B. Wildemann
Etiology
Polyneuropathies are caused by acquired or hereditary disorders (Table 13.1). Diabetes and alcohol abuse provide the most common etiologies, followed by immune-mediated or idiopathic diseases and hereditary disorders. About 30% of idiopathic polyneuropathies can be diagnosed by repeated well-structured diagnostic tests. For about 20% of neuropathies the etiology remains obscure.
Diagnosis
Basic information. Laboratory tests are helpful in the differential diagnosis of polyneuropathies, but they should be carefully targeted on the basis of the clinical and neurophysiological manifestations, and should be carried out in a stepped manner if unnecessary and expensive testing is to be avoided. The following basic information should be available before a selective program of laboratory diagnosis is embarked upon:
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Table 13.1 Etiologies of polyneuropathy |
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Acquired disorders |
Examples |
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Metabolic diseases |
• Diabetes • Vitamin deficiency (B12, B6) • Uremia • Hypothyroidism • Secondary amyloidosis |
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Immune-mediated diseases |
• Guillain-Barré syndrome • Chronic inflammatory demyelinating polyneuropathy • Multifocal motor neuropathy • Vasculitis • Connective tissue diseases • Paraproteinemia • Cryoglobulinemia • Plexus neuritis |
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Infectious diseases |
• Herpes zoster (shingles) • Neuroborreliosis • HIV/AIDS • Syphilis • Sarcoidosis • Leprosy |
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Toxic diseases |
• Alcohol abuse • Chemotherapy, medication • Heavy metal intoxication |
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Paraneoplastic diseases |
• Sensory neuronopathy |
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Hereditary disorders |
Examples |
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HMSN (CMT) |
• HMSN 1–3 • HNPP |
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HSAN |
• HSAN 1–3 |
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Hereditary neuralgic amyotrophy |
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Others |
• Familial amyloidosis • Porphyria • Fabry's disease • Metachromatic leukodystrophy • Adrenoleukodystrophy • Refsum's disease |
CMT, Charcot-Marie-Tooth disease; HMSN, hereditary motor and sensory neuropathy; HNPP hereditary neuropathy with liability to pressure palsy; HSAN, hereditary sensory and autonomic neuropathy.
• Family history.
• Underlying and concomitant diseases.
• Medication history.
• Age at onset of symptoms.
• Time course of symptom development:
– Acute (up to 4 weeks).
– Subacute (4–8 weeks).
– Chronic (> 8 weeks).
• Type of clinical manifestation:
– Symmetric/asymmetric.
– Sensory/sensorimotor/motor.
– With/without autonomic impairments.
– With/without pain.
• Neurophysiological characteristics:
– Demyelinating.
– Axonal.
– Mixed.
Stepped analysis. Laboratory tests guide the diagnosis of metabolic, immune-mediated, infectious, and hereditary polyneuropathies. Relevant additional information is largely obtained from serological screening tests and a more detailed serological analysis. CSF analysis is helpful if an immune-mediated or infectious etiology is suspected. Molecular genetic analysis helps with the precise classification of hereditary etiologies; as this is cost-intensive, it should always be used in a targeted manner, depending on the clinical and neurophysiological manifestation. In a very few cases, nerve biopsy is required as the final diagnostic step to elucidate the etiology.
Serum Analysis
Basic analysis. As a first step, a few serological screening tests (Table 13.2) will give an indication of:
• The presence of any of the main metabolic causes of polyneuropathy (diabetes mellitus, renal failure, vitamin deficiency).
• Any signs of inflammation or hepatic dysfunction, indicating immune-mediated disease or chronic alcohol abuse.
Detailed analysis. The next stage in laboratory analysis includes as a first step:
• Serological detection of various immunological markers.
• Infection serology.
• Selective laboratory diagnosis of suspected hypovitaminosis and nondiabetic metabolic disorders.
• CSF analysis.
If the results are negative, screening for rare metabolic and toxic etiologies can be done as a second step, depending on the manifestation of the neuropathy (Table 13.3). Molecular genetic analysis also forms part of this stage in the stepped screening program.
Serum Analysis: Stage 1
Immune-mediated diseases. Laboratory diagnosis of immunemediated neuropathies is discussed in detail in Chap. 10, “Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies.” Determination of autoantibodies against gangliosides is primarily helpful when the following disorders are suspected:
• Miller-Fisher syndrome: strong association with anti-GQ 1 b antibody.
• Multifocal motor neuropathy (MMN): association with anti-GM1 antibody and, in rare cases, anti-GM2 antibody.
The diagnostic importance of other antibody reactivities for immune-mediated neuropathies is low (e. g., antibodies against gangliosides GD 1 a and GalNac-GD 1 a, disialosyl gangliosides GD 1 b, GD 3, GT1 b, and GQ 1 b, acidic glycolipids SGPG and SGLPG, and sulfatides), and broad screening for these is therefore not generally recommended. Indications for targeted testing are listed in Chap. 10, “Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies.”
On the other hand, all patients with polyneuropathic syndromes of undetermined etiology should be screened for paraproteins. Serum immunoelectrophoresis and serum immunofixation electrophoresis are sensitive screening methods, as is detection of Bence Jones proteins in urine by immunofixation electrophoresis. If IgM paraproteins are detected, the serum should be tested specifically for antibodies against myelin-associated glycoprotein (MAG), since about 50% of IgM paraproteins bind this target antigen. Other IgM subspecificities (e. g., against sulfatides, disialosyl gangliosides) are rare, and they are tested for only on particular selected indications.
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Table 13.2 Basic serological tests |
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Laboratory parameters |
Possible cause of polyneuropathy |
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• ESR • CRP • Differential blood count • Protein electrophoresis |
Immune-mediated disease |
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• Fasting glucose • Daily blood glucose profiles • Oral glucose tolerance test • HbA1 c |
Diabetes mellitus |
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• GOT • GPT • GGT • CDT • MCV |
Alcohol abuse |
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• Electrolytes • Urea • Creatinine |
Renal failure |
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• Vitamin B12 • Folic acid |
Hypovitaminosis |
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Table 13.3 Detailed laboratory analysis |
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Suspected cause of polyneuropathy |
Laboratory parameters |
Diagnostic importance |
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Step 1 |
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Immune-mediated diseases |
Antibodies to GQ 1b |
Miller-Fisher syndrome, Guillain-Barré syndrome with ophthalmoplegia |
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IgM antibodies to GM1 and GM2 |
Multifocal motor neuropathy |
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• IgM, IgG, IgA paraproteins • MAG antibody • Bence Jones protein in the urine |
Monoclonal gammopathy of undetermined significance, malignant paraproteinemia |
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Cryoglobulins |
Cryoglobulinemic vasculitis |
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Antibodies to Hu, amphiphysin, CV2 |
Paraneoplastic sensory neuronopathy |
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Vasculitis, connective tissue diseases |
ANA; ANA subspecificities |
Connective tissue diseases and subtypes |
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Antibodies to Ro/SS-A and La/SS-B |
Sensory neuronopathy in Sjögren's syndrome |
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Anti-neutrophil cytoplasmic antibody with specificity for proteinase 3 (PR3-cANCA) |
Wegener's disease, Churg-Strauss angiitis |
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Anti-neutrophil cytoplasmic antibody with specificity for myeloperoxidase (MPO-pANCA) |
Microscopic polyangiitis, Churg-Strauss angiitis |
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Complement factors C 3, C 4, CH50 |
Immune complex vasculitis |
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Infections |
Borrelia spp. |
Neuroborreliosis |
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Treponema pallidum (screening test) |
Neurosyphilis |
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Varicella zoster virus |
Herpes zoster polyneuroradiculitis |
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CMV |
CMV polyneuroradiculitis, Guillain-Barré syndrome |
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Epstein-Barr virus |
Guillain-Barré syndrome |
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Human immunodeficiency virus |
Guillain-Barré syndrome, distal symmetric neuropathy, sensory neuronopathy, mononeuritis multiplex, Miller-Fisher syndrome |
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Campylobacter jejuni |
Guillain-Barré syndrome |
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Mycoplasma pneumoniae |
Guillain-Barré syndrome |
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Mycobacterium leprae |
Leprosy |
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Hepatitis B virus, hepatitis C virus |
Vasculitic neuropathy |
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Angiotensin-converting enzyme |
Sarcoidosis |
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Acquired metabolic diseases |
Thyroid-stimulating hormone (TSH) |
Hypothyroidism when levels increased (reference range: 0.4–4.0 mU/L) |
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Free thyroxine (FT4) |
Hypothyroidism when levels decreased (reference range: 10–23 pmol/L) |
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Methylmalonic acid |
Vitamin B12 deficiency when values increased (reference range: 53–376 nmol/L) |
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Homocysteine |
Vitamin B12 deficiency when levels increased (reference value: < 10 μmol/L; gray area up to 12 μmol/L) |
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Parietal cell antibody |
Autoimmune gastritis, sensitivity 80%, specificity 50% |
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Intrinsic factor antibody |
Autoimmune gastritis, sensitivity 40%, specificity 90% |
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Vitamin B12 (absorption test) |
Autoimmune gastritis, malabsorption (reference range for vitamin B12 absorption test: > 10% of oral dose eliminated in 24-h urine); in patients with intrinsic factor deficiency—but not in patients with malabsorption—elimination normalizes when the test is repeated with intrinsic factor added |
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Step 2 |
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Hereditary metabolic diseases |
• δ-Aminolevulinic acid (urine) • Porphobilinogen (urine) • Porphyrins (urine, stool) • Erythrocyte porphobilinogen deaminase |
Porphyria, lead intoxication |
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Phytanic acid (serum) |
Refsum's disease |
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Very long chain fatty acids (serum) |
Adrenoleukodystrophy |
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α-Galactosidase (serum, leukocytes, fibroblasts) |
Fabry's disease |
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Arylsulfatase A (leukocytes, fibroblasts) |
Metachromatic leukodystrophy |
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Toxic diseases |
• Lead • Mercury • Arsenic • Thallium |
Intoxication with heavy metals |
ANA, antinuclear antibody; CMV, cytomegalovirus, MAG, myelin-associated glycoprotein.
In cases of sensory neuronopathy, it is obligatory to test for a paraneoplastic etiology by determining the presence or otherwise of autoantibodies against Hu, amphiphysin, and CV2 (Chap. 10, “Paraneoplastic Neurological Syndromes”). These antineural antibodies are detected in about 50% of cases. Important differential diagnoses with relevant altered laboratory findings include sensory neuronopathies associated with Sjögren's syndrome, vitamin B6deficiency, and HIV infection.
Vasculitis and connective tissue diseases. A vasculitic etiology should be considered particularly for neuropathies of the multiplex type, and also for focal neuropathies with or without additional symmetric motor and sensory deficits. In a patient with connective tissue disease, indicative laboratory markers are antinuclear antibodies (ANA) and—if the immunofluorescence test is positive—the fine differentiation of ANA subspecificities by ELISA. Systemic vasculitis is characterized by serological detection of anti-neutrophil cytoplasmic antibodies (ANCA) in the immunofluorescence test. Allergic vasculitis caused by deposition of immune complexes is associated with complement depletion (Chap. 10, “Systemic Vasculitis and Connective Tissue Diseases”). If screening for ANA is negative, the laboratory analysis is supplemented by determination of cryoglobulins and of angiotensin-converting enzyme (ACE) as a screening test for sarcoidosis.
Infections. The most common infectious agents leading to neuropathy include Borrelia, varicella-zoster virus, and CMV (in immunosuppressed patients) causing polyneuroradiculitis. Infections with HIV, CMV, Mycoplasma pneumoniae, and Campylobacter jejuni may prompt chronic inflammatory demyelinating polyneuropathy (CIDP). Distal symmetric neuropathies are associated with HIV infection, syphilis, and borreliosis. Vasculitic neuropathies related to the deposition of cryoglobulins may be caused by hepatitis B and hepatitis C viruses. In developing countries, leprosy is one of the most common differential diagnoses.
Metabolic dysfunction. To exclude hypothyroidism, thyroid function should be analyzed by measuring thyroid-stimulating hormone (TSH) and free thyroxine (FT4). Decreased FT4 and increased TSH levels indicate hypothyroidism due to thyroid dysfunction.
If vitamin B12 deficiency is suspected but there is no macrocytic anemia and plasma vitamin B12 values are between 148 and 221 pmol/L (values > 221 pmol/L exclude deficiency), serum levels of methylmalonic acid (MMA) and homocysteine should be determined. Both of these substances require the vitamin as a cofactor for metabolization, so increased levels of them indicate vitamin B12 deficiency (Lindenbaum et al., 1988) (Chap. 6, “Systemic Vasculitis and Connective Tissue Diseases”). If impaired absorption is suspected (autoimmune gastritis, intestinal malabsorption), the vitamin B12 absorption test (Schilling's test) should be used. For this purpose, one capsule of [57Co]vitamin B12 is administered by mouth, and elimination of the vitamin in 24-hour urine is measured. ELISA detection of antibodies to parietal cells or intrinsic factor suggests autoimmune gastritis.
Neuropathy may also be caused by vitamin B1 or vitamin B6 deficiency. Suspicion of vitamin B1 or B6 hypovitaminosis is usually based on a suggestive history (alcohol abuse, medications), so determination of serum levels is required. only exceptionally.
Serum Analysis: Stage 2
Metabolic and hereditary diseases. Rare metabolic disorders that cause neuropathic syndromes and can be diagnosed by laboratory tests include:
• Porphyria.
• Refsum's disease.
• Fabry's disease.
• Metachromatic leukodystrophy.
• Adrenoleukodystrophy.
Among the various forms of porphyria, the hepatic variants of autosomal dominant inheritance—acute intermittent porphyria, variegate porphyria, hereditary coproporphyia —are associated with asymmetric motor neuropathies. Attacks are often induced by medications.
The common feature of all forms of porphyria is a defect in the enzymes of porphyrin and heme biosynthesis and, as the result, the accumulation and increased elimination of porphyrin metabolites.
Determination of δ-aminolevulinic acid, porphobilinogen, and porphyrins in the 24-hour urine and porphyrins in the stool during clinically manifest attacks is diagnostically important. The pattern of elimination indicates the variant of the disease. In the intervals between attacks, determination of erythrocyte porphobilinogen deaminase (PBG-D) activity may reveal the presence of acute intermittent porphyria. Typical constellations of findings are listed in Table 13.4.
• δ-Aminolevulinic acid.
– Specimen: 24-hour urine (collected as cool as possible).
– Examination method: ion exchange chromatography.
– Reference values: 250–6400 μg/24 h; 2–4 μmol/24 h.
• Porphobilinogen.
– Specimen: 24-hour urine (collected as cool as possible).
– Examination method: ion exchange chromatography.
– Reference values: 100–1700 μg/24 h; 0.5–7.5 μmol/24 h.
• Porphyrins.
– Specimen: 24-hour urine (collected as cool as possible and protected from light), stool (protected from light).
– Examination method: thin layer chromatography, HPLC.
– Reference values for total porphyrins (urine): < 100 μg/24 h; < 120 nmol/24 h.
– Reference values for total porphyrins (stool): 0–2 μg/g; 0–3 nmol/g.
– Reference values for individual porphyrins: see special textbooks.
• PBG-D.
– Specimen: heparinized blood.
– Examination method: spectrophotometry, spectrofluorometry.
The laboratory analysis of rare hereditary metabolic disorders is discussed in detail in Chap. 17. Refsum's disease and adrenoleukodystrophy (ALD) are peroxisomal disorders; Fabry's disease and metachromatic leukodystrophy (MLD) are lysosomal storage diseases (sphingolipidoses). Diagnostically important are the detection of increased levels of phytanic acid in patients with Refsum's disease and the detection of very long chain fatty acids (VLCFA) in the serum of those with ALD. Diagnosis includes determination of α-galactosidase activity in serum, leukocytes, and fibroblasts (Fabry's disease), determination of arylsulfatase A in leukocytes and fibroblasts (MLD), and detection of ceramides (Fabry's disease) and sulfatides in the urine (MLD).
Toxic neuropathy. The primary important of laboratory analysis in toxic neuropathy is in the diagnosis of heavy metal intoxication. It is particularly relevant in the area of expert opinions in occupational medicine.
• Lead: The typical findings in case of lead polyneuropathy are microcytic hypochromic anemia and basophilic stippling of erythrocytes in routine laboratory tests. Since lead interferes with hemoglobin synthesis, elimination of δ-aminolevulinic acid and porphyrins into the urine (see above) increases. The best parameter for assessing lead exposure and/or body load is the determination of lead in whole blood and 24-hour urine (Table 13.5). The detection method is flameless atomic absorption spectrophotometry using graphite tube cuvettes.
• Mercury: Intoxication is demonstrated by increased mercury concentrations in whole blood or 24-hour urine (Table 13.6). Hair analysis is also helpful. The detection method is atomic absorption spectrophotometry using cold vapor or hydride.
• Arsenic: Increased arsenic concentrations in 24-hour urine are diagnostic. Blood determinations are unsuitable for this purpose because arsenic is rapidly eliminated. The detection method is flameless atomic absorption spectrophotometry using hydride.
• Thallium: Increased thallium concentrations in whole blood or 24-hour urine are diagnostic. Hair analysis is used only for orientation. Owing to the rapidity of elimination, low or normalized thallium levels may be measured just a few days after intoxication. The detection method is atomic absorption spectrophotometry using graphite tube cuvettes.
CSF Analysis
CSF analysis should be carried out when the following etiologies are suspected:
• Guillain-Barré syndrome (Chap. 10, “Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies”).
• Chronic inflammatory demyelinating polyneuropathy (CIDP; Chap. 10, “Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies”).
• Vasculitis and connective tissue diseases (Chap. 10, “Systemic Vasculitis and Connective Tissue Diseases”).
• Paraneoplasia (Chap. 10, “Paraneoplastic Neurological Syndromes”).
• Sarcoidosis (Chap. 10, “Neurosarcoidosis”).
• Infections (Chap. 10, “Infections”).
Variations in CSF markers are usually not characteristic. The only reliable evidence is direct or indirect demonstration of pathogens in the CSF of patients with polyneuropathies that are caused by viral or bacterial pathogens. In patients with suspected Guillain-Barré syndrome, it should be noted that the characteristic increase in total protein is often not detected before the 2nd week of disease.
Molecular Genetic Analysis
The primary indication for molecular genetic diagnostic analysis is when hereditary motor and sensory neuropathy is suspected (Chap. 8). Knowledge of the mode of inheritance and neurophysiological findings are essential for selection of the target gene. The two most common forms Charcot-Marie-Tooth disease (CMT1, also called hereditary motor and sonsory neuropathy 1, HMSN1) and hereditary neuropathy with liability to pressure palsy (HNPP) can be detected with little effort by Southern blot or PCR analysis.
CMT1. In 60–90% of cases this autosomal dominant demyelinating disease is caused by a duplication in the gene for peripheral myelin protein 22 (PMP22) on the long arm of chromosome 17 (CMT1A). In rare cases, similar phenotypes are also caused by point mutations within PMP-22 (CMT1B) or mutations in the gene for myelin protein zero (P0; CMT1C) or connexin-32 (Cx-32 on the X-chromosome; CMTX).
Hereditary neuropathy with liability to pressure palsy. In most cases HNPP is caused by a deletion in the PMP22 gene. More rarely, a point mutation in the PMP22 gene is responsible.
When clinical and neurophysiological findings are compatible with CMT1 or HNPP, the first step should involve screening for a duplication (CMT1) or deletion of the PMP22 gene (HNPP). If the result is positive, nerve biopsy is unnecessary. Screening for point mutations involves more expensive tests and is therefore reserved for cases where it is particularly needed (Pareyson, 2003).
Familial amyloidosis. Diagnosis of familial amyloidosis is confirmed by detection of mutations in the transthyretin gene on chromosome 18.
Nerve Biopsy
Indications. Nerve biopsy is indicated when neither the clinical phenotype nor the neurophysiological and laboratory findings indicate a cause of neuropathy, and when the neuropathy is sufficiently severe or progressive to justify the side effects of biopsy (Chap. 9).
Nerve biopsy is essential to confirm the diagnosis in cases of isolated vasculitis of the nervous system, suspected deposition of pathological products (e. g., amyloid), neuropathies caused by sarcoid granuloma, and tumor cell infiltration of peripheral nerves.
To show the presence of vasculitis or amyloidosis, a combined nerve-muscle biopsy is helpful. A probable immunemediated etiology also represents an indication for nerve biopsy before the start of immunosuppressive treatment, if it was not possible to clarify the etiology by noninvasive analysis (Chap. 10, “Systemic Vasculitis and Connective Tissue Diseases”; Chap. 9, “Nerve Biopsy”).
Contraindications. Biopsy is not indicated when a diagnosis is already very probable or confirmed, such as in Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, paraproteinemic neuropathy, genetically detectable hereditary neuropathies, and neuropathies due to known metabolic disorders or confirmed systemic vasculitis and connective tissue diseases.
References
Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988;318:1720–1728
Pareyson D. Diagnosis of hereditary neuropathies in adult patients. J Neurol 2003;250:148–160
Further Reading
Barohn RJ. Approach to peripheral neuropathy and neuronopathy. Semin Neurol 1998;18:7–18
Dengler R, Heidenreich F, eds. Polyneuropathien. Stuttgart: Kohlhammer; 1999
Leitlinien DGN. Diagnostik bei Polyneuropathien. www.dgn.org
Thomas L, ed. Labor und Diagnose. Indikation und Bewertung von Laborbefunden für die medizinische Diagnostik. 6th ed. Frankfurt am Main: TH-Books; 2005