alone,
whether either diagnosis is more likely.

3. The conscious level fluctuation might be a function of a greater effect of DLB on


the ascending cholinergic sysem arising from the nucleus basalis in the forebrain. In
turn this might be the reason for some of the spectacular responses to procholinergic
drugs (with increases in MMSE scores as well as symptomatic improvement) that
have been reported in DLB by McKeith and others. In this particular case the
response was entirely symptomatic, and not reflected in an improvement in repeat
neuropsychometry after six months of treatment (you might argue here that no
decrement is a good response in view of the previous rather aggressive course).

4. As in AD the definitive diagnosis can only be made on the basis of autopsy.

Refs

Calderon J, Perry RJ, Erzinclioglu SW, Berrios GE, Dening TR, Hodges JR.
Perception, attention and working memory are disproportionately impaired in
Dementia with Lewy bodies comapred with Alzheimers disease. J Neurol Neurosurg
Psychiatry 2001; 70: 157-164.
McKeith IG, Perry RH, Fairburn AF, Jabeen S, Perry EK. Operational criteria for
senile dementia of Lewy body type (SDLT). Psychol Med 1992; 22: 911-922.

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Case 5

86 year old right handed man with no family history of neurological or cognitive
disorder of which he was aware. No index neurological events or fits. He was
schooled until his teens at a secondary modern. He has had a variety of jobs including
managing a cinema and work as council planning department manager. He had a
history of several years of deterioration of walking and altered behaviour but he was
unaware of this when he was assessed in the cognitive clinic and he had no family to
corroborate the story. He has also had a history of possible TIAs. He volunteered no
vascular risk factors and was on aspirin when assessed.

The initial assessment was striking for him being disinhibited and showing echolalia
and perseveration.

Cognitive testing using the Cambridge Screen revealed him to be oriented to the year
and the season only with good registration but poor anterograde verbal memory (3/3
registration of three items but 0/3 1 minute recall even with cueing). There was
difficulty with strategy with new learning of a name and address, with the same score
based on different items over three attempts. Language comprehension was good,
repetition mildly impaired and naming also mildly impaired but he had a striking
deficit in verbal fluency with only two ‘p’ words in a minute and a tendency to
perserveration. Category fluency was also strikingly reduced with one neologism for
an animal he made up. Reading of regular and irregular words was normal but writing
strikingly impaired and his copying of figures was also mildly impaired.

Neurological examination revealed no abnormality in the cranial nerves apart from a


probable physiological limitation of upgaze and slowness of initiation of voluntary
lateral saccades. There was no bulbar or pseudobulbar palsy. In the limbs he had an
asymmetrical increase in tone, more marked on the right hand side and a tendency to
posturing of the right upper limb with additional stimulus sensitive myoclonus. There
was no limb dysmetria. There was wasting of the intrinsics of both hands without any
fasciculation. Reflexes were symmetrical and normal with bilateral downgoing
plantars. His stance was normal with impaired postural reflexes forwards and
backwards and he had a shuffling gait with slow initiation, decreased armswing and
an increase in the posturing of the right upper limb. He had bilateral grasp, pout and
palmomental reflexes. Frontal sequencing was extremely poor and testing of praxis
revealed body part substitution for mime actions.

• What is the diagnosis?

17
NEUROPSYCHOMETRY

He was rather difficult to assess. For example, he sang four lines from the song ‘love
and marriage’ when asked to explain the similarity between love and hate

Cambridge score 48/100 MMSE 19/30

NART estimate of premorbid FSIQ: 111

WASI (abbreviated version of WAIS III): FSIQ 74 VIQ 71 PIQ 83

Other tests:

Very poor peformance on Hayling and Brixton tests of executive functioning. The
Hayling test is a sentence completetion task requiring subjects to complete a sentence
with a nonsense ending (and suppress a sensible one) The Brixton test is a visiospatial
sequencing task with rule changes.

• Does the neuropsychometry help?

18
Investigations

• MRI showed mild diffuse cortical atrophy, a left sided acoustic neuroma
without significant brainstem compression and a single infarction in the left
basal ganglia

• EEG showed no abnormality

• Screening blood tests normal

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Discussion

1. This patient suffered from the most striking frontal lobe syndrome I have ever seen,
in combination with an asymmetrical extrapyramidal syndrome and stimulus sensitive
myoclonus. In addition to the frontal features there is some dyspraxia. The diagnosis
is corticobasal degeneration and there is really no differential here. The
extrapyramidal syndrome is often associated with alien limb (not present here), and
the helpful feature is the asymmetry of the extrapyramidal syndrome that is only a
striking feature in idiopathic Parkinson’s disease, dementia with Lewy bodies and
this. The acoustic neuroma and peripheral wasting are not associated features.

2. Studies of the associated cognitive features are few but it can present as something
that might be called ‘progressive apraxia’.

Ref

Watts RL, Mirra SS, Richardson EP. Corticobasal ganglionic degeneration. In:
Marsden CD and Fahn S, editors. Movement Disorders 3. Oxford: Butterworth-
Heinemann, 1994: 282-299.

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