A case of unsteadiness and limb weakness

A Case of Unsteadiness and Limb Weakness Dr Richard McCrory CT2 Medicine 9 th 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 alcohol Elevated cholesterol (on Simvastatin 40mg) No recent head injury / trauma No 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disorders Systematic Enquiry: Collateral history suggested episodic forgetfulness past 2 months, occasionally withdrawn and dropped crockery at home.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 clear Abdomen: NAD Neurological Exam Dysarthric, slight loss nasolabial fold on left Pronator drift left arm, hypotonia Power LUL 4+/5 LLL4+/5, mild truncal ataxia Impaired co-ordination on left side No visual field defect, coarse nystagmus on leftward gaze Abbreviated 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But there’s more… Week 2 of admission: Limited progress with Physio/OT Unsteady on feet Apathetic / Withdrawn – started on SSRI Safety awareness problematic, several IR1 forms re.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 3 Choking intermittently on food SLT recommended pureed diet Worsening dysarthria Power LUL 3/5 LLL 4/5 Further ischaemia queried – switched to clopidogrel Week 4 Progressing 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 30/9/10 MRI Brain and Angiogram Bilateral Periventricular Ischaemia Several high signal changes in cerebellar peduncles and left medulla on T2 images ‘ Unusual distribution’ but could correlate with ischaemic changes No vessel abnormalities Started on LMWH for posterior circulation ischaemia

But there’s (still) more… Week 5 Only safe in bed Unintelligible speech Doubly incontinent Evolving right sided cerebellar signs Deteriorating swallow – referred to dietician for NG tube and enteral feeds, and on IV fluids Repeat 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 1 Remove 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

A case of unsteadiness and limb weakness

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