Case 97 – Summary

This week we looked at a neuropathy presenting via the neurology team associated with a plasma cell dyscrasia.

This area of haematology is often challenging! The diagnosis can be difficult and even after diagnosis there is a lack of evidence to formulate management plans. It is important to diagnose correctly as it is estimated that 10% of all idiopathic neuropathies are associated with an M protein (1).

It should be noted that in an aging population having an M protein is common indeed MGUS is seen in 1% of the population over age 50 (1). However, it should also be noted that MGUS is ten times as common in patients with polyneuropathies as it is with controls (2). This means that not all patients with an M protein have a treatable autoimmune neuropathy. The challenge is therefore in trying to identify the patients where the M protein is significant. It is now known that patients with CIDP like polyneuropathy and an Ig A or Ig G MGUS most likely have a coincidental MGUS that isn’t the key to the neuropathy. In contrast an Ig M M protein patient with neuropathy does usually have a distinct phenotype and should always be treated as Ig M associated autoimmune neuropathy. (2)

The above points although interesting don’t really assist you in clinical practice in assessing a patient in clinic with an M protein and a neuropathy.

The differential diagnosis for neuropathies can be assisted by knowing the type of M protein and associated light chain, the pattern of neuropathy and predominant feature of the neuropathy (sensory/motor/sensorimotor or autonomic). The associated clinical features and Electromyograph may also help. It should be stressed there are no definites as in every branch of medicine and some patients may have both axonal and demyelinating features on their EMG so in some cases tests may not be as conclusive as you would hope! Therefore involvement of the neurology team is critical with these patients as neuropathy is compex!

Here is a useful table that has been adapted from two different useful journal articles (References 1 and 3) that may help you in determining the cause of an autoimmune neuropathy:

M Protein type Disorder Pattern of neuropathy Associated clinical features EMG pattern Demyelination (DM) or Axonal
IgM
Ig M kappa LPL Slowly progressive distal sensory/ sensorimotor. (Similar to CIDP) Anaemia

Weight loss

Headaches

Visual disturbances

DM
Ig M Kappa MM/ MGUS Usually mild symmetrical distal sensory/sensorimotor Bone pain

Renal failure

Hypercalcaemia

Anaemia

Axonal
Ig M Cryoglobulinemia Symmetrical distal or multifocal painful sensory or sensorimotor. Occasionally mononeuritis Raynauds phenomenon

Purpura

Arthralgia

Leg ulceration

Axonal
Ig G/A
Ig G Cryoglobulinemia Symmetrical distal or multifocal painful sensory or sensorimotor. Occasionally mononeuritis Raynauds phenomenon

Purpura

Arthralgia

Leg ulceration

Axonal
Ig G Lambda

 

Ig A Lambda

POEMS Symmetrical and Proximal and distal sensorimotor.

Motor often predominant

Organomegaly

Papilloedema

Hypothyroidism

Effusions

Thrombocytosis

Clubbing

Hyperpigmentation

DM
Ig G Lambda Ig A Lambda Amyloidosis Symmetrical, distal painful sensory and autonomic neuropathy CCF features

Organomegaly

Macroglossia

Axonal
Ig G or Ig A Kappa MM/MGUS Usually mild symmetrical distal sensory/sensorimotor Bone pain

Renal failure

Hypercalcaemia

Anaemia

Axonal

Red Italics: useful diagnostic features

Initial history and examination should focus on signs of the above disorders (see table for details). Consider establishing features of hyperviscosity Raynauds phenomenon/ purpura if an Ig M M protein. If considering amyloidosis, cryoglobulinemia or POEMS a good systemic inquiry is essential. It is  important not to neglect to consider other causes of neuropathy as after all not all Patients with an M protein will have neuropathy attributable to this.

Useful aide to memory for distal peripheral neuropathies:

A – Alcohol

B – B 12

C – Connective tissue disorders

D – Diabetes /Drugs

With regards to investigations these should again be focused depending on type of M protein but should include:

M protein characterisation: FBC, U&E, LFT, Bone profile, SFLC, serum protein electrophoresis.

Neuropathy investigation: B12 and folate, Glucose, Nerve conduction studies and Anti MAG Ab and anti-ganglisoide antibodies. These should involve a neurologist if possible.

Specific tests that may be needed depending on presentation:

Amyloid: 24 hour urine protein, Echo, ECG and possible fat pad biopsy.

POEMS: VEGF level, TFT’s, skeletal imaging

LPL: CT scan, Bone Marrow Biopsy with testing for MYD88.

Myeloma: Skeletal imaging, Bone marrow biopsy with cytogenetics.

Cryoglobulinemia: check for cryoglobulinemia, Bone Marrow biopsy, Hepatitis screen, Auto Antibodies.

Our patient had an Ig M M protein without signs of hyperviscosity. He had loss of proprioception, temperature and fine touch symmetrically to around ankle level. He also has got bilateral reduced ankle jerks with preserved knee reflexes. This pattern of sensory symmetrical distal peripheral neuropathy that slowly progresses to some motor involvement is typical of Ig M associated Anti MAG Ab secondary to LPL.

Ig M Anti MAG Ab associated with an LPL:

Before going further it is important to understand what an Anti MAG Antibody is. Myelin associated glycoprotein (MAG) is a glycoprotein which is part of the central and peripheral nerve myelin. It was found that around 50% of patients with neuropathy and Ig M M-Protein gave serum that will react with MAG (2). These patients will also  have serum that co reacts with a specific glycolipid on the nerve which was identified as sulfogluconyl glycosphingolipid (SGPG). SGPG is found only in peripheral nerves and is part of the large MAG molecule and other parts of the peripheral nerve structure. All patients with Anti-MAG antibodies will also react to SGPG.

The testing therefore is for Anti MAG Ab using an ELISA principle, occasionally labs do use SGPG as their antigen instead of MAG and this may cause low affinity MAG Ab to be missed as binding to MAG is 10-100x stronger than to SGPG and it is worth bearing this in mind (2).

It is now thought that Anti MAG Ab are related to the neuropathies seen clinically for a few reasons:

  1. Biopsies from these patients show IgM and compliment in nerve fibres suggesting Ab is able to activate the compliment system to cause the characteristic demyelination.
  2. Animal studies have also shown that injecting the purified anti MAG Ab does seem to induce neuropathy in other animals.

Of the remaining 50% who don’t have a Anti MAG Ab about half of them will instead have another ganglioside Ab detected such as Anti GM 1 and Anti GM2 etc and these can be tested for by the neurology team and usually cause axonal neuropathies (2).

Given the above information it should make sense that in suppressing antibody production the patient would improve, however there is not great evidence to show large benefits when these patients  are treated as we will go on to discuss.

Returning to our patient he had Anti MAG Ab and LPL. With regards to his LPL he had no other indications for treatment apart from his neuropathy.  He didn’t have a lumbar puncture (LP) as he declined it. The clinical team felt as his symptoms were slowly progressive over more than 6 months and were consistent with a symmetrical distal neuropathy rather than Bing Neel syndrome and didn’t press the issue (4). If the patient had rapidly progressive symptoms or other odd neurology an MRI Brain and spine and LP should be performed with CSF examination. The CSF sent for cytology, flow and molecular studies for MYD 88. An MRI should be performed prior to LP to avoid false positive meningeal enhancement from the LP (4).

In making decisions regarding treatment of a patient with neuropathy secondary to Anti MAG Ab in context of otherwise asymptomatic LPL it is important to recall that cure is not possible and hence any treatment is only about improving quality of life. An MDT discussion is warranted as it is not always necessary or in the patients best interests to treat Anti MAG Ab neuropathy initially. Watch and wait is valid and this needs discussion with the MDT and the patient.

If treatment is being considered then generally Rituximab monotherapy is used without other chemotheraputic agents if neuropathy is the only problem related to LPL. Initially weekly rituximab for 4 weeks when neuropathy disabling.  The response to treatment in small case series of 13 patients has been reported at 60% with Rituximab monotherapy (4). Response times are slow as myelin regeneration is slow and typically 9 months is needed to perceive an improvement (4). Predictors of response include a lower pre treatment Anti MAG Ab titre, the authors postulate this may be because a particular threshold of Ab needs to be reached before improvements are seen (5).

There was a Cochraine meta-anaylsis (6) in 2016 looking at benefits and harms of immune therapies in patients with Ig M antibody that may bind to MAG it concluded that there was inadequate reliable evidence to support any particular treatment. There is it stated low quality evidence to show benefit from Rituximab in two small trials but again stressed larger well designed RCT’s are needed to assess the effectiveness.

In the case of our patient he felt he could not continue to function in his work without some treatment and he received Rituximab weekly and did derive some improvement after 6 months. He continues on a watch an wait follow up.

Thanks for your help with the case Please feel free to post any comments or questions.

References:

1) Rosenbaum E eat al. Diagnosis and management of neuropathies associated with plasma cell dyscrasias. Haematological oncology 2017. vol 36, Issue 1.

2) Dalakas, M. Advances in the diagnosis, immunogenesis and therapies if Ig M anti MAG antibody-mediated neuropathies. Theraputic advances neurological disorders. 2018; Vol 11.

3) Ropper, A et al. Neuropathies associated with paraproteinemia. NEJM 1998.Vol 38;22; 1601-1607.

4) Simon, L et al. How we manage patients with Waldenstrom Macroglobulinemia. British Journal of Haematology. 2018. Vol 181;737-751.

5) Benedetti et al. Predictors of response to rituximab in patients with neuropathy and anti-myelin associated glycoprotein immunoglobulin . Journal of the peripheral nervous system 2007. 12:102-107.

6) Cochraine Review Feb 2016 What are the benefits and harms of immune treatments for peripheral neuropathy caused by an Ig M paraprotein antibody that may bind to Myelin-associated glycoprotein (MAG)?

 

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