symptoms

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MRC Centre for
Neuromuscular Disease
Neuropathy and Waldenström's
Macroglobulinaemia
London
January 2011
Dr Michael Lunn
Consultant Neurologist and Clinical Lead in Neuroimmunology
National Hospital for Neurology and Neurosurgery
Queen Square
London WC1N 3BG
michael.lunn@uclh.nhs.uk
Neuropathy and Waldenström's
Macroglobulinaemia
•
•
•
•
•
What is a nerve?
What is a neuropathy?
What are the symptoms and signs?
How is it diagnosed?
Why and how does Waldenstrom’s cause
neuropathy?
• What can be done about it? Treatment.
• Where might I find out more?
What is a nerve?
A nerve conducts electrical impulses around the
nervous system
A nerve conducts electrical impulses around the
nervous system
skin
Nerve from real life
– normal and damaged
Normal nerve
CIDP
Brandner S - NHNN
The nerve cell surface is covered in
‘targets’ for antibodies
Neuropathy and Waldenstrom’s
Macroglobulinaemia
•
•
•
•
•
What is a nerve?
What is a neuropathy?
What are the symptoms and signs?
How is it diagnosed?
Why and how does Waldenstrom’s cause
neuropathy?
• Are there any similar conditions?
• What can be done about it?
• Where might I find out more?
What is a neuropathy?
What is a neuropathy?
• A neuropathy is present when a peripheral
nerve is damaged
• There are many causes of peripheral
neuropathy
– Compression (carpal tunnel syndrome)
– Diabetes
– Toxins (e.g. alcohol) and vitamin deficiencies
– Infections (e.g. leprosy)
– Inflammatory causes
Neuropathy represents damage to the myelin
sheath or the axon
How common is it?
Prevalence (per 100,000)
Martyn CN and Hughes RAC
Peripheral Neuropathies in Epidemiology of Neurological Disorders BMJ 1997
All types
Carpal tunnel
Diabetic
HMSN
CIDP and Waldenström's
2400
5800 f 600 m
300
8 - 41
>1
Neuropathy and Waldenstrom’s
Macroglobulinaemia
•
•
•
•
•
What is a nerve?
What is a neuropathy?
What are the symptoms and signs?
How is it diagnosed?
Why and how does Waldenstrom’s cause
neuropathy?
• Are there any similar conditions?
• What can be done about it?
• Where might I find out more?
Symptoms of peripheral neuropathy
• Positive
• Negative
– Pins and needles
– Pain
– Loss of sensation –
numbness
– Muscle twitching
– Cramps
– Restlessness
– Tremor
– Weakness
– Wasting
18
Distal length
dependent
neuropathy
symptoms
Signs of peripheral nerve disease
•
•
•
•
•
•
•
•
•
Weakness
Wasting
Loss of reflexes
Sensory loss
Ataxia (unsteadiness)
Thickening of nerves
Skin changes
Consequences of sensory loss – ulcers, arthropathy
Others
21
Distal wasting
Courtesy of imagesMD Taken from: Thomas D. Bird, S. Mark Sumi In Atlas of
Clinical Neurology: Clinical Neurology. Edited by Roger N. Rosenberg. Current
Medicine, Inc. 2000
22
Neuropathy and Waldenstrom’s
Macroglobulinaemia
•
•
•
•
•
What is a nerve?
What is a neuropathy?
What are the symptoms and signs?
How is a neuropathy diagnosed?
Why and how does Waldenstrom’s cause
neuropathy?
• Are there any similar conditions?
• What can be done about it?
• Where might I find out more?
How do we diagnose a
neuropathy?
• Clinical symptoms and patient characteristics
• Clinical signs on examination
• Neurophysiological testing
– nerve conduction studies and electromyography
• Special blood tests
An EMG Lab…
Median Sensory Study
B
Conduction velocity
= A/B ms-1
A
What does Waldenström's
neuropathy look like?
Anti-MAG paraproteinaemic demyelinating
peripheral neuropathy (PDPN)
• Chronic progressive sensorimotor demyelinating
neuropathy
–
–
–
–
Older person (average 65-75 years), male
Numb in feet and unsteady
Tremor of hands (sometimes mild, sometimes worse)
Ataxic (unsteady) walking
• IgM paraprotein in serum
• Paraprotein has ‘anti-MAG’ activity
• The antibody ‘sees’ a nerve sugar on MAG called HNK-1
• also on some other nerve molecules but MAG most
likely
• Characteristic pathology
Widely spaced myelin
Neuropathy and Waldenstrom’s
Macroglobulinaemia
•
•
•
•
•
What is a nerve?
What is a neuropathy?
What are the symptoms and signs?
How is it diagnosed?
Why and how does Waldenström's cause
neuropathy?
• Are there any similar conditions?
• What can be done about it?
• Where might I find out more?
Inflammatory Peripheral Neuropathy
Idiopathic
Vasculitic Neuropathy
Acute
Acute inflammatory demyelinating polyradiculoneuropathy (AIDP)
Acute motor axonal neuropathy (AMAN)
Acute motor-sensory axonal neuropathy (AMSAN)
Fisher Syndrome and other regional variants
Pharyngeal-cervical-brachial
Paraparetic
Facial palsies
Pure oculomotor
Functional variants of GBS
Pure dysautonomia
Pure sensory GBS
Ataxic GBS
Subacute
Primary vasculitis
Polyarteritis nodosa and Churg
-Strauss disease
Wegener’s vasculitis
Isolated nerve vasculitis
Temporal arteritis
Systemic autoimmune diseases with associated vasculitis
Rheumatoid arthritis
Systemic lupuserythematosus
Sjörgren’s syndrome
Mixed connective tissue disease
Other
Serum sickness
Infectious, malignant, related to chemotherapy
Subacute inflammatory demyelinati
ng polyradiculoneuropathy (SIDP)
Chronic
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
Multifocal motor neuropathy with conduction block (MMNCB)
Chronic relapsing axonal neuropathy
Chronic ataxic sensory neuronopathy
Inflammatory neuropathy associated with infection
HIV neuropathies, including CMV neuropathy
Leprosy
Lyme disease
Chaga’s disease
Paraproteinaemic neuropathy
Monoclonal gammopathy of undetermined significance (MGUS)
Multiple myeloma
Solitary plasmacytoma
Lymphoma or chronic lymphocytic leukaemia
Waldenström’s macroglobulinaemia
Cryoglobulinaemia
Cold agglutinin disease
Primary amyloidosis
POEMS syndrome
Paraneoplastic
Sub-acute sensory neuropathy/neuronopathy
- small cell lung
carcinoma and anti-Hu Abs
Other paraneoplastic tumour
-antibody syndromes
Metabolic
Diabetic lumbo-sacral plexopathy
Waldenström's causes an ‘inflammatory’
neuropathy
• Paraprotein associated neuropathies part of
group of inflammatory neuropathies
• Inflammatory neuropathies have presumed
‘immune mediated’ pathogenesis
• Inflammatory cells infiltrate nerves and
damage myelin and/or axons
The IgM in Waldenström's sometimes targets
Myelin Associated Glycoprotein (MAG)
MAG
Myelin Associated Glycoprotein (MAG)
• A myelin sugar-protein
• 1% brain protein 0.1% nerve proteins
• MAG is localised in specific sites on the myelin
surface
• MAG associates with other signalling molecules
that control the axon and the myelin
• MAG normal functions
• Cell-cell recognition
• signal transduction through the membrane,
• myelin-axon inter-communication
Lunn et al Brain 2002
Conclusions
• Neurofilaments are significantly closer in diseased
axons from patients with anti-MAG paraproteins.
• We think that thinned nerves are not able to
transport substances so easily
• This leads to damage to the ends of the nerves
• Treating earlier may be of benfit but we don’t
know for definite
Treatment for Waldenstrom’s
Neuropathy
IgM paraproteinaemic (anti-MAG)
neuropathy treatment
• Is treatment required at all?
• Do you need to treat the Waldenström's?
• IVIG confers short term benefit – RCT
– Multiple other immunosuppressants used
• Melphalan, chlorambucil, cyclo +/- steroid, fludarabine
• Rituximab (anti-CD20) – promising in some studies
• 8 studies – 6 (79 pts) positive (1 (3 pts) negative)
• 3 fully published, 2 not adequately controlled
• 1 Randomised trial published (Dalakas 2009) with serious flaws –
reported ‘positive’
• Another trial completed – mixed results
• 375mg/m2 usual dose – recent high dose study added
improvement
• Some published cases of worsening
• We give in close discussion with haematology services
Mechanisms of B-cell Functions
Dalakas M Neurology
2008;70:2252
B cell development 2
Dalakas M 2008
Nature
Rituximab
• Chimeric (Mouse-human) antiCD20 antibody
• 1st monoclonal approved for
use in cancer (1997)
• Depletes CD20 +ve cells in
hours to days for 8-12months
Rituximab - Safety
• 84% infusion reactions – 97% mild
• 30% post infusion infection – 1-2% severe
• Maintained Ig levels and T-cell function
• Concomitant anti-T-cell therapy hazardous
• Serious infections more common with concomitant
illness/immunosuppression
– PML
• 2 cases in SLE treated with Rituximab (+ additional
immunsuppressants)
• 23 cases in neoplasia Rx with Rituximab
• HACA antibodies uncommon
• Some high titre, more common in AI disease
• Effects unclear – may cause depletion failure
Other treatments
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Not usually painful – pain medications
Physiotherapy for walking and balance
Foot care
Walking and balance aids
– Ankle foot orthoses
– Sticks
– Walkers
• Driving advice
Where might I find out more?
• GBS Support Group
– http://www.gbs.org.uk
• GBS-CIDP Foundation International
– http://www.gbs-cidp.org/
• The Neuropathy Trust
– http://www.neurocentre.com/
National Hospital for Neurology
and Neurosurgery
Guy’s Hospital
Dept of Neuroimmunology
Ken Smith
Mary Reilly
Richard Hughes
Norman Gregson
Johns Hopkins University
Dept of Neurology
Kazim A Sheikh
John W. Griffin
Tony W. Ho
David R. Cornblath
Guy M. McKhann
Johns Hopkins University
Dept of Pharmacology
Ronald L. Schnaar
James E.K. Hildreth
Susan Fromholt
Saki Itonori
NIH, Bethesda
Richard Proia
Second Teaching Hospital
Shijiazhang, China
Chun Y. Li
Beijing Children Hospital
H Wu
Patrick Berthoud Charitable Trust
MRC Centre for
Neuromuscular Disease
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