27 - Monoclonal Gammopathy of Undetermined Significance (MGUS) Flashcards Preview

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Describe the history of the patient in this case

68 y/o white male relates 3 months of “burning and tingling” in his feet-referred by PCP

Typically "burning" is temperature-related (spinothalamic tract of temperature)


Describe the PROS for this patient

- Diet (and exercise) controlled diabetic of 3 years duration
- Feels lethargic (does not “walk as much as before”)
- Denies chest pain or dyspnea
- Denies fever or chills, cough, bloody stools, or hematuria
- Has gained 5 lbs since last appointment (6 months ago)


Acute or chronic condition?



How do we define acute? How do we define chronic?

Acute = days to weeks

Chronic = months to years


If the onset had been acute, what would our differential be?


P = Proximal diabetic neuropathy *** (diabetic amyotrophy
A = Arterial vasculitis
T = Toxins

P = Paraneoplastic syndrome
A = Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) - Guillain-Barre
T = Trauma


What are the different types of chronic neuropathies?

Chronic (2 years)
- Hereditary neuropathies
- Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
- Diabetic polyneuropathy***

Note: when the neuropathy clearly starts in adulthood, it is more likely to be acquired than hereditary


What neuropathy conditions follow a "exacerbation-remission" pattern?

- Guillain-Barre
- Toxins
- Porphyria
- MS***


What else do you find in the history of this patient?

- History of hypertension***, treated with ACE inhibitor
- Negative for hyperlipidemia, heart disease (based on ECG every 2 years)
- Denies tobacco, alcohol, illicit drug use
- Denies depression
- Married, teaches part-time at community college


What do you find in the physical exam of this patient?


- Hyperesthesia of soles of feet with diminished pinprick sensation ***
- Decreased vibratory sensation ***
- Normal reflexes
- Normal thyroid exam
- Normal pulses
- Normal musculoskeletal exam
- Could toe walk and heel walk ***

Starred things were RED

Vibratory is in the posterior column, not with pain and temperature (spinothalamic tract), so it is more than just spinothalamic as we had initially thought


What does decreased vibratory sensation indicate?

Decreased vibration sensation suggests large fiber involvement and “dying-back” phenomenon (distal symmetric axonal damage)


What does diminished pinprick and light touch suggest?

Diminished pinprick and light touch suggest involvement of small fibers (generally unmyelinated)


What does an inability for a patient to stand on their heels suggest?

Inability to stand on heels suggests a peripheral neuropathy-if most neuropathies are of the distal variety, they will be prone to the “dying-back” phenomenon which affects the longest nerves first


What does an inability for the patient to stand on their tip toes suggest?

Inability to stand on tiptoes suggests a CNS problem (e.g., spinal cord tumor or lesion)


Describe the importance of signs in diagnosing your patients with neuropathy

Most statistically relevant combination of signs that increase the likelihood of distal symmetrical polyneuropathy are:
- Decreased or absent ankle reflexes
- Decreased distal sensation***

***Distal symmetric polyneuropathy. Muscle and Nerve


What were your laboratory findings in this patient?

- FBS-149 mg/dL
- A1C-7.2% (up from 6.1% 6 months ago)
- CBC, complete metabolic panel- normal
- PSA-normal


What is the mneumonic for diagnosing a CHRONIC neuropathy?


A DUMB = metabolic
MMedIcAl = toxic
BLmOG = malignancy
to CHARt = hereditary
Infections = infections


What are the metabolic causes of chronic neuropathy?


A = amyloidosis

D = diabetes
U = uremia
M = myxedema
B = B12, B6, B1 (thiamine) deficiencies


What are the toxic causes of chronic neuropathy?


M = metal (heavy) exposure
Med = medications
Ic - insecticides
Al = alcohol


What types of medications can have toxicity leading to neuropathy?

Cancer drugs
- Vincristine, Taxol®, Interferon, Cisplatin

Arthritic drugs
- Colchicine, Chloroquine, Gold

Psychotropic drugs
- Lithium, Amitriptyline, Phenytoin

- Metronidazole, retrovirals, dapsone, nitrofurantoin, isoniazid

Cardiac drugs
- Hydralazine, amiodarone


What types of malignancies can cause neuropathy?


B = bronchogenic carcinoma
L = lymphoma
mO = monoclonal paraproteinemia
G = gastric carcinoma


What types of hereditary conditions can cause neuropathy?

to CHARt

CHAR = Charcot-Marie-Tooth


What types of infections can cause neuropathy?

- Lyme
- Borreliosis
- Leprosy
- Hepatitis


What is the next step in treating this patient?

- Refer back to PCP with diagnosis of diabetic distal polyneuropathy
- Patient started on Prandin (0.5 mg) BID, continue exercise and good diet, followed up 2 months later


How did the patient present at the follow up appointment?

- FBS-105 mg/dL
- A1C-5.6%
- Lost 9 pounds
- Feet more painful
- Fatigue still present
- Slight ataxia noted

Patient was referred back to podiatry because pain was WORSE despite diabetes being better


What does the gait unsteadiness indicate?

Gait unsteadiness suggests proximal and/or distal muscle weakness or loss of position sense


What does the fatigue indicate?

Fatigue is associated with a variety of neurological, muscular, metabolic, and hematological disorders


What tests should you do now?

First blood testing...
- Fasting blood glucose and A1C, creatinine, TSH, and B12 are the only truly informative blood tests for neuropathy.
- Consider a plasma electrophoresis in older men to rule out multiple myeloma

- NCV and EMG testing


Describe the NCV and EMG testing

- NCV and EMG (the two components of an NCS or Nerve Conduction Study)
- Most accurate for diagnosing peripheral neuropathy


What are the uses of NCV and EMG tests? What are their limitations?

- NCV-distinguishes axonal from demyelinating disease
- EMG-distinguishes nerve from muscular disease
- Limitation-unreliable at diagnosing small fiber neuropathy; gold standard for diagnosing large fiber neuropathy


What are NCV and EMG tests good at diagnosing?

Large fiber neuropathies ***

They are unreliable when trying to diagnose small fiber


Is diabetes small or large fiber?

- Diabetes is classically described as a small fiber disease
- However, diabetic distal symmetric polyneuropathy has damage to both large and small fibers

Diabetes Care suggests that “after 40 years of living with type 1 diabetes, nearly all patients have small-fiber sensory neuropathy and a majority also has large-fiber nerve dysfunction”


What is highly predictive of peripheral neuropathy?

Painful or painless lower limb dysethesias are highly predictive of peripheral neuropathy: comparison of different diagnostic modalities

42 patients had NCS
- 90% had signs of small fiber neuropathy
- 50% had signs of large fiber neuropathy


What would be the next step in diagnosing?

Nerve biopsy
- Sural nerve biopsy
- Evaluates only a small segment of nerve and can miss the pathology
- Difficult to evaluate presence of demyelination
- Use if vasculitis, amyloid, sarcoid, or malignancy are suspected


What is intra-epidermal nerve fiber density biopsy useful for diagnosing?

Useful only for diagnosing small fiber neuropathy

Sensitivity of 90%
Specificity of 95%
PPV of 95%
NPV of 91%

There is LITTLE evidence that diagnosing by skin biopsy alters treatment options (so is it worth it?)


What is the Michigan Neuropathy Screening Instrument (MNSI)?

- A 2-part screening instrument composed of a 15 item questionnaire and a physical examination composed of a general inspection of the feet, checking for ulcerations, reflexes, vibratory sensation, and SWM
- Neuropathy is defined as 7 or more positive responses on the questionnaire or a score >2.0 on the examination


How sensitive and specific is an MNSI?

Is MNSI valid?
- Sensitivity-95%
- Specificity-80%


What is quantitative sensory testing (QST)?

- Assesses and quantifies sensory function
- Different systems measure the detection threshold of accurately calibrated sensory stimuli (Vibratory, thermal, or painful)
- These stimuli are often chosen because they relate to distinct neuroanatomic pathways with discrete fiber populations
- QST systems are separable into devices that generate specific physical vibratory or thermal stimuli and those that deliver electrical impulses at specific frequencies


How should you interpret QTS results?

- QST results should not be the sole criteria utilized to diagnose structural pathology
- Abnormalities on QST must be interpreted in the context of a thorough neurologic examination and other appropriate testing such as the EMG, nerve biopsy, skin biopsy, or appropriate imaging studies***


How accurate is the monofilament test (SWM)?

- Sensitivity ranged from 41% to 93% and specificity ranged from 68% to 100%.
- Because of the heterogenous nature of the studies, a meta-analysis could not be accomplished…
- We do not recommend the sole use of monofilament testing to diagnose peripheral neuropathy ***


What percent of diabetics have a positive SWM test?

Semmes-Weinstein monofilament exam

25% of diabetics have a positive SWM test


How do the results on your blood work come back?

- All results negative except IgM level elevated at 2.4 gm/dL
- Further studies showed less than 10% plasma cells in bone marrow, no monoclonal protein in urine, no lytic bone lesions, anemia, hypercalcemia, or renal insufficiency


What is the diagnosis?

MGUS (monoclonal gammopathy of undetermined significance)


What is MGUS (monoclonal gammopathy of undetermined significance)?

- A form of paraproteinemia [monoclonal gammopathy due to clonal proliferation of B-cells (plasma cells)]
- Also includes multiple myeloma, Waldenstrom’s macroglobulinemia, lymphoma


How common is MGUS (monoclonal gammopathy of undetermined significance)?

- Affects 1% of population with 10% of these (0.1%) having a neuropathy
- IgG is most common, but IgM most common when neuropathy is found


Describe the pathophysiology of MGUS

- Nerve tissue damaged by deposition of antibodies specific for a myelin or axonal component
- IgM usually associated with antibodies to myelin-associated glycoprotein (MAG) found in the paranodal regions of Schwann cells resulting in demyelination and remyelination
- Other autoantibodies to peripheral nerve antigens include anti-asialo GM1, anti-GD1a, anti-GD1b, anti-GM-1, anti-GM-2, anti-GQ 1b, anti-sulfatide


How common is malignancy in patients with MGUS?

17-30% of patients with MGUS transform to a malignancy in 10 years (usually lymphoma)


How do you treat MGUS?

- Steroids
- Cyclophosphamide
- IV immunoglobulin
- Plasma exchange
- Rituximab


What did the Rochester Diabetic Neuropathy study indicate?

66% of diabetic patients have some variety of neuropathy (current studies suggest 50%)
- Polyneuropathy-50%
- Carpal tunnel-35% (symptomatic and asymptomatic)
- Visceral autonomic neuropathy-6%
- Other-9%

Only 20% of diabetics with neuropathy had symptoms


What percent of diabetics with neuropathy had neurologic deficits attributable to NON-DIABETIC causes?



This means that not all of your diabetics with neuropathy have the neuropathy because of the diabetes


What is the "food for thought" from this lecture?

The diabetic with neuropathy is only due to diabetes if there is coexisting retinopathy and nephropathy ********


What is the take home message from this lecture?


10% of diabetics with neuropathy have an etiology other than diabetes

NEED to know that it is NOT ALWAYS diabetes *****