A Case of Unsteadiness and Limb Weakness

Dr Richard McCrory

CT2 Medicine

9th March 2011

Case Presentation: Mrs E.W. (1)

Previously fit and well 73 year old lady• Right Handed• Independently Mobile

Admitted from A&E Mater Hospital 27/8/2010

PC: 1 week history of dizziness, “clumsiness” (especially with the left hand) and unsteadiness on her feet.

Referral to A&E prompted by two falls in preceding 24 hours when trying to walk

Mrs E.W. (2)

PMHx:Hypertension (on Ramipril 2.5mg)Non-smoker, No alcoholElevated cholesterol (on Simvastatin 40mg)No recent head injury / traumaNo family history of neurological disorders

Systematic Enquiry:Collateral history suggested episodic

forgetfulness past 2 months, occasionally withdrawn and dropped crockery at home.

Initial assessment 27/8/10

CVS: Pulse 80 regular, BP 139/74 2HS no murmurs, no bruits, no postural BP drop

RS: Chest clearAbdomen: NAD

Neurological ExamDysarthric, slight loss nasolabial fold on leftPronator drift left arm, hypotoniaPower LUL 4+/5 LLL4+/5, mild truncal ataxiaImpaired co-ordination on left sideNo visual field defect, coarse nystagmus on

leftward gazeAbbreviated Mental Test - 8/10

Initial Investigations

ECG – Normal Sinus Rhythm

Bloods – All within normal range, ESR normal, TFT’s normal

CXR – Heart size normal, no lung field abnormalities

CT Brain (29/08/10)

Chronic Ischaemic Periventicular and deep white matter changes, no acute infarct seen. No bleed visible.

Initial Clinical Diagnosis - Left Cerebellar Stroke

Aspirin 300mg for 2/52

MRI Brain + Angiogram booked for assessment of posterior circulation

Trans-thoracic Echocardiogram – Normal structure and function, Normal Valves

Seen by PT/OT

Berg Score 30/8/10 – 32/56

Limited safety awareness, mobilised with assistance of 1 + ZF

But there’s more…

Week 2 of admission:

Limited progress with Physio/OT

Unsteady on feet

Apathetic / Withdrawn – started on SSRI

Safety awareness problematic, several IR1 forms re. falls at bedside, poor retention of information, tended to move unsupervised. MMSE 21/30

Week 3Choking intermittently on food

• SLT recommended pureed diet

Worsening dysarthria

Power LUL 3/5 LLL 4/5

Further ischaemia queried – switched to clopidogrel

Week 4Progressing truncal and neck ataxia

Deteriorating sitting balance, standing assistance of 2

Fell out of chair 21/9/10 attempting to stand despite repeated assertions to not mobilise independently

Sustained contusion and laceration to right scalp – no loss of consciousness

Repeat Berg Score - 4/56

21/9/10 Repeat CT Brain – no interval change

30/9/10MRI Brain and Angiogram

Bilateral Periventricular IschaemiaSeveral high signal changes in cerebellar

peduncles and left medulla on T2 images‘Unusual distribution’ but could correlate

with ischaemic changesNo vessel abnormalities

Started on LMWH for posterior circulation ischaemia

But there’s (still) more…

Week 5Only safe in bedUnintelligible speechDoubly incontinentEvolving right sided cerebellar signsDeteriorating swallow – referred to dietician for NG

tube and enteral feeds, and on IV fluidsRepeat bloods – no signs of infection / inflammation

Re-evaluated initial diagnosis and differential, proceeded to Lumbar Puncture

Investigations

Lumbar Puncture (09/10/10)• Clear colourless fluid• CSF glucose – Normal• Gram Stain and Culture – Negative• Cell Count – WCC 5 cells/mm3• CSF Protein elevated: 0.79g/dl (Normal range 0.1 –

0.3 g/dl), confirmed on repeat LP

ANCA/ANA/Serum ACE / Oligolonal Bands – Negative

HSV/CMV PCR on CSF - Negative

Sought Neurology advice from RVH

Advised

Check Anti-Neuronal Antibodies – sent to London

Breast Exam - Normal

CT Chest / Abdomen / Pelvis to seek occult malignancy

CT Chest/Abdo/Pelvis 19/10/10

• No evidence of mediastinal or para-aortic lymphadenopathy

• Lung fields and visceral organs appeared normal

• However a 2.5 x 1.7 cm soft tissue mass was identified in the right breast.• Plans made for transfer to BCH breast clinic for

triple assessment

• Became unwell with Tachycardia, Tachypnoea

• CXR noted new pulmonary filling defects consistent with consolidation

• Started Tazocin• Blood cultures positive for Methicillin

Sensitive Staph Aureus• Possible venflon associated infection• Switched to Vancomycin / Meropenem

Final Diagnosis –

Paraneoplastic Cerebellar Degeneration secondary to Primary B-Cell Lymphoma of the Breast

The Cerebellum – A Brief Overview of Functional Anatomy

• Archicerebellum – maintenance of equilibrium

• Paleocerebellum – muscle tone and posture

• Neocerebellum – muscular co-ordination

Paraneoplastic Neurological Syndromes

‘A humoral or immune-mediated mechanism other than a metastatic complication in patients with an underlying malignancy.’

‘Remote effect’ immune mediated CNS pathology affects 1-3% of all cancer patients.

Paraneoplastic cerebellar degeneration (PCD)

• Constitutes 25-35% of paraneoplastic neurologic syndromes diagnosed.

• Characterised by diffuse loss of Purkinje cells throughout the cerebellar cortex.

• Antibodies directed to Purkinje cytoplasmic and nuclear proteins regulating cell survival trigger apoptosis• Anti-Yo, Anti-Tr, Anti-Hu plus others• 40% no recognisable antibody identified

• In 60–70% of patients, neurological symptoms precede diagnosis of the cancer by a few months to 2–3 years.

Common Neoplasms associated with PCD• Breast and Ovary (Anti-Yo)• Small Cell Lung Cancer (Anti-Hu, Anti-Ri)• Lymphoma (Anti-Tr highly specific)

Clinical Features of PCD

• Mild unilateral cerebellar signs evolving (days-weeks) into severe bilateral cerebellar dysfunction, then symptoms stabilise with profound physical disability.• Mild cognitive deficits as well as

affective symptoms seen in 20% of cases (Cerebellar Cognitive Affective Syndrome)

A Large Diagnostic Differential

Cerebrovascular• Ischaemic or Haemorrhagic Stroke

Toxins• Alcohol / Chemotherapy / Anticonvulsants

Inflammatory Disorders• Multiple Sclerosis / Neurosarcoidosis

Encephalomyelitis

Intracranial Neoplasm• Primary CNS / Metastatic / Leptomeningeal

Neurodegenerative Disorders• Spinocerebellar Ataxia (Sporadic)• Prion Related Diseases

Findings not Consistent with paraneoplastic cerebellar degeneration

Include the following:• Severely altered mental status with

myoclonus and ataxia• Predominantly corticospinal tract

dysfunction• Unilateral cerebellar dysfunction• Familial cerebellar degeneration

Investigations

CT / MRI Brain may be initially normal

Cerebellar atrophy more pronounced in latter stages of disease

Lumbar Puncture

High CSF protein, Pleocytosis

Can identify auto-antibodies in CSF and help exclude leptomeningeal disease

CT / PET to look for occult malignancy

Treatment

Variable but generally unsatisfactory• Complete and Partial remission

possible but uncommon

Approach 1Remove antigen source (Tumour)

Surgery, Chemoradiotherapy as applicable

Approach 2 Suppress immune response

Steroids, Cyclophospamide, Rituximab

Prognosis

Commonly disability correlates with onset of treatment – ‘The Horse has bolted’

May require extended follow-up if occult malignancy suspected

Oncologic outcome of patients with antibody-associated paraneoplastic syndromes does not significantly differ from that of patients without syndrome.

Take Home Messages

• Consider a diagnosis of PCD in patients who present with acute or subacute cerebellar degeneration and no risk factors for cerebellar disorders

• Identification of specific auto-antibodies may help guide diagnostic assessment