Peripheral neuropathy is a common presentation on neurology inpatient wards, and may also complicate systemic illness. As such, a systematic approach to diagnosis and management is an important skill. Clinical features of peripheral neuropathy, in particular the time course of symptom evolution, the distribution of clinical involvement, and associated features of systemic disease, provide indicators of the underlying pathophysiological mechanism of nerve dysfunction. Electrodiagnostic studies are indispensable to categorize the neuropathy as predominantly demyelinating or axonal and may also demonstrate specific diagnostic features. Further investigations and management are tailored based on the findings of these initial assessments.

The prevalence of peripheral neuropathy is estimated at 8% of primary care patients more than 55 years of age,¹ and this increases to more than 25% of patients with type 2 diabetes mellitus.² Common causes of neuropathy include diabetes mellitus and neurotoxins such as alcohol, chemotherapy, and other medication, which are frequently encountered in inpatient medical settings, making peripheral neuropathy a common referral for neurological consultation.

The present chapter will use illustrative clinical examples to provide a framework for clinical diagnosis of patients presenting with peripheral neuropathy as well as motor neuron disease (MND), along with a suggested approach to the investigation and management of such patients.

Clinical features of peripheral neuropathy

Patients with peripheral neuropathy present with various combinations of symptoms, including alterations in sensation, pain, muscle weakness, and autonomic symptoms such as postural hypotension and altered gastrointestinal motility. Peripheral neuropathy may be suspected when these symptoms are combined with appropriate signs on clinical examination, such as diminished muscle stretch reflexes and acral sensory loss. It is important, however, to consider other differential diagnoses during the workup, including myelopathy, polyradiculopathy, neuromuscular junction disorders, and myopathy, which may all mimic peripheral neuropathy and MND.

An important initial step in the diagnosis of peripheral neuropathy and MND is identifying clinical patterns that may enable differential diagnoses to be developed. In general, peripheral neuropathy may be categorized based on a number of factors: (1) the rapidity of onset and evolution; (2) the distribution of nerve involvement; (3) the elements of the peripheral nervous system involved; (4) associated neurological features; and (5) associated systemic features.

Electrodiagnosis of peripheral neuropathy

Electrodiagnostic studies are the cornerstone investigation for patients presenting with peripheral neuropathy. Electrodiagnostic studies may include one or more of nerve conduction studies (NCS), electromyography (EMG), repetitive nerve stimulation (RNS), and single-fiber EMG (SFEMG), with NCS and EMG the bulk of studies performed. Additional specific electrophysiological testing, such as evoked potential studies, may also be indicated. Autonomic studies such as sympathetic skin responses, heart rate variability with Valsalva, and quantitative sweat testing may also be of value when evaluating patients with autonomic involvement.

Nerve conduction studies

NCS are essential to characterize peripheral neuropathy and enable a more refined workup and management approach. In particular, NCS give an indication of the pathophysiology of the underlying nerve injury. The key metrics in NCS are response amplitude and conduction velocity, with each parameter useful in sensory and motor studies (Figure 41-1). These metrics allow the electromyographer to determine whether the neuropathy demonstrates predominantly “axonal” or “demyelinating” features.

Axonal neuropathies demonstrate loss of axons on histopathological studies. On NCS, this manifests as reduced motor and/or sensory amplitudes (Figure 41-1). Conduction velocity is usually preserved, although on motor NCS, conduction velocity typically slows with greater reduction of the compound muscle action potential (CMAP) amplitude, reflecting loss of large-caliber fast-conducting fibers. Slowing of conduction velocity should not usually exceed 25% of normal limits in axonal neuropathies.

The myelin sheath is necessary for rapid saltatory conduction. Demyelinating neuropathies in which there is primary or prominent myelin damage may be delineated on NCS by the presence of slowing of nerve conduction velocity, which may be predominantly distal, segmental, diffuse, or predominantly proximal (Figure 41-1). When isolated distal slowing is identified, it is necessary to ensure that the temperature of the limb is adequate (at least 30°C in the lower limbs and 32°C in the upper limbs), as conduction velocity demonstrates a linear positive relationship with nerve temperature.

Segmental slowing of nerve conduction may be associated with conduction block, where the amplitude of the motor response is greater with distal than proximal stimulation (Figure 41-1). The finding of conduction block is central to the electrodiagnostic criteria of certain inflammatory neuropathies including chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). In some instances, conduction velocity with standard NCS may be normal despite the clinical suspicion of inflammatory neuropathy. In these patients, conduction slowing may be confined to proximal segments. Proximal segments may be tested by measuring the F-wave latency, which assesses proximal motor conduction, or the H-reflex, which assesses the proximal sensory and motor segments.

The pattern of involvement on NCS provides additional diagnostic and pathophysiological information. Neuropathies with greatest clinical and electrodiagnostic involvement in distal lower limb nerves, with less or no involvement of upper limbs, suggests a “length-dependent” process. This pattern is commonly seen in toxic, metabolic, idiopathic, and hereditary neuropathies and reflects “dying back” of the longest axons serving the distal lower limbs. In some instances, the length-dependent pattern is not observed. Inflammatory neuropathies may be associated with normal lower limb sensory NCS but abnormal upper limb sensory NCS, the reverse of the length-dependent pattern. Asymmetric involvement may suggest vasculitic neuropathy.

The relative burden of sensory and motor nerve involvement on NCS may also help guide clinical diagnosis, and complements clinical assessments. For example, isolated sensory nerve involvement in a patient with symptoms of connective tissue disease may suggest sensory ganglionopathy, such as may be seen in 
Sjögren syndrome. Isolated motor nerve involvement 
in a patient with progressive limb weakness is typical of MND. Early autonomic nerve involvement may be seen in patients with amyloid neuropathy.

Electromyography

Electromyography (EMG) is routinely performed in the workup of peripheral neuropathy and MND. EMG assesses the presence of spontaneous electrical activity in muscles, including fibrillations and fasciculations. Fibrillations (and positive sharp waves) indicate the presence of denervated muscle fibers within the muscle. Fasciculations represent the spontaneous discharge of a motor unit and are reflective of motor axonal hyperexcitability. Motor unit recruitment with muscle activation is reduced following motor nerve injury.

Motor unit analysis looks for evidence of reinnervation following axonal loss (Figure 41-2), and the presence of motor unit changes suggests at last some chronicity as muscle reinnervation processes take several weeks to develop. EMG is useful to detect muscle denervation due to motor nerve involvement, and may be abnormal even when motor NCS are within normal limits. Changes on EMG give an indication of the acuity of the disease process. For example, an acute neuropathy may be associated with fibrillations on EMG but minimal motor unit changes. A chronic process may demonstrate neurogenic motor unit changes with few or no fibrillations.

EMG is also useful to exclude mimic conditions such as myopathy, and specialized single-fiber EMG studies may be performed to evaluate for disorders of the neuromuscular junction.

Additional diagnostic modalities

Imaging

Peripheral nerve imaging studies including MRI and ultrasound have emerged as valuable complementary investigations in the workup of peripheral neuropathy. In peripheral neuropathy, imaging may identify nerve enlargement, disturbance of the normal internal fascicular pattern, or change in signal intensity that may suggest disease. Peripheral nerve imaging is particularly useful for the workup of inflammatory neuropathy as it may detect abnormalities in segments inaccessible to routine electrodiagnostic studies. MRI or ultrasound studies of muscles may also provide additional diagnostic information, in particular when assessing for evidence of muscle denervation.^4,5

Nerve and muscle biopsy

Nerve biopsy is only occasionally indicated in the workup of peripheral neuropathy but sometimes may be required for difficult-to-diagnose cases. The sural nerve is most frequently biopsied, but other noncritical sensory nerves such as the superficial radial nerve, antebrachial cutaneous nerve, or lateral femoral cutaneous nerves are selected in specific clinical scenarios, for example upper limb or proximal predominant neuropathy. Fascicular biopsy of major nerves may also be considered where there is electrophysiological or imaging confirmation of focal nerve involvement and where the diagnosis has eluded other investigative efforts. Fascicular nerve biopsy may be particularly relevant to identify evidence of peripheral nerve vasculitis, which commonly shows patchy and asymmetric involvement. Concomitant muscle biopsy is frequently performed in suspected vasculitis to increase the diagnostic yield.

What are the important clinical indicators in this case?

The tempo of onset and progression of symptoms was acute, involving motor, sensory, and autonomic nervous systems. In terms of localization, acute peripheral neuropathy is the most likely cause.

Clinical features that may indicate the most likely neuropathy subtype are:

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  Symmetry of limb involvement

  
  
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  Rapid evolution of symptoms

  
  
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  The history of viral infection preceding the onset of symptoms

Important missing clinical information includes drug and environmental exposures prior to the onset of neuropathy.

What other diagnostic studies are useful to help confirm the diagnosis?

CSF studies

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  CSF studies can provide important clues in the workup of GBS.

  
  
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  The typical CSF finding in AIDP is cytoalbuminologic dissociation.

  
  
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  Increased CSF protein is seen in 50–90% of patients with GBS, while CSF white cell count is typically normal or marginally elevated (maximum 10 cells, all lymphocytes).

  
  
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  CSF studies may be normal within 1 week of onset, despite typical changes being seen on subsequent studies.

Routine blood panels

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  Routine blood panels do not provide diagnostic information.

  
  
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  Liver enzymes may be elevated in some patients with GBS.

  
  
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  Serum albumin and glucose should be measured to compare with CSF measurements.

Serological diagnosis of preceding infection

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  There are not often great rewards in pursuing a serological diagnosis of the preceding infection in most cases.

  
  
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  The identification of the preceding infection does not usually substantially change the management of the GBS once manifest.

  
  
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  One exception to this statement is testing for human immunodeficiency virus (HIV), as AIDP can be associated with seroconversion or early asymptomatic phases of HIV infection. As such, HIV serology may be considered in the routine workup of patients with GBS given the significant management implications of a positive result.

Antiganglioside antibodies

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  Antiganglioside antibodies are identified in a small proportion of patients with GBS.

  
  
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  Testing for antiganglioside antibodies may not be necessary in patients with classic GBS, but may be useful in patients with GBS variants, such as acute ataxic neuropathy (GD1b), Miller Fisher syndrome (GQ1b), AMAN (GM1), and Bickerstaff encephalitis (GT1A and GQ1B).

  
  
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  The presence of GD1a/GD1b and/or GD1b/GT1b in GBS is associated with severe disease and the need for ventilator support.⁹

Lung function tests

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  Respiratory muscle strength testing, typically measuring forced vital capacity or peak expiratory flow, should be performed at presentation and then as part of regular observations to detect the development of respiratory muscle weakness.

What differential diagnoses should be considered?

Besides GBS, a number of other processes should be considered in patients presenting with features of acute neuropathy as they may produce similar presenting features (Table 41-3):

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  Acute spinal cord disease may present with motor, sensory, and autonomic deficits. Hypo- or areflexia may be apparent early in the course of illness. Arguing against spinal cord disease is the absence of bladder involvement despite other autonomic features, as bladder dysfunction is a common presenting feature of spinal cord disease including compressive and inflammatory myelopathy. A defined sensory level may also be observed in spinal disease.

  
  
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  In terms of neuropathy, acute hepatic porphyrias may present with acute-onset motor neuropathy and autonomic dysfunction. Sensory loss is usually minor, but pain may be prominent.¹⁰ Acute lead poisoning produces a similar clinical picture.

  
  
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  Paraneoplastic neuropathy may present with acute-onset sensory ataxic neuropathy, associated with anti-Hu antibodies in approximately 50% of cases.¹¹

  
  
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  Rarely, connective tissue disorders such as Sjögren disease may present with an acute sensory ganglionopathy with prominent sensory ataxia, potentially mimicking the acute ataxic neuropathy subtype of Miller Fisher Syndrome (MFS; Table 41-3).

  
  
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  When CSF pleocytosis or polymorphonuclear cells are detected, polyradiculitis from infection (HIV, VZV, CMV, Lyme), sarcoid, carcinomatous, or lymphomatous causes may be considered.¹²

  
  
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  West Nile and polio virus infections may present with acute and progressive motor abnormalities, sharing similarities with AMAN.

  
  
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  Acute drug-induced neuropathies are usually easily discriminated from GBS on history. Causative agents include chemotherapeutic agents, anti-retroviral agents, and some antibiotics.

What are the management strategies for GBS?

Treatment of GBS includes disease-modifying immunomodulatory therapy and supportive care to avoid complications.¹³

Disease-modifying treatment

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  Intravenous immunoglobulin (0.4 g/kg bodyweight repeated on 5 consecutive days) is the most frequently prescribed treatment in GBS. Randomized controlled trials have demonstrated efficacy of IVIG given to patients with GBS, specifically reducing residual disability and duration of ventilation.¹⁴

  
  
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  Plasma exchange (PLEX) demonstrates similar efficacy to IVIG but is now no longer the preferred option due to the ease of use and safety profile of IVIG. Combining PLEX and IVIG does not add therapeutic benefit over IVIG or PLEX alone.

  
  
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  Corticosteroids alone do not alter the course of GBS, and combining methylprednisolone with IVIG was not more effective than IVIG alone.

  
  
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  Up to 10% of patients treated with IVIG for GBS experience clinical deterioration following initial improvement from IVIG. This is considered a treatment-related fluctuation, and although there are not clear data to guide treatment decisions, a second course of IVIG is frequently given in these patients. If there are more than 2 deteriorations, an acute presentation of CIDP may be considered.

Supportive care in GBS

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  Monitoring of respiratory muscle strength is important throughout the period of clinical deterioration; 20–25% of patients require artificial ventilation.

  
  
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  Close monitoring of vital signs to detect autonomic involvement, although autonomic dysfunction is often transient.

  
  
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  Prophylaxis of deep venous thrombosis

  
  
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  Pressure care in patients with severe weakness

  
  
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  Eye care in patients with facial muscle weakness

  
  
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  Pain management

  
  
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  Early rehabilitation input

  
  
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  Joint stretching and splinting to avoid joint contractures

Theoretical considerations—Guillain-Barré syndrome

GBS is the most common cause of acute peripheral neuropathy with an estimated incidence of 1.7/100000.¹⁵ GBS 
includes a number of overlapping clinical entities including AIDP, AMAN, and AMSAN (Table 41-4). GBS also shares common pathogenic mechanisms with MFS and Bickerstaff’s encephalitis (BE). As such they are considered a spectrum of disorders ranging from presentation with primarily single-modality involvement in the limbs, to complex disorders with central and peripheral involvement (Table 41-4).

GBS has well-recognized clinical features with acute-onset symmetric limb and/or cranial nerve weakness. Weakness most often starts in the lower limbs and then ascends, but upper limb onset weakness may also be seen. Motor symptoms typically predominate; however, there are commonly distal paraesthesiae at or before the onset of weakness. Pain, in particular back and proximal limb pain, is common, and pain may be a prominent feature. Generalized reduced or absent deep tendon reflexes are seen in the 
majority of patients, but reflexes may be preserved or increased in a minority of patients. By definition, GBS is a monophasic illness with the interval between onset and nadir from 12 hours to 28 days followed by clinical plateau.

Many infections have been associated with GBS including Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, influenza, and Mycoplasma pneumoniae,¹⁶ and antecedent diarrheal or upper respiratory tract infection is reported in about 60% of patients. There have also been clusters of cases of GBS associated with specific vaccines, in particular several strains of the influenza vaccine. Molecular mimicry is advocated as the mechanism underlying the development of GBS, with polysaccharides on the microbe resembling glycoconjugates on human nerve.

What are the important clinical indicators in this case?

This case describes the subacute onset of symptoms, involving sensory and motor systems, without apparent autonomic involvement. Notable clinical features are:

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  Symmetrical involvement

  
  
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  Synchronous upper and lower limb involvement

  
  
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  Proximal more than distal weakness

  
  
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  Background of diabetes mellitus

Additional elements of history and examination that may help clarify the diagnosis are:

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  History of diabetic control

  
  
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  Medication history

  
  
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  History of autoimmune disease

  
  
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  Abdominal examination to assess for hepatomegaly and splenomegaly

  
  
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  General physical examination to look for stigmata of malignancy, lymphoproliferative disease, and connective tissue disease.

What differential diagnoses should be considered?

CIDP

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  CIDP is the most likely cause of the current presentation and NCS findings, particularly given the evidence of median motor nerve conduction block identified.

Diabetic neuropathy

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  The patient was diabetic, and a diabetic peripheral nerve complication may be considered. Diabetic peripheral neuropathy typically demonstrates a chronic onset; however, occasionally patients present with a subacute onset.

  
  
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  Subacute diabetic proximal neuropathy (or diabetic amyotrophy; diabetic lumbosacral plexopathy) most commonly involves the lower limbs, in particular 
quadriceps, but is often asymmetrical. Pain may be prominent. Weight loss is also frequently 
reported.¹⁸

  
  
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  Acute painful small fiber neuropathy may also present in diabetics, but is not associated with motor dysfunction in the acute stages.

  
  
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  NCS in diabetic peripheral neuropathy may demonstrate mixed axonal and demyelinating features; however, axonal features usually dominate.