Friday, July 30, 2010

MGUS Pearls

from Ramchandren S, Lewis RA.  Monoclonal gammopathy and neuropathy.  Curr Opin Neurol 2009; 22:480-485.

Note-  search this blog for "MGUS" and various information posted elsewhere will not be repeated

Pearl -  Differentiate into subtypes based on type of proteins found, and clinical syndromes

eg.  osteosclerotic myeloma has an 85-100 % incidence of neuropathy, depending on whether they have partial syndrome or full POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M spike and skin changes).  In myeloma one third of patients have subclinical PN, and half of these may be small fiber neuropathy, in others, NCS and EMG is required to detect.  In contrast, PN is much less frequent in Waldenstrom's macroglobulinemia (5-10 %) and amyloidosis (17 %). 

IgM paraprotein patients have half of patients with paraprotein and neuropathy, and 15 % of those with paraprotein and no neuropathy. IgG patients only have 35 % of patients with paraprotein and neuropathy, but 75 % of patients with paraprotein and no neuropathy.  IgA patients have 15 % of those with paraprotein and neuropathy, 10 % of those with paraprotein and no neuropathy.   Thus IgM is NOT the most common paraprotein, but is the most common to cause neuropathy.  Most have MGUS, a few haveWaldenstrom's and  other lymphoproliferative disorders.  IgM binds myelin sheath and neural antigens in patients with IgM and neuropathy, not in those with IgM and no neuropathy.  Of those with IgM paraprotein and neuropathy, half have anti MAG antibodies.  Electron microscopy shows deposition on myelin and separation of myelin by MAG via complement.  Reducing anti MAG IgM also improves the neuropathy. 

IgG paraprotein patients are as above, less likely to develop PN by far, and those that do have all types of neuropathies (distal , length dependent axonal and CIDP).  CIDP patients with IgG paraprotein are otherwise identical to those CIDP patients without IgG paraprotein.  Unless in a patient with myeloma, amyloid or POEMS, IgG paraprotein is likely to be incidental.  A few patients with IgG or IgA paraprotein also have deposition on myelin like IgM patients so previous statement is not absolute.

IgM paraprotein patients with PN usually have kappa light chains and half have anti MAG antibodies.  They are older males (60s) with "DADS" which stands for "distal acquired demyelinating sensory neuropathy."  Large fibers affecting VS and proprioception cause problems with balance that are progressive.  DADS M (DADS with an IgM paraprotein) is probably distinct from DADS no M.  A few patients have an aggressive course.  EMG in DADS M has accentuated distal slowing and long latency motor nerves and attenuated or absent sensory nerves. 

IgG/IgA MGUS have no homogenous presentation, but usually have less balance problems. 

2. Myeloma patients have peripheral neuropathy due to perineural or perivascular IgG kappa deposition, or treatment related neuropathy.  IgM paraprotein is seen rarely in myeloma, and have sensory > motor symptoms.  If amyloid is present, its more likely to be painful.  EP is more likely to show axonal damage, but may show demyelinating sometimes.No intervention changes PN but therapy of MM exacerbates PN. 

3.  POEMS-- Paraprotein is usually IgA or IgG lambda.  Synonyms for condition are Crow-Fukase syndrome or Takatsuki syndrome.  Patients are younger (40s) with severe sensory and motor features.  Presentation is progressive distal weakness, paresthesias, and numbness more often than CIDP like.  Weakness if usually in ankles most severely.  Patients are wheelchair bound within a year.  There is 40 % mortality at five years.  EMG shows demyelination with secondary axonal loss. Conduction block is rare. Nerve biopsy can show endoneurial deposits.  Treatment is for underlying, and PN is reversible for localized process such as plasmacytoma.  High dose chemotherapy with autologous blood stem cell rescue is being explored.  Misdiagnosed early as CIDP.  Diagnosis of: demyelinating PN, monoclonal gammopathy and one of the three:  osteosclerotic myeloma, Castleman's disease or increased VEGF.  Also must have one or more of following:  organomegaly, endocrine dysfunction, edema , skin changes (hypertrichosis or hyperpigmentation), papilledema, thrombocytosis, polycythemia). 

4.  Waldenstrom's is rarely associated with PN but when it is, its usually IgM kappa with or withour anti MAG antibodies.  Its clinically indistinguishable from MGUS related PN with anti MAG or DADS M.  Responds to plasma exchange since IgM paraprotein is intravascular, may also use steroids and alkylating agents and Rituxan.

5.  Amyloidosis PN is usually present for a long time first.  A. is a multisystem disorder with IgG or IgA lambda paraproteins and deposition of light chains in target organs.  Either vascular insufficiency or toxicity of amyloid causes the PN.  Painful progressive distal sensory and motor PN  often with autonomic findings is seen.  NCS show axonal sensory > motor neuropathy.  Mean prognosis is 25 months. 

6.  Patients with DADS and IgG or IgA MGUS respond to treatment regimens used for CIDP patients without MGUS.  DADS M polyneuropathy may be misdiagnosed as CIDP but respond more poorly to treatment regimens used for CIDP.

7.  CANOMAD is a rare disorder (chronic ataxic neuropathy with opthalmoplegia, M protein, cold agglutinins, and anti disialosyl antibodies against gangliosides, including GD1b, GD3, GQ1b, and GT1b.  There is a chronic PN with sensory ataxia and areflexia, with sparing of strength.  Its similar to Miller Fisher syndrome that has antibodies to GQ1b, but is chronic and progressive rather than monophasic and acute. 

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