Contributing causes of distal sensory neuropathy in diabetic patients

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By Douglas J Lanska MD MS MSPH

Article under review: Gorson KC, Ropper AH. Additional causes for distal sensory polyneuropathy in diabetic patients. J Neurol Neurosurg Psychiatry 2006;77:354-8.

Background: Many authorities have recommended at most a very limited investigation of distal sensory polyneuropathy in diabetic patients and some have advocated no further investigation of diabetic patients with neuropathy (Rosenberg et al 2001; Pourmand 2002). However, previous studies have reported that between 10% (Dyck et al 1993) and a third (Lozeron et al 2002) of patients with diabetes and neuropathy have other potential contributing causes for their neuropathies.

Purpose: To determine the frequency of additional potential causes of distal polyneuropathy in patients with diabetes mellitus.

Methods: This was a retrospective review of 103 consecutive patients with diabetes and distal sensory neuropathy referred over a 5-year period. The authors reviewed clinical, laboratory, and electrophysiological data.

Diabetic patients were classified as having diabetic sensory polyneuropathy and included if they had:

  1. established diabetes mellitus meeting American Diabetes Association criteria
    a. fasting serum glucose greater than 126 mg/dL
    b. serum glucose greater than 200 mg/dL on oral glucose tolerance testing
  2. symptoms and signs consistent with a symmetric, distal, sensory-predominant polyneuropathy
  3. symptoms for at least 3 months
  4. a static or slowly progressive course
  5. none of the following
    a. MRC grade 4/5 or greater leg weakness
    b. any hip or upper limb weakness
    c. mononeuropathy or multiple mononeuropathies
    d. lumbosacral plexopathy
    e. radiculopathy
    f. prominent asymmetric or multifocal symptoms or signs

Laboratory evaluation was extensive and included the following studies:

  1. all patients
    a. complete blood count
    b. renal, liver, and thyroid function tests
    c. lipid screen
    d. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)
    e. anti-nuclear antibody (ANA), anti-encapsulated nuclear antibody (anti-ENA), anti-SSA and SSB antibodies, and anti-neutrophil cytoplasmic (ANCA) antibodies
    f. serum immunofixation electrophoresis
    g. cryoglobulins
    h. angiotensin converting enzyme (ACE)
    i. anti-hepatitis B and C antibodies
    j. anti-Lyme antibodies
    k. anti-HIV antibodies
    l. rapid plasma reagin (RPR)
    m. vitamin B1 and B6 levels using high pressure liquid chromatography
    n. vitamin B12
    o. folate
    p. vitamin E
  2. selected patients (done in a majority of patients but not universally)
    a. urine immunofixation electrophoresis
    b. methylmalonic acid and homocysteine levels
    c. anti-gliadin and tissue transglutaminase antibodies
    d. anti-myelin-associated glycoprotein (MAG) antibodies
    e. SGPG, GD1A, GM2, sulfatide, GM1, asialo-GM1, B-tubulin, chondroitin sulfate, heparin sulfate, GALNAc-GD1a, and Hu antibodies

Results: There were 58 men (56%). The average age was 64 years (range 26 to 92 years). The mean duration of diabetes was 10 years. 10 had type 1 diabetes mellitus. The mean hemoglobin A1c level was 7.4% (range 4.6 to 14.2%). 25 (24%) were receiving insulin therapy.

Additional potential contributing causes to polyneuropathy were identified from medical history in 25 patients (24%). Neurotoxic medications were the most commonly identified potential contributing cause and included chronic exposure to amiodarone, colchicines, and platinum chemotherapy.

Potential contributing causes of neuropathy: historical features

Neurotoxic medications 7
Alcohol abuse 6
Vitamin B12 deficiency 4
End-stage renal disease 4
Inflammatory bowel disease 3
Rheumatoid arthritis 1
Total 25 (24%)

Laboratory testing detected additional recognized causes of distal sensory polyneuropathy in 41 patients:

Potential contributing causes of neuropathy: laboratory evaluation

Vitamin B6 deficiency 11
Vitamin B1 deficiency 10
Monoclonal gammopathy 8
Hypertriglyceridemia 8
Connective tissue disease 2
Vitamin B6 excess 2
Total 41 (40%)

Collectively, 55 patients (53%) with diabetic sensory polyneuropathy had at least 1 additional potential cause of polyneuropathy, with 29 (28%) having 1 additional potential cause, 18 having 2 additional potential causes, and 8 having 3 or 4 additional potential causes. Sensory symptoms and signs in the hands were more common in patients with additional potential causes: (45% of those with multifactor polyneuropathy had sensory symptoms in the hands compared with only 15% of those with diabetes alone; similarly 42% of those with multifactor polyneuropathy had sensory signs in the hands compared with only 15% of those with diabetes alone).

Conclusions and commentary: When I was a busy PGY-2 neurology resident responsible for admitting patients at University Hospitals in Cleveland, I remember being quite irritated when a community neurologist arranged for direct hospital admission of an insulin-dependent diabetic for a "neuropathy work-up." I was quite surprised to ultimately discover that the patient had previously undiagnosed and clinically relevant hypothyroidism and megaloblastic anemia. The patient had a polyglandular autoimmune syndrome (PAS). While this patient could still have certainly been adequately evaluated and managed as an outpatient, it taught me an important lesson that it is essential to evaluate patients for a reasonable spectrum of possible contributing causes, especially if such possible contributing causes are readily treatable, even if an adequate cause is already known.

Even if there is an identified cause which is, by itself, able to cause a condition, progression under appropriate treatment should be a red flag that there may be additional unrecognized and untreated contributing causes. While a simple explanation is often preferred in a given situation, real patients often have multiple contributing conditions to their diseases and the associated causal webs are often complex and messy. In the present study, half of the diabetic patients with a predominantly sensory distal symmetric polyneuropathy had another potential contributing cause for their neuropathy. Treating only 1 of a group of contributing causes will often not adequately treat the patient and it may not result in the expected clinical improvement or prevention of clinical progression.

A "do everything" diagnostic evaluation is often an expensive and unrewarding exercise (as this study also demonstrates). Still, it is important to "cover the bases," but the limits of which bases need covering certainly require some judgment (Pourmand 2002). If a potential contributing cause is readily treatable and reasonably possible (ie, relatively common) it should certainly be covered (ie, screened for). Much of this diagnostic testing can be focused with a proper history (including a careful review of medications and family history) and physical exam.

In the case of patients with diabetes and neuropathy, a thyroid stimulating hormone assay, vitamin B12 level, and possibly (depending on the B12 level) a methylmalonic acid level and fasting homocysteine level should be checked as hypothyroidism and vitamin B12 deficiency are by themselves common and readily treatable causes of peripheral neuropathy and may occur in conjunction with diabetes. Polyglandular autoimmune syndrome is a consideration, particularly in type 1 diabetics (Richman et al 1975; Riley et al 1982; Leshin 1985; Di Mario et al 1990; Davis et al 1992; Weyermann et al 1994; Bell 1995; Rodriguez Quiroz et al 1995; Kessler et al 1998; De Block et al 1999; 2001a; 2001b; Forster et al 1999; Be Block 2000; Hartmann et al 2000; Perros et al 2000; Siewert et al 2001; Sipetic et al 2002; Dittmar and Kahaly 2003; Suzuki et al 2004; Laberge et al 2005; Hershko et al 2006; Sinclair et al 2006; Ulinski et al 2006; Wun Chan et al 2006). Accompaniments of polyglandular autoimmune syndromes (juvenile PAS 1and adult PAS 2 or 2/3 depending on the classification) can include insulin-dependent diabetes, Grave disease, Hashimoto thyroiditis, Addison disease, vitiligo, alopecia, primary hypogonadism, fertility problems, pernicious anemia, candidiasis, celiac disease, myasthenia gravis, connective tissue disorders, etc. The most common combination is type 1 diabetes and autoimmune thyroid disease (Dittmar and Kahaly 2003). It is surprising that there were no cases of reported thyroid deficiency in the cohort reported by Gorson and Ropper. Even in older type 2 diabetics, it is not uncommon to find them with concomitant B12 deficiency or hypothyroidism, perhaps simply by chance, as all of these disorders are relatively common.

Gorson and Ropper's discussion of vitamin B12 deficiency and assay of methylmalonic acid and homocysteine levels is confusing, they utilize a very low threshold for vitamin B12 deficiency (less than 200 pg/mL), there is no clear indication that low "normal" values (eg, less than 300 pg/mL) of vitamin B12 were specially studied in a staged fashion (with methylmalonic acid levels and fasting homocysteine levels) to identify potential cases with functional vitamin B12 deficiency, there is no consideration that methylmalonic acid levels may be increased for reasons other than vitamin B12 deficiency (eg, renal insufficiency), and there are several typographical errors in the relevant table (Table 3). Therefore, other sources should be utilized for consideration of an approach to detecting vitamin B12 deficiency (including functional B12 deficiency with laboratory "normal" - usually low normal - values for serum vitamin B12 levels) (Pruthi & Tefferi 1994; Savage et al 1994; Teffferia & Pruthi 1994; Green 1995; Green and Kinsella 1995; Stabler 1995; Snow 1999).

A fasting lipid profile should also be obtained in diabetic patients with sensory polyneuropathy as hypertriglyceridemia is a common accompaniment of diabetes and may cause or contribute to polyneuropathy in diabetics ( McManis et al 1994; Drory et al 1999; Gottsater et al 1999; Kassem et al 2005). Specifically, hypertriglyceridemia in diabetics has been identified as a cause of axonal polyneuropathy (McManis et al 1994; Drory et al 1999; Hughes et al 2004; Kassem et al 2005) and autonomic neuropathy (Gottsater et al 1999); although the hypertriglyceridemia-associated neuropathy is often a mild axonal polyneuropathy (Drory et al 1999; Kassem et al 2005), reportedly often subclinical, it may be painful (McManis et al 1994), and in some cases correction of hypertriglyceridemia may be associated with significant clinical improvement (Hughes et al 2004; McManis et al 1994).

Based on the present study by Gorson and Ropper, other laboratory studies that should be considered include measures of vitamins B1 and B6 (particularly in alcoholics), and immunofixation electrophoresis (particularly in older patients) (Gorson and Ropper 2006). Assays for vitamins B1 and B6 are not always readily available, and further studies would be helpful in clarifying under which circumstances these are necessary. Certainly alcoholics with the appropriate clinical picture could just be empirically treated with thiamine and a multivitamin.

Based on the present study and general clinical experience, laboratory tests associated with systemic immune disorders rarely lead to a specific treatable diagnosis even if occasional tests among large barrages of tests in various panels are reported as having "abnormal" levels. In addition, in the absence of other risk factors, testing for HIV, hepatitis, and Lyme disease is not likely to be helpful.