Peripheral Nerve Disorders: Pathology and Genetics

By Joachim Weiss

Peripheral Nerve Disorders: Pathology and Genetics is a definitive, clinically-oriented guide to the pathology of peripheral nerve disorders.

These commonly seen neurological challenges have many causes and accurate diagnosis is often necessary via pathological analysis. New techniques exploiting molecular biological knowledge have opened up new vistas to understanding the pathogenesis of these disorders, and hence their effective management.

This new title takes a disease-oriented approach to understanding the pathology of these conditions. It combines classical and contemporary techniques to enable practitioners in neurology and neuropathology to better understanding of the disease processes underlying patients’ presentations and to formulate appropriate management plans.

Peripheral Nerve Disorders: Pathology and Genetics is a valuable resource for neurologists, neuropathologists, pathologists, neurobiologists and geneticists.

• Language: English
• Publisher: Wiley
• Release date: Aug 1, 2014
• ISBN: 9781118618417

Book preview

Chapter 1

Clinical assessment and classification of peripheral nerve diseases

Pierre Bouche

Department of Clinical Neurophysiology, APHP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

Pathophysiology

The major processes underlying peripheral nerve lesions will be detailed in Chapter 7 entitled Basic pathologic reactions.

Wallerian degeneration occurs following a physical interruption of healthy axons in a nerve trunk. The changes occur distal to the transection site. There is complete paralysis and loss of sensation in the territory of the nerve trunk immediately following the nerve lesion. Axons and myelin sheaths degenerate distal to the site of transection. Nerve conduction disappears in a few days in myelinated fibers (usually between 5 and 8 days) but takes longer to vanish in unmyelinated fibers.

Segmental demyelination is due to damage to the myelin sheath, sparing the axons. Depending on the extent of demyelination, nerve conduction is slowed or blocked. Slowing of nerve conduction without block does not lead to a motor deficit. Conduction block may be transient and remyelination may be rapid with complete recovery in few days but may take up to 3 months. Pure segmental demyelination is not common and there is usually a variable degree of associated axonal degeneration. In chronic polyneuropathies, demyelination and remyelination proceed, leading to hypertrophic nerve fibers (onion bulb formations).

Axonal degeneration causes a distal breakdown of axons. Paralysis is roughly proportional to axonal loss. The clinical features are usually a symmetric distal sensorimotor deficit in the lower limbs. It is frequently due to metabolic disorders or toxins. Recovery takes much longer than in demyelinating neuropathies; axonal regeneration may take more than a year.

Neuronopathy corresponds to a lesion of the nerve cell body and can be a motor neuronopathy (anterior horn cell) or a sensory ganglionopathy (sensory ganglion).

Clinical examination

Pattern of distribution of nerve involvement

The pattern of distribution of peripheral nerve involvement is very helpful and important for initial diagnostic workup.

The main patterns are:

Mononeuropathy, which comprises focal lesions of peripheral nerves. The usual causes are trauma, focal compression by external pressure or entrapment. It may also be an isolated feature of a more widespread process such as a vasculitis or a hereditary neuropathy with liability to pressure palsies (HNPP).

Multiple mononeuropathy (or multiplex mononeuropathy, mononeuritis multiplex) is the involvement of multiple separate peripheral nerves, which may appear simultaneously or serially. The main causes are vasculitis, diabetes, and leprosy but it may also be due to a focal variant of chronic inflammatory demyelinating polyneuropathy (CIDP, or a multifocal motor neuropathy. HNPP may also present as a multiple mononeuropathy.

Polyneuropathy is a generalized neuropathy and is symmetrical or slightly asymmetrical. It may be distal or distal and proximal if roots are also involved as in polyradiculoneuropathy. In distal symmetrical polyneuropathy, nerve fibers appear affected in a length-dependent way: toes and feet are affected first. This type of polyneuropathy is mainly due to metabolic diseases (diabetes). In polyradiculoneuropathy, both roots and nerves are affected and an inflammatory/immune cause is generally found.

Other presentations are plexopathy and radiculopathy.

Medical history

Clinical assessment of neuropathies should include a careful past medical history, current and past medications, exposure to heavy metals and solvents, social and family history, and review of systemic diseases.

Social history review includes patient’s occupation, hobbies, and behavior (smoking, alcohol, sexual preference, recreational or intravenous drug use).

Family history is important, especially in chronic, long-standing neuropathies. General inquiries are frequently not helpful; examination of family members is better.

Course of the disease: The course may be acute, over days to four weeks, subacute, weeks to months, chronic, or long standing (onset during childhood). The course may be monophasic, progressive, or relapsing.

Clinical presentation

Peripheral nerve diseases may present with motor and/or sensory and autonomic symptoms (see Table 1.1).

Table 1.1 Causes of neuropathy according to the clinical presentation.

The main presenting complaints for most neuropathies are some combination of weakness, sensory disturbance, and walking difficulties.

Patients variably describe their sensory symptoms as tingling, swelling, stabbing, bunched-up socks, prickling, icy, hot, and clumsy. Frequently all these abnormal feelings are referred to as paresthesia. Neuropathic painful symptoms may be described as throbbing, burning, or like an electric shock.

Motor symptoms are frequently distal at the onset: patients often complain of tripping over kerbs, or difficulty walking. They may notice a stepping gait due to foot drop. Limb ataxia is the major complaint in large-fiber neuropathies (ganglionopathies). Whether the onset is proximal or distal, in upper or lower limbs, is diagnostically important.

Other positive motor symptoms include tremor, fasciculation, myotonia, cramps, neuromyotonia, and the syndrome of continuous motor unit activity, moving toes (in the painful legs and moving toes syndrome), and restless legs syndrome.

Examination

Neurological examination needs to be complete. A general physical examination may provide clues to the diagnosis.

Neurological examination

Motor examination

It is a good practice to begin by watching the patient stand and walk, then do the Romberg’s test, asking the patient to rise onto their heels and toes. Thereafter, look for wasting of distal upper and lower limb muscles, especially in the peroneal muscles in the lower limbs and the intrinsic muscles of the hand.

Strength is usually graded using the Medical Research Council (MRC) grading scale (see Table 1.2).

Table 1.2 Expanded MRC scale for manual muscle testing [1].

Source: Bromberg & Smith, 2002. Reproduced with permission of Lippincott Williams & Wilkins.

Mild or early weakness is best assessed in muscles such as the toe flexors and extensors. The interosseous and thenar intrinsic muscles of the hands must be examined as well as the proximal muscles in the upper and lower limbs.

The distribution of weakness is crucial for diagnosis. Does the weakness involve distal extremities, or is it both proximal and distal? Does the weakness have a symmetric distribution? Does the weakness involve neck or facial muscles?

Sensory examination

Sensory examination is difficult since it is mainly subjective and dependent on the patient’s cooperation. Examination should involve testing for light touch, pain, vibration, and proprioception.

The inability to distinguish between touch and pin suggests a loss of nociceptive fibers.

The joint position sense that assesses large diameter fibers is usually tested in the big toe.

Temperature must be tested using cold and hot tubes over the skin. It assesses unmyelinated and small fibers.

Deep tendon reflexes

Sensory fibers of the reflex arc are more vulnerable than motor fibers.

Loss of tendon reflex is usually an indication of loss or lesions of large-diameter fibers and is common in peripheral neuropathy, but may not develop until late stage in small-fiber neuropathy.

Autonomic signs

Few neuropathies have subjective and severe autonomic disturbances (orthostatic hypotension, bowel or bladder dysfunction, impotence in men).

Evaluation of autonomic and small nerve fiber involvement requires specialized tests, including quantitative sensory testing (QST) and skin biopsy (cf. Chapter 3).

Neuropathies associated with autonomic disturbances are very similar to those associated with small fiber involvement (diabetes, amyloidosis). Rare purely autonomic disturbances include pandysautonomia (usually acute), hereditary dysautonomia (Riley–Day syndrome), and idiopathic dysautonomia (usually cholinergic or adrenergic).

General examination

Skeletal deformities are usually associated with inherited neuropathies with an onset in infancy. They frequently involve the foot (pes cavus) and spine (scoliosis). Joint deformities are associated with disorders in which there is a marked loss of sensory fibers. Neuropathic joint deformities are called Charcot or pseudotabetic joints, resulting from repeated trauma in the absence of pain sensation. Bone resorption, pathologic fractures, and osteomyelitis are features of inherited sensory neuropathy.

Changes in skin, hair, and nails. Mutilating acropathy is characterized by plantar painless ulcerations and is observed in diabetes, amyloidosis, lepromatous, alcoholic, hereditary sensory, and autonomic neuropathies. Hyperpigmentation (melanodermia) may be present in the POEMS syndrome (polyneuropathy, organomegaly, endocrine features, M protein, skin lesions). Purpura, livedo reticularis can be seen in vasculitic neuropathies with or without cryoglobulinemia. Angiokeratomas are especially associated with the Fabry disease. Curly hair is the main sign of giant axonal neuropathy. Mee’s lines are observed in arsenic and thallium neuropathies.

Xerostomia, xerosis or cutaneous sicca (dry mouth, eyes, and skin), and salivary gland swelling are features of Sjögren’s syndrome. Enlarged orange tonsils are the main mucosal sign in Tangier disease.

Ocular manifestations. Uveitis may be observed in sarcoid and rheumatoid arthritis neuropathies. Scleritis is mainly found in connective tissue disease and vasculitic neuropathies. Corneal opacities are seen in Fabry disease and are the main characteristic feature of gelsolin amyloid neuropathy. Vitreous opacities are found in transthyretin amyloid neuropathies. In Refsum’s disease, lens subluxation, optic atrophy, and retinitis pigmentosa are the main ocular signs.

Electrophysiological examination

Electrophysiological examination must be considered as an extension of the clinical evaluation.

Electrodiagnostic studies are the most useful laboratory test in the assessment of a patient with peripheral neuropathy. They can validate peripheral nerve involvement and eliminate other causes (central nervous system diseases, myopathic disorders, non-organic symptoms). They provide crucial information as to the type of fibers involved (motor, sensory, or both), the pathophysiology (axonal or demyelinating neuropathy), the pattern of involvement (symmetric or multifocal), the severity and time course (mild, severe, acute, or chronic). Electrodiagnostic testing for neuropathies includes needle electromyography (EMG) and nerve conduction studies.

Electromyography

EMG is important to differentiate neurogenic from myopathic disorders.

Spontaneous activity

In normal subjects, needle insertion in muscles is normal at rest, outside the end-plate zone. In the end-plate zone spontaneous activity may be observed (end-plate noise). Elsewhere there is no spontaneous activity.

In acute ongoing denervation of muscle, fibrillation potentials and/or positive sharp waves (PSW) are observed. They appear within 1–3 weeks after loss of axonal continuity, depending on the length of the distal nerve stump. Therefore, fibrillation potentials can persist for many years after denervation. They also are observed in some myopathies, mainly in the inflammatory myopathies (myositis) and some muscular dystrophies.

Fibrillation potentials and PSW have the same significance. In acute nerve lesions, fibrillation potentials do not appear before 7 days in short nerve segments. In chronic neuropathies, it indicates the amount of axonal damage.

Other abnormal spontaneous activities may occur in pathological muscles:

Fasciculation potentials: these are similar to motor unit action potentials in dimensions and have been attributed to spontaneous activation of muscle fibers of individual motor units. They are found in pathological processes involving the anterior horn cell, especially amyotrophic lateral sclerosis.

Myotonic discharges: these consist of high-frequency trains of action potentials. Their frequency waxes and wanes (they sound like a dive bomber on loudspeaker). They are found in patients with various forms of myotonia.

Involuntary muscle contraction

In normal subjects, with minimal muscle contraction, single motor-unit action potentials (MUPs) are elicited and the shape, voltage (amplitude), duration, and frequency of firing must be noted. Amplitude and duration depend on the number of muscle fibers within the motor unit.

In patients with disorders due to peripheral nerve disease, functional motor units are reduced. The density of electrical activity recorded from affected muscles is diminished when the voluntary contraction is maximal (loss of MUPs). To respond to the maximal contraction, there is an increase in the rate of firing of motor units. The morphology of MUPs is modified: there is an increase in amplitude due to augmentation of the motor unit territory as a consequence of collateral sprouting, sometimes giving rise to giant MUPs. This feature is best observed in anterior horn cell diseases. In peripheral nerve lesions, MUPs do not increase significantly, except sometimes in very chronic polyneuropathies such as some CIDP and CMT cases.

Nerve conduction studies

Motor conduction studies

These studies involve stimulation of a nerve and recording an evoked response from the corresponding muscle. For example, the ulnar nerve is stimulated at the wrist, below and above the elbow and at the axilla, the evoked response is taken from the abductor digiti minimi in the hand (see Fig. 1.1). If possible, the nerve should be stimulated all along its length. Generally, muscular evoked responses (compound muscle action potential, CMAP) are expressed in millivolts (mV). Duration, area, and amplitude of the CMAP are measured.

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Figure 1.1 Motor nerve conduction study of the ulnar nerve in a normal subject.

Distal latency (i.e., the time between the stimulation and the onset of the negative wave of the CMAP) is measured. Nerve conduction velocity is expressed in meters per second (m/s) and is calculated by dividing the distance between two points of stimulation by the time delay between these two points (conduction velocity in m/s = distance in mm/(proximal latency minus distal latency in m/s). The conduction velocity cannot be measured accurately in the distal segment as the latency is partly due to conduction along the neuromuscular junction and within the muscle.

Reduction of the CMAP amplitude reflects the amount of fiber loss and is mainly observed in rapidly progressive neuropathies. In more chronic disorders, the CMAP amplitude does not correlate well with fiber loss, because motor units remodel during collateral sprouting. Motor nerve conduction velocity is determined by the largest fibers of the nerve. The nerve conduction velocity value may therefore be normal if the large fibers are spared, although the CMAP amplitude may be markedly reduced. This is found in axonal disorders (see Table 1.3 here).

Table 1.3 Electrodiagnostic criteria to distinguish primary demyelinating neuropathy from primary axonal neuropathy.

In demyelinating neuropathy, motor nerve conduction velocity is markedly reduced if the study incorporates the demyelinating zone. Conduction block and temporal dispersion may also be observed. Focal conduction block is due to the inability of the stimulated nerve fibers to normally conduct action potentials. It may be complete or partial. The clinical effect of conduction block is a motor deficit which correlates with the number of nerve fibers that are blocked. Conduction block may be located at every part of the nerve. In focal neuropathies (compressive or entrapment) it is located at the site of entrapment or compression due to focal paranodal or segmental demyelination. When located outside the usual sites of compression, conduction block usually occurs in acquired demyelinating neuropathies. Detection of conduction blocks is important to distinguish between acquired and hereditary demyelinating neuropathies; it may be a transient phenomenon with a rapid recovery, which is mainly due to ischemia.

Temporal dispersion results from the spectrum of arrival times of nerve impulses into the muscle. It is due to slow conduction velocities of individual nerve fibers caused by demyelination. Temporal dispersion may be observed with distal stimulation (see Fig. 1.2) and is characteristic of chronic demyelinating polyneuropathy. In multifocal motor neuropathy conduction block occurs alone, usually without temporal dispersion. It is observed in acute inflammatory polyneuropathy (Guillain–Barré syndrome), especially during the early stages. They may be difficult to elicit because of their very proximal localization. In chronic demyelinating polyneuropathy, conduction blocks and temporal dispersion usually occur in the inflammatory forms. Conduction blocks are not observed in demyelinating polyneuropathy associated with paraproteinemia, including IgM monoclonal gammopathy. In CMT, there is neither conduction block nor temporal dispersion as the demyelination is uniform all along the nerve length (see Fig. 1.3).

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Figure 1.2 Temporal dispersion in a patient with a chronic inflammatory demyelinating polyneuropathy.

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Figure 1.3 Motor conduction velocity in a patient with CMT 1A.

The terminal latency index (TLI) is the ratio between proximal and distal conduction velocities. For example, the median nerve TLI is the ratio between motor conduction velocity at the forearm and distal conduction from distal stimulation at the wrist over a 6-cm distance. In normal subjects, the TLI is 0.34. In patients with distal demyelination (in some CIDP and IgM polyneuropathies) the TLI is low, usually under 0.25. In CMT type 1A, the TLI is the same as in normal subjects, because the demyelination is uniform, identical in proximal and distal segments of the nerve.

Sensory nerve conduction study

The nerve is stimulated, usually using surface electrodes; the evoked potential is recorded over the same nerve using either needle or surface electrodes. The sensory nerve action potential (SNAP) amplitude is much lower than the motor evoked potential and is usually expressed in microvolts (µv). The nerve may be stimulated using orthodromic or antidromic techniques. Sensory conduction velocity is measured in the most rapidly conducting fibers from the site of stimulation to the onset of the negative peak of the compound sensory action potential (CSAP). Small fibers cannot be tested and the compound sensory nerve action potential (CSNAP) amplitude depends on the number of large myelinated fibers (8–9 µm or more).

A normal SNAP implies that large diameter dorsal root ganglion cells and large distal myelinated axons are normally functioning.

Other techniques

F-wave study. This measures the latency over the complete length of the motor nerve pathway in both antidromic and orthodromic directions, that is, towards and as far as the anterior horn cell and back to the muscle. It is easily obtained by stimulating the distal part of the nerve (peroneal, tibial, median, and ulnar). The results are expressed in milliseconds. F-wave study is useful in investigating patients with suspected more proximal peripheral nerve lesions, such as in polyradiculoneuropathies, especially in very early Guillain–Barré