Peripheral neuropathies are syndromes, seen in association with a variety of anatomic or physical, metabolic, toxic, ischemic, nutritional, inflammatory (e.g., autoimmune, infectious), paraneoplastic, or inherited processes. They may be present as mononeuropathies, polyneuropathies, autonomic neuropathies, or polyneuropathies associated with autonomic neuropathies. Additionally, they may be further characterized by:

  • Frequency of occurrence (common causes: diabetes, alcohol, thiamine deficiency, and hepatitis C)

  • Acuity of onset (e.g., Guillain-Barré syndrome, porphyria, paraneoplastic, vasculitic, medications, tick paralysis, critical illness polyneuropathy, post-diphtheria, and buckthorn toxicity).


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They also can be characterized by the degree to which they result in motor dysfunction, a loss of sensory function (‘negative” sign), or an increase in a particular sensation (“positive” sign), and the fiber sizes that correlate. Small fiber neuropathies more classically are associated with positive signs, whereas large fiber neuropathies are more classically associated with loss of function, or negative signs.

Regardless of the cause or presentation, the pathology is uniformly related to some form of damage to either the peripheral axons and/or their myelin sheaths. While brief reference will be made to the mononeuropathies, the focus of this discussion will primarily address the polyneuropathies.

Polyneuropathy is a common syndrome in practice, and occurs in about 2.4% of the population.

There are hundreds of individual causes of peripheral neuropathy, thus it is important to develop different reasoning or thorough constructs to guide one to different etiologic themes, so that one can then focus on those themes…and look them up! Accordingly, peripheral neuropathies may be characterized by their inheritance, clinical patterns or pathologic presentations. Additionally, patients may present with findings suggesting of autonomic or small fiber involvement, which may suggest a different underlying disorder. Thus, a history assessing the potential features and causes of neuropathy might focus upon the:

  • Frequency of occurrence

    Common causes: diabetes, alcohol, thiamine deficiency, and hepatitis C.

  • Acuity of presentation (acute, sub-acute, chronic)

    Acute syndromes to consider: Guillain-Barré syndrome, porphyria, paraneoplastic, vasculitic, medications, tick paralysis, critical illness polyneuropathy, post-diphtheria, and buckhorn toxicity.

  • Presence or absence of ‘positive’ (e.g., pain, dysesthesias) or ‘negative’ (e.g., loss of touch, vibration, position sense) neuropathic symptoms or signs.

  • Pure motor or pure sensory disorders;

    Pure motor: porphyria, myeloma, dapsone, suramin, heavy metal toxicity, organophosphates, and anterior horn cell disorders.

    Pure sensory: especially consider leprosy, paraneoplastic, but can also be associated with diabetes, B-12 deficiency, celiac disease, acromegaly, myeloma, and monoclonal gammopathy of undetermined significance.

  • Distribution (e.g., mononeuropathy, polyneuropathy, multiple mononeuropathies, autonomic)

  • Acquisition (inherited, and all the rest)

  • Pattern on electrophysiologic testing

    Axonal patterns are suggestive of diabetes, alcohol, toxins, metabolic, and drug toxicities.

    Demyelinating patterns are suggestive of acute (Guillain-Barré syndrome) and chronic inflammatory polyneuropathies (CIDP), paraneoplastic disorders, and medications and toxins.

  • Fiber involvement (e.g., small versus large fiber neuropathies)

  • Presence of a family history of neuropathy (e.g., Charcot Marie Tooth syndrome)

The approach to evaluating patients for peripheral neuropathies is composed of efforts to identify and discriminate various clinical syndromes with history, exam, and diagnostic studies listed below.

Historical questions really relate to determining the presence or absence of a neuropathy as well as then probing as to the cause. Thus, questions can be characterized as follows.

Questions trying to elucidate whether a neuropathy is present:

  • Inquire about ‘positive’ symptoms such as burning, tingling, lancinating or shooting pains. Positive symptoms support an acquired neuropathy involving at least the small sensory fibers.

  • Inquire about ‘negative’ symptoms such as numbness, clumsiness, orthostasis, weakness, falls, stumbling or gait abnormalities. While patients inherited neuropathies typically report loss of function, one may also see negative symptoms in malnutrition, inflammatory, toxic, or metabolic syndromes.

Questions exploring different potential etiology’s as well to discriminate between syndromes:

  • Etiologic questions

    Duration of symptoms (acute versus sub-acute syndromes).

    Distribution (mononeuropathy, polyneuropathy, multifocal, proximal, distal, symmetry, bulbar).

    Distal versus proximal onset of symptoms. In addition to the ‘asymmetries’ discussed below, symmetric, progressive distal to proximal symptoms or evolution suggest more of a length dependent, ‘toxic/metabolic’ etiology.

    Patchy or more proximal onset of symptoms suggest inflammatory, anatomic, or vasculitis processes.

    Exposures (environmental, household or therapeutic toxins, ill contacts, medications)

    Underlying systemic illness (diabetes, weight loss, malignancy, renal disease, rashes, fever, infection, HIV risks)

  • Differentiating questions

    Bulbar symptoms? Suggesting a need to explore for myasthenia gravis, Miller-Fisher variant Guillain-Barré Syndrome, bulbar ALS, carcinomatous meningitis, basilar meningitis, or botulism.

    Proximal muscle involvement or myalgias? Suggesting a need to explore more of a myopathic process.

    Diurnal variation? Suggesting a need to consider myasthenia gravis.

    Orthostasis symptoms? In addition to cardiovascular, medications, or other hemodynamic issues, this finding should raise the question of an autonomic neuropathy such as amyloidosis, diabetes, Guillain-Barré, paraneoplastic syndrome, or even Sjögren syndrome.

Questions to explore severity and acuity (e.g., need for more urgent intervention such as mechanical ventilation):

  • Pace of onset

    The more rapid the symptom onset, the more one should consider vascular ischemia, an immune mediated process, such as Guillain-Barré, paraneoplastic neuropathy, or an infectious process such as hepatitis C or HIV.

    Subacute to chronic processes are less specific, and could be associated with inherited, immune, toxic, or metabolic processes.

  • Associated dyspnea

    This alarm symptom should suggest either a bulbar disorder such as myasthenia gravis, or progressive diaphragmatic weakness from syndromes such as Guillain-Barré, or bulbar or progressive Amyotrophic lateral sclerosis.

  • Any signs of asymmetry

    Either upper versus lower, or left-right asymmetric lesions may suggest either a spinal cord lesion, hemispheric or thalamic lesions.

    Crossed findings (e.g., ipsilateral face with contralateral body asymmetry) should suggest a brainstem cause.

  • Bulbar symptoms (an alarm sign, suggesting the disorders noted above)

For an asymptomatic patient a simple assessment of the primary sensory modalities (pinprick, soft touch, vibration), and some integrated examination (e.g., gait, heel walk, Romberg) should suffice. However, if pursuing positive or negative symptoms, a more thorough examination should be employed to also include deep tendon reflexes, bulk and tone, proprioception, temperature assessment, and potentially an evaluation for a cortical sensory loss.

There is some evidence reporting likelihood ratios for the assessment of neuropathies, but this is primarily limited to evaluating patients with diabetes. However, data from an attempt to identify patients at risk for falling was unimpressive, yielding poor likelihood ratios for proprioceptive loss or physical deconditioning, suggesting a limited utility in using the physical examination to predict adverse outcomes in peripheral neuropathy.

With respect to techniques, there are no special objective examination maneuvers for discovering or further elucidating peripheral neuropathies, other than what we employ daily. As a general rule, try to perform at least one exam on each of the tracks. Thus:

  • The ventral (anterior) spinothalamic tract carries fibers that sense soft touch. For this one should employ a cotton wisp or even grossly a piece of tissue paper.

  • The dorsal column carries fibers that sense soft and deep pressure, vibration, and position sense. Thus, soft pressure may be assessed with finger touch, vibration should be assessed over a bony prominence with a 128 Hz tuning fork (some argue for use of a 256 Hz fork for improved assessment of Pacinian fibers), and proprioception should routinely be assessed in the lower extremity, and would include the upper extremity if suspicion for a syrinx or upper cord lesion existed.

  • The lateral spinothalamic track carries fibers associated with superficial and deep pain, and temperature sense. To best evaluate this track, one should employ a pin prick or other sharp object. A torqued-break of a ‘wooden’ tongue depressor yields the perfect disposable sharp-dull instrument. The frigid end of a tuning fork or bell of a stethoscope, when used in alternation with some warm, cylindrical object (pen, plastic reflect hammer handle, etc.) allows for a quick and handy bedside assessment of temperature.

The only caution is that a patient may have a clinically significant neuropathy in the absence of any overt ‘positive’ symptoms (e.g., a large fiber or a pure motor neuropathy), or overt findings on examination (e.g., small fiber neuropathies).

A recent evidence-based review of the role of laboratory testing has codified some standards for the initial evaluation of patients with distal symmetric polyneuropathy. While evidence is limited on many their recommendations, reasonable initial testing is as follows:

1. Hematology:

  • Complete blood count

  • Erythrocyte sedimentation rate or C-reactive protein

  • Vitamin B-12 (or methylmalonic acid) (was assessed as having a high yield)

2. Biochemical tests:

  • Comprehensive metabolic panel, to include;

  • Fasting blood glucose (was assessed as having a high yield)

3. Thyroid function tests

4. Serum protein electrophoresis (was assessed as having a high yield)

5. Glucose tolerance test of suspicion of diabetes (was assessed as having a high yield)

6. Urine studies

  • Urinalysis

  • Urine protein electrophoresis with immunofixation

  • Drugs and toxins: inquire

7. Complete electrodiagnostic studies [Nerve conduction studies (NCS) and needle electromyography (EMG)]:

  • Perform if unclear after initial workup or presence of atypical symptoms: asymmetry, motor predominance, non-length dependence, prominent autonomic involvement, acute onset

8. Hepatitis C virus (HCV) serology

  • Due to its rising prevalence and association with cryoglobulinemia and vasculitic neuropathy, some will also perform analysis hepatitis C virus during the initial evaluation as well. Additional studies may be ordered based on suspicion of disease. Others would make this a follow up test based on suspicion.

Enumerating the specific diagnostic criteria for each of the disorders is beyond the scope of this chapter.

The most important ‘wasted’ tests are those adding little value to diagnosis or management. Adhering to the rational, two-step, evaluation noted above is a reasonable approach to a more measured diagnostic evaluation of peripheral neuropathy. Additionally, if the diagnosis is readily identifiable from history or exam (e.g., diabetes, alcoholism, or drug toxicity), some argue little yield in any further testing.

The management options for individual peripheral neuropathies are best left to the discussion of the specific neuropathies, but are generally focused upon relief of symptoms and maintenance or improvement in function. The management of symptoms is primarily focused upon neuropathies with predominantly positive phenomenon, such as pain or paresthesias. A recent evidence-based systematic review of pharmacotherapy for neuropathic pain continued to find the most benefit from tricyclic antidepressants, revealing a number needed to treat (NNT) of 4 to improve symptoms. Serotonin-noradrenaline reuptake inhibitors (duloxetine or venlafaxine), pregabalin, and gabapentin all had similar efficacy compared to placebo with NNT’s in the range of 7-9. These are also considered first-line treatment along with tricyclic antidepressants. There is little evidence for strengthening exercises in improving outcomes, but more study is needed.

Certain neuropathies with pulmonary and bulbar sequelae are worthy of recognition, such as the acute ascending weakness of Guillain-Barré Syndrome, and the bulbar weakness of myasthenia gravis or botulism. For neuropathies that are rapidly progressive or present with acute bulbar symptoms, the initial assessment should include the measurement of ventilatory reserve to determine if the patient may require urgent intubation.

This consists of bedside measurement of negative inspiratory force (NIF), and forced vital capacity (FVC). There is no uniform agreement on which individual parameter is more predictive of ventilatory failure, but in addition to reviewing the admitting presentation for predictors of needing mechanical ventilation the following values would necessitate close monitoring for ventilatory failure.

  • A negative inspiratory force (NIF) of < 30 cm H20, or the forced vital capacity (FVC) is less than 60% predicted (or less than 20 mL/Kg),

  • By convention a forced vital capacity (FVC) of < 15 mL/Kg is considered an indication for mechanical ventilation. (Guillain-Barré Syndrome)

Treatment Options (see Table I).

Table I.n

Treatment Options for Neuropathic Pain

Probably the most common pitfalls of evaluation and management of peripheral neuropathies are a) the overall reliance on the sensitivity of physical examination and diagnostic testing, and b) a lack of a complete historical database or physical examination to allow guidance. With respect to physical examination, most recommendations are based on experiential recommendations, likely no one exam finding can rule in or out a peripheral neuropathy. This may be especially true in the setting of a clinical syndrome suggestive of small fiber neuropathy, where one may need to continue to pursue diagnostic testing should the first tier return negative.

There have been numerous evidenced-based reviews focusing on the treatment of painful peripheral neuropathies, which overall conclude that there is limited evidence for universal success, and all with adverse effects worth noting. An additional problem with the existing evidence is that the vast majority of positive studies report symptom improvements when compared to placebo, rather than active treatment, thus conclusions are mostly inferential rather than data driven (Table I).

It appears the best evidence for symptomatic improvement is with tricyclic antidepressants and some of the newer antidepressants. There is less good evidence for the efficacy of serotonin reupdate inhibitor antidepressants. However, the choice of first-line therapies are likely more related to patient factors and costs when choosing between tricyclic antidepressants, serotonin reuptake inhibitors, anticonvulsants, antiarrhythmics, or even topical agents such as capsaicin.

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