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Peripheral Neuropathies and Motor Neuron Diseases


Acknowledgments

The authors would like to acknowledge the contributions of Dr. Yadollah Harati who authored this chapter in the previous edition.

  • 1.

    What are the most common diseases affecting the peripheral nerve?

    • Alcohol

    • Amyloid

    • Diabetes

    • Environmental toxins and drugs

    • Guillain–Barré

    • Hereditary

    • Infections

    • Nutritional

    • Paraneoplastic

    • Rheumatic (collagen vascular)

    • Systemic disease

    • Trauma

    • Tumors

  • 2.

    What is the anatomy of a peripheral nerve?

    The outer layer of a peripheral nerve is called the epineurium. Each nerve is made up of a bundle of nerve fibers called fascicles and each fascicle is surrounded by a perineurium. Each fascicle is made up of a number of axons and each axon is sheathed in the endoneurium.

  • 3.

    How does a nerve’s size and structure contribute to its speed of conduction? How are the peripheral fibers classified?

    The larger the fiber, the less the electrical resistance and the faster the speed of conduction. Myelin increases a nerve’s diameter and also insulates the current between nodes of Ranvier, increasing the overall conduction velocity. In myelinated nerves, the conduction velocity can be estimated to be 6 m/s/μm (e.g., a nerve that is 10 μm in diameter will conduct at approximately 60 m/s). In unmyelinated nerves, the velocity is approximately 1.7 m/s/μm. Peripheral nerve fibers are classified according to diameter and conduction velocity ( Table 6-1 ).

    Table 6-1
    Peripheral Nerve Fibers
    Classification Alternate Classification Myelinated? Type Conduction Velocity
    A Yes Somatic nerves
    α I Yes Subset of afferent nerves supplying the muscle spindle
    Sensitive to the rate of change in fiber length
    Also efferent motor neurons     		80-120 m/s
    Ia Afferent fibers from the muscle spindle
    Ib Afferent fibers serving the Golgi tendon organ at the junction between muscle and tendon
    β II Yes Subset of afferent nerves supplying the muscle spindle
    Respond to the overall length of the muscle spindle fiber
    Fastest cutaneous afferent fibers, supplying the hair and skin follicles     		35-75 m/s
    δ III Yes Convey “fast pain” sensation from skin and muscle 5-30 m/s
    B Yes Preganglionic efferent fibers of the autonomic nervous system 3-15 m/s
    C IV, afferent No Postganglionic efferent nerves of the autonomic nervous system
    Convey afferent “slow pain” sensation in somatic nerves     		1-2 m/s

  • 4.

    What are the patterns of peripheral nerve damage?

    The nerve can be damaged by injury to the myelin, axon, cell body, or vasa nervorum. Four basic pathologic mechanisms underlie nerve injury ( Fig. 6-1 ):

    • 1.

      Wallerian degeneration develops after injury to the axon and myelin, as in transection of the nerve. Distal to the transection, the axon and then myelin degenerate, followed within 3 to 5 days by failure to generate and conduct a nerve action potential. The axon may regrow within the architecture provided by the basement membrane of Schwann cells, but the degree and efficiency of regrowth depend on good approximation of the nerve ends.

    • 2.

      Segmental demyelination develops after damage to the myelin sheath or Schwann cell. Because the muscle is not denervated, no atrophy develops. Prognosis for complete recovery is good.

    • 3.

      Axonal degeneration develops from damage to the axon resulting in distal dying of the axon and subsequent loss of myelin. Once the distal nerve dies, the muscle is denervated; hence, muscle atrophy develops. The denervated muscle fibers can be reinnervated by surrounding nerves, but recovery may not be complete.

    • 4.

      Neuronopathy develops when damage to the cell body of the neuron results in the breakdown of the entire nerve, peripherally and centrally, involving the anterior horn cell or dorsal root ganglion.

    Figure 6-1, Segmental remyelination may follow segmental demyelination. The remyelinated segments are shorter and have a smaller diameter. Axonal regeneration is associated with the formation of clusters of small and thin myelinated fibers.

    In acute nerve injuries, the extent and degree of damage can be graded using Sunderland’s classification Grade I-V or Seddon’s classification of neurapraxia, axonotmesis, and neurotmesis. Neurapraxia (Grade I) occurs when the myelin alone has been damaged with good prognosis for recovery within hours to weeks. Axonotmesis (Grades II-IV) refers to varying degrees of damage to the axons and surrounding connective tissues. Neurotmesis (Grade V) involves injury to the entire nerve including the epineurium (e.g., in a nerve transection). Usually both axonotmesis and neurotmesis result in incomplete or no recovery of function.

  • 5.

    What are the electrophysiologic mechanisms that correlate with weakness in peripheral neuropathy?

    Conduction block, denervation with loss of motor units, and failure of neuromuscular transmission. One or more of the above are needed. Slowing of motor conduction velocity in itself, even if severe, does not result in weakness.

  • 6.

    What is conduction block?

    Conduction block is a focal abnormality across a nerve segment that results in failure to conduct an action potential typically due to focal disruption of the myelin sheath. Distal to the block, conduction is preserved. In conduction block, a compound muscle action potential (CMAP) drop of 30% to 50% is recorded between the distal and proximal stimulation sites.

  • 7.

    What is the significance of conduction block in peripheral neuropathy?

    Conduction block occurs only in certain limited acquired settings of acute reversible ischemic injury, compression-induced demyelination, and acquired demyelinative neuropathies but not in hereditary neuropathies, with one major exception—hereditary neuropathy with liability to pressure palsy (HNPP). Clinically, conduction block is important because it implies a potentially reversible defect-causing weakness.

  • 8.

    Define an “onion-bulb” formation.

    An onion-bulb formation is the pathologic hallmark of the hypertrophic neuropathies, in which repeated segmental demyelination and remyelination have occurred ( Fig. 6-2 ). When viewed in transverse sections, onion-bulb formations are multiple concentric layers of intertwined, attenuated Schwann cell processes surrounding the remaining nerve fibers. The Schwann cell processes are separated from each other by layers of collagen fibers. The onion-bulb formations may be seen in any condition with chronic segmental demyelination and remyelination but are frequently seen in Charcot–Marie–Tooth (CMT) disease, Dejerine–Sottas syndrome, Refsum’s disease, and chronic relapsing idiopathic (inflammatory) demyelinating neuropathy.

    Figure 6-2, Semithin section. Note proliferation of Schwann cells with onion-bulb formation.

  • 9.

    Which nerves are commonly used for biopsy?

    The most common and best nerve to use is the sural nerve, a purely sensory nerve located lateral to the lateral malleolus. The nerve can be biopsied at this level or at a higher level between the heads of the gastrocnemius muscles. The superficial peroneal and radial cutaneous nerves can be sometimes used as well.

  • 10.

    What are the indications for sural nerve biopsy?

    Sural nerve biopsy is most helpful when the underlying condition is multifocal and asymmetric—mainly when a vasculitic etiology is suspected. It may be obtained in chronic demyelinating neuropathies with the aim of confirming the diagnosis when the clinical and electrophysiologic findings have been inconclusive, especially in patients who may be candidates for therapies with potentially harmful side effects. With the advent of genetic and other testing modalities, nerve biopsy is less necessary but may be of value as a final resort in patients with progressive, disabling peripheral neuropathy of undetermined etiology. The yield of nerve biopsy when vasculitis is suspected ranges from 50% to 60% while the yield in unknown neuropathy is in the 15% to 25% range.

  • 11.

    What are the common pathological findings on teased nerve fiber preparations?

    With teased nerve fiber preparation, segmental demyelination, remyelination, or axonal degeneration is identified. In segmental demyelination, the diameter of demyelinated segments is reduced. In remyelination, the internodal length varies. Axonal degeneration causes breakdown of myelin into “ovoids and balls” ( Fig. 6-3 ).

    Figure 6-3, Teased nerve fiber preparation. A, Segmental demyelination. B, Remyelination. C, Axonal degeneration.

  • 12.

    What is the outcome of the evaluation of patients with “peripheral neuropathy of undetermined etiology” when referred for a second opinion to a peripheral nerve expert at a tertiary referral center?

    Forty-two percent of patients have a hereditary neuropathy, 21% have an inflammatory neuropathy, and other conditions are discovered in 13% of patients. In 24% of the cases, even after extensive evaluation, no etiology for the neuropathy is identified.

Common Neuropathies

  • 13.

    What is the most common cause of peripheral neuropathy in the world?

    Diabetes mellitus. Approximately 150 million people have diabetes and up to half of them have symptomatic diabetic neuropathy. The prevalence of diabetes is increasing every year. Alcoholic neuropathy is the second most common cause of peripheral neuropathy. Therefore, all patients with distal symmetric polyneuropathy should be screened for diabetes mellitus as well as unhealthy alcohol use. Leprosy was once the most common cause of neuropathy worldwide, but its incidence has dramatically decreased since 1982.

  • 14.

    What are the clinical forms of diabetic neuropathy?

    Diabetic neuropathies include distal symmetric sensory or sensorimotor polyneuropathy, small fiber neuropathy, diabetic neuropathic cachexia, hypoglycemic neuropathy, treatment-induced neuropathy (insulin neuritis), polyradiculopathy, diabetic lumbosacral radiculoplexus neuropathy (diabetic amyotrophy), mononeuropathies, and cranial neuropathies.

    Distal symmetric sensory polyneuropathy, the most common form, is a slowly progressive length-dependent axonal sensory polyneuropathy that presents with numbness and paresthesias in the feet, usually minimal motor weakness, and possibly autonomic changes.

  • 15.

    Which diabetic neuropathies are painful?

    • Third cranial nerve neuropathy

    • Acute thoracoabdominal neuropathy

    • Acute distal sensory neuropathy

    • Acute lumbosacral radiculoplexus neuropathy

    • Chronic distal small-fiber neuropathy

  • 16.

    What are the risk factors for developing diabetic peripheral neuropathy?

    • Duration of diabetes

    • Degree of glycemic control

    • Older age

    • Male sex

    • Excessive alcohol consumption

    • Nicotine use

    • Dyslipidemia

    • Angiotensin-converting enzyme D allele

    Ruth FJ, Schulmeyer M, Roesch C, et al: Diagnostic and therapeutic value due to suspected diagnosis, long-term complications, and indication for sural nerve biopsy. Clin Neurol Neurosurg 107:214–217, 2005.

    England JD, Franklin G, Gjorvad G, et al: Quality improvement in neurology: Distal symmetric polyneuropathy quality measures Neurology 82;1745-1748, 2014.

    Russell JW, Zilliox LA: Diabetic neuropathies. Continuum (Minneap Minn) 20(5):1226–1240, 2014.

    Harati Y: Diabetic neuropathies: Unanswered questions. Neurol Clin 25:303-317, 2007.

  • 17.

    Describe alcoholic neuropathy.

    Between 10% and 50% of alcoholics develop alcoholic neuropathy though in many it is asymptomatic. Usually it develops in alcoholics with prolonged and severe (>100 g/day) alcohol use. As a result, it is difficult to distinguish the direct effects of alcohol from the secondary effects of chronic malnutrition. Clinically, alcoholic neuropathy presents with dull aching or burning in the feet, hyperesthesia and/or sensory loss, distal hyporeflexia, and thin muscles with mild weakness in the feet sometimes with associated autonomic symptoms. Electromyography/nerve conduction velocity (EMG/NCV) would show a length-dependent axonal neuropathy. Symptoms can slowly improve with reduced alcohol intake and a balanced diet.

  • 18.

    How does the global importance of leprous neuropathy compare to its importance in the United States?

    The global registered prevalence of leprosy at the beginning of 2012 was 181,941 cases. In 2011, the number of new cases detected worldwide was 219,075. In contrast, the prevalence of leprosy in the United States is low (<10,000). In 2011, the number of new cases in the United States was 173. Most cases in the United States are in immigrants, but endemic areas include Texas, Louisiana, Florida, and Hawaii.

    Vittadini G, Buonocore M, Colli G, et al: Alcoholic polyneuropathy: A clinical and epidemiological study. Alcohol Alcohol 36(5):393-400, 2001.

    Mellion M, Gilchrist JM, de la Monte S: Alcohol-related peripheral neuropathy: Nutritional, toxic, or both? Muscle Nerve 43(3):309-316, 2011.

  • 19.

    What is small fiber neuropathy?

    Small fiber neuropathies affect the small myelinated A δ and unmyelinated C fibers. Symptoms usually consist of pain, numbness, burning, “pins and needles-like” sensations, and autonomic disturbances. On examination, patients may have decreased pinprick and temperature sensation with allodynia and hyperalgesia. Most patients will have normal sensory nerve conduction studies with a pure small fiber neuropathy and may have an abnormal Quantitative Sensory Testing. The most common etiologies are diabetes, genetic including amyloidosis, and idiopathic.

  • 20.

    What are the tests used to diagnose small fiber neuropathy?

    Most of the time small fiber neuropathies are diagnosed based on the history and physical examination since the nerve conduction studies are often normal. Other tests that can be used include:

    • Skin biopsy

    • Quantitative sensory testing

    • Autonomic testing (see Chapter 12 )

  • 21.

    Which clinical features aid in the diagnosis of carpal tunnel syndrome?

    • Pain, paresthesias, or numbness worse at night or during activities that maintain wrist extension or flexion (e.g., driving) or require repetitive wrist motion

    • Shaking, wringing, or flicking motions of the hands to relieve symptoms

    • Numbness often involving only partial median nerve innervation (e.g., thumb and index finger) rather than entire first three and one-half digits. Pain but not numbness may occur above the wrist.

    • Symptoms of intermittent hand weakness before overt weakness of thenar muscles and lateral lumbricals

    • Provocative tests such as Tinel’s sign, Phalen’s sign, and reverse Phalen’s sign lack sufficient sensitivity and specificity to be reliable in the clinical setting. The gold standard remains electrodiagnostic confirmation.

  • 22.

    What is the second most common entrapment neuropathy?

    The second most common entrapment neuropathy is ulnar neuropathy at the elbow. The two most common sites of entrapment are at the ulnar groove and the cubital tunnel. Symptoms commonly are more motor than sensory involving weakness of the intrinsic hand muscles and sensory loss in the fifth digit, medial fourth digit, and hypothenar region, but not proximal to the wrist. Electrodiagnostic studies can be helpful in localizing the lesion and recent studies have shown efficacy using ultrasonography.

  • 23.

    What are the symptoms of peroneal (fibular) nerve compression at the fibular neck?

    Injury of the nerve usually involves both the deep and common peroneal nerves resulting in a foot drop and sensory loss over the lateral calf and dorsum of the foot. It is important to differentiate a peroneal nerve lesion from a sciatic nerve lesion, a lumbosacral plexopathy, or an L5 radiculopathy. Common causes of injury are trauma, stretch, or compression of the nerve.

  • 24.

    What are the three most common neurogenic causes of winging of the scapula?

    • 1.

      Long thoracic nerve palsy: The long thoracic nerve innervates the serratus anterior muscle. Serratus anterior weakness leads to the most pronounced winging, which is accentuated with forward flexion of the arms and decreased with the arms at rest. The superior (medial) angle of the scapula is displaced closer to the midline, whereas the inferior angle swings laterally and away from the thorax.

    • 2.

      Spinal accessory nerve palsy: The spinal accessory nerve innervates the trapezius muscle. Trapezius muscle weakness leads to mild winging of the scapula at rest, which is accentuated by arm abduction to 90° and decreased by forward flexion to 90°. The superior (medial) angle of the scapula is displaced away from the midline, but the inferior angle is medially rotated. The shoulder is lower on the affected side because of atrophy of the trapezius muscle.

    • 3.

      Dorsal scapular nerve palsy: The dorsal scapular nerve innervates the rhomboid muscle. Weakness of this muscle produces minimal winging at rest, which is accentuated by slowly lowering the arm from the forward overhead position and decreased by elevation of the arms overhead. The superior (medial) angle is displaced away from the midline, and the inferior angle is laterally displaced.

      In addition, there are many nonneurogenic causes of winging of the scapula, including myopathies and muscular dystrophy (e.g., facioscapulohumeral muscle dystrophy).

    Tavee J, Zhou L: Small fiber neuropathy: A burning problem. Cleve Clin J Med 76(5):297-305, 2009.

    Miedany YE, et al: Clinical diagnosis of carpal tunnel syndrome: Old tests-new concepts. Joint Bone Spine 75:451-457, 2008.

    Campbell WW, et al: Ulnar neuropathy at the elbow: Five new things. Neurol Clin Pract 5(1):35-41, 2015.

  • 25.

    Which peripheral neuropathies may have cranial nerve involvement?

    See Table 6-2 .

    Table 6-2
    Neuropathies with Cranial Nerve Involvement
    Neuropathy Most Commonly Involved Cranial Nerves Less Commonly Involved Cranial Nerves
    Diphtheria IX II, III
    Sarcoid VII I, III, IV, VI
    Diabetes III ∗ IV, VI, VII
    Guillain-Barré syndrome (GBS) VI, VII
    Miller–Fisher variant of GBS III, IV
    Sjögren’s syndrome V
    Celiac disease V
    Polyarteritis nodosa VII, III, VIII
    Wegener’s granulomatosis VIII
    Lyme disease VII, V All but I
    Porphyria VII, X III, IV, V, XI, XII
    Refsum’s disease I, VIII
    Primary amyloidosis VII, V, III VI, XII
    Syphilis III IV, V, VII, VIII
    Arsenic V

    ∗ Pupil is usually not affected.

  • 26.

    Which neuropathies begin proximally rather than distally?

    Guillain–Barré syndrome (GBS), chronic inflammatory demyelinating neuropathy (CIDP), diabetic lumbosacral radiculoplexus neuropathy/diabetic amyotrophy, porphyric neuropathy, idiopathic acute brachial plexus neuropathy (Parsonage–Turner syndrome), and Tangier disease.

  • 27.

    Which neuropathies can begin in the arms rather than the legs?

    • Compression/entrapment syndromes (e.g., carpal tunnel syndrome, ulnar neuropathy at the elbow)

    • Diabetes

    • Vasculitic neuropathy

    • GBS

    • Multifocal motor neuropathy

    • Lead toxicity

    • Porphyria

    • Sarcoidosis

    • Leprosy

    • CMT disease (rare)

    • Tangier disease

    • Inherited recurrent focal neuropathies

    • Some forms of familial amyloid polyneuropathy

  • 28.

    Which neuropathies are often predominantly motor?

    GBS, diphtheric neuropathy, dapsone-induced neuropathy, porphyria, and multifocal motor neuropathy are often predominantly motor.

  • 29.

    Which neuropathies are often predominantly sensory?

    • Drug toxicity: pyridoxine, doxorubicin, cisplatin, thalidomide, metronidazole

    • Autoimmune: Miller–Fisher syndrome, sensory variants of acute and chronic inflammatory demyelinating polyneuropathy, IgM paraproteinemia, paraneoplastic syndrome, Sjögren’s syndrome

    • Infectious: diphtheria, human immunodeficiency virus (HIV), Lyme disease

    • Deficiency: vitamin E, pyridoxine

    • Inherited: neuropathies associated with abetalipoproteinemia and spinocerebellar degeneration

  • 30.

    Which neuropathies are demyelinating?

    • Toxic/metabolic/infectious: diphtheria, buckthorn, hepatic, Creutzfeldt–Jakob disease (CJD), Hansen’s disease (mixed)

    • Autoimmune: GBS, CIDP and variants, multifocal motor neuropathy (MMN), POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes)

    • Inherited: CMT syndromes, storage disorders (Krabbe, metachromatic leukodystrophy, Niemann–Pick, Farber’s), Pelizaeus–Merzbacher, Refsum, Cockayne

    • Drug toxicity: chloroquine, tacrolimus, procainamide, amiodarone (mixed), gold (mixed), taxol (mixed)

  • 31.

    What are the causes of multiple mononeuropathy (mononeuritis multiplex)?

    • Trauma or compression

    • Diabetes

    • Vasculitis, with or without connective tissue diseases; also virus associated (HIV, hepatitis B and C)

    • Leprosy

    • Lyme disease

    • Sarcoidosis

    • Sensory perineuritis

    • Tumor infiltration

    • Lymphoid granulomatosis

    • Demyelinating idiopathic and paraproteinemic neuropathies (MMN, multifocal acquired demyelinating sensory and motor neuropathy [MADSAM])

    • Hereditary neuropathy with liability to pressure palsies (HNPP)

  • 32.

    In which conditions are the peripheral nerves palpably enlarged?

    • Hereditary motor and sensory neuropathies (HMSN) or CMT disease (demyelinative type) and Dejerine–Sottas syndrome (HMSNIII)

    • Amyloidosis

    • Refsum’s disease

    • Leprosy

    • Acromegaly

    • Neurofibromatosis

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