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Overview of Peripheral Nervous System Disorders

by Michael Rubin, MDCM

The peripheral nervous system refers to parts of the nervous system outside the brain and spinal cord. It includes the cranial nerves and spinal nerves from their origin to their end. The anterior horn cells, although technically part of the CNS, are sometimes discussed with the peripheral nervous system because they are part of the motor unit.

Motor neuron dysfunction results in muscle weakness or paralysis. Sensory neuron dysfunction results in abnormal or lost sensation. Some disorders are progressive and fatal.

Anatomy

A motor unit consists of an anterior horn cell, its motor axon, the muscle fibers it innervates, and the connection between them (neuromuscular junction). The anterior horn cells are located in the gray matter of the spinal cord and thus are technically part of the CNS. In contrast to the motor system, the cell bodies of the afferent sensory fibers lie outside the spinal cord, in dorsal root ganglia.

Nerve fibers outside the spinal cord join to form anterior (ventral) motor roots and posterior (dorsal) sensory root nerve roots. The ventral and dorsal roots combine to form a spinal nerve. Thirty of the 31 pairs of spinal nerves have dorsal and ventral roots; C1 has no sensory root (see Figure: Spinal nerve.).

The spinal nerves exit the vertebral column via an intervertebral foramen. Because the spinal cord is shorter than the vertebral column, the more caudal the spinal nerve, the further the foramen is from the corresponding cord segment. Thus, in the lumbosacral region, nerve roots from lower cord segments descend within the spinal column in a near-vertical sheaf, forming the cauda equina. Just beyond the intervertebral foramen, spinal nerves branch into several parts.

Branches of the cervical and lumbosacral spinal nerves anastomose peripherally into plexuses, then branch into nerve trunks that terminate up to 1 m away in peripheral structures. The intercostal nerves are segmental.

The term peripheral nerve refers to the part of a spinal nerve distal to the root and plexus. Peripheral nerves are bundles of nerve fibers. They range in diameter from 0.3 to 22 μm. Schwann cells form a thin cytoplasmic tube around each fiber and further wrap larger fibers in a multilayered insulating membrane (myelin sheath).

Physiology

The myelin sheath enhances impulse conduction. The largest and most heavily myelinated fibers conduct quickly; they convey motor, touch, and proprioceptive impulses. The less myelinated and unmyelinated fibers conduct more slowly; they convey pain, temperature, and autonomic impulses. Because nerves are metabolically active tissues, they require nutrients, supplied by blood vessels called the vasa nervorum.

Etiology

Disorders can result from damage to or dysfunction of the cell body, myelin sheath, axons, or neuromuscular junction. Disorders can be genetic or acquired (due to toxic, metabolic, traumatic, infectious, or inflammatory conditions—see Table: Some Causes of Peripheral Nervous System Disorders). Peripheral neuropathies may affect one nerve (mononeuropathy), several discrete nerves (multiple mononeuropathy, or mononeuritis multiplex), or multiple nerves diffusely (polyneuropathy). Some conditions involve a plexus (plexopathy) or nerve root (radiculopathy). More than one site can be affected; eg, in the most common variant of Guillain-Barré syndrome, multiple segments of cranial nerves, usually the 2 facial nerves, may be affected.

Some Causes of Peripheral Nervous System Disorders

Site

Type

Examples

Motor neuron*

Hereditary

Spinal muscular atrophy types I–IV

Acquired, acute

Polio, infections due to coxsackievirus and other enteroviruses (rare), West Nile virus infection

Acquired, chronic

Amyotrophic lateral sclerosis, paraneoplastic syndrome, postpolio syndrome, progressive bulbar palsy

Nerve root

Hereditary

Neurofibroma

Acquired

Herniated disk, infections, metastatic cancer, spinal foraminal stenosis, trauma

Plexus

Acquired

Acute brachial neuritis, diabetes mellitus, hematoma, local tumors (eg, schwannoma), metastatic cancer, neurofibromatosis (rare), traction during birth, severe trauma

Peripheral nerve

Entrapment

Carpal tunnel syndrome, cubital tunnel syndrome, radial nerve palsy, peroneal nerve palsy, tarsal tunnel syndrome, ulnar nerve palsy

Hereditary

Hereditary adult-onset neuropathies, hereditary sensory and motor neuropathies, hereditary sensory and autonomic neuropathies

Infectious

Hepatitis C, herpes zoster, HIV infection, Lyme disease, syphilis

In developing nations: Diphtheria, leprosy, parasite infections

Inflammatory

Chronic inflammatory demyelinating polyradiculoneuropathy, Guillain-Barré syndrome and variants

Ischemic

Femoral nerve infarction (diabetic amyotrophy), vasculitis causing multiple mononeuropathy (mononeuritis multiplex)

Toxic-metabolic

Amyloidosis, diabetes mellitus, dysproteinemic neuropathy, chronic excessive alcohol consumption with undernutrition (particularly deficiency of B vitamins), ICU neuropathy, leukodystrophies (rare), renal insufficiency, toxins (eg, arsenic, lead, thallium, chemotherapy drugs, pyridoxine toxicity)

Neuromuscular junction

Botulism in infants, congenital myasthenia (very rare), Eaton-Lambert syndrome, myasthenia gravis, toxic or drug-induced neuromuscular junction dysfunction (eg, due to exposure to insecticides or nerve gas, abnormally high Mg levels, or use of neuromuscular blockers)

Muscle fiber

Dystrophies

Distal muscular dystrophy (late distal hereditary myopathy; rare), Duchenne muscular dystrophy and related dystrophies, fascioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, oculopharyngeal dystrophy (rare)

Channelopathies (myotonic)

Familial periodic paralysis, myotonia congenita (Thomsen disease), myotonic dystrophy (Steinert disease)

Congenital

Central core disease, centronuclear myopathy, nemaline myopathy (very rare)

Endocrine

Acromegaly, Cushing syndrome, diabetes mellitus, hypothyroidism, thyrotoxic myopathy

Inflammatory

Infection (viral more than bacterial), polymyositis and dermatomyositis

Metabolic

Acid maltase deficiency, alcoholism, carnitine deficiency, glycogen storage and lipid storage diseases (rare), hypokalemia

*Upper motor neuron disorders (eg, spinal muscular atrophies) technically involve the CNS because the cell body of the motor neuron (anterior horn cell) is located in the spinal cord.

Adapted from Tandan R, Bradley WA: Amyotrophic lateral sclerosis. Part I: Clinical features, pathology and ethical issues in management. Annals of Neurology 18:271–280, 1985; used with permission of Little, Brown and Company.

Pathophysiology

Because sensory and motor cell bodies are in different locations, a nerve cell body disorder typically affects either the sensory or motor component but rarely both.

Damage

Damage to the myelin sheath (demyelination—see Demyelinating Disorders) slows nerve conduction. Demyelination affects mainly heavily myelinated fibers, causing large-fiber sensory dysfunction (buzzing and tingling sensations), motor weakness, and diminished reflexes. The hallmark of acquired demyelinating polyneuropathy is severe motor weakness with minimal atrophy.

Because the vasa nervorum do not reach the center of a nerve, centrally located fascicles are most vulnerable to vascular disorders (eg, vasculitis, ischemia). These disorders result in small-fiber sensory dysfunction (sharp pain and burning sensations), motor weakness proportional to atrophy, and less severe reflex abnormalities than in other nerve disorders. The distal two thirds of a limb is affected most. Initially, deficits tend to be asymmetric because the vasculitic or ischemic process is random. However, multiple infarcts may later coalesce, causing symmetric deficits (multiple mononeuropathy).

Toxic-metabolic or genetic disorders usually begin symmetrically. Immune-mediated processes may be symmetric or, early in rapidly evolving processes, asymmetric.

Damage to the axon transport system for cellular constituents, especially microtubules and microfilaments, causes significant axon dysfunction. First affected are the smaller fibers (because they have greater metabolic requirements) at the most distal part of the nerve. Then, axonal degeneration slowly ascends, producing the characteristic distal-to-proximal pattern of symptoms (stocking-glove sensory loss, followed by weakness).

Recovery

Damage to the myelin sheath (eg, by injury or Guillain-Barré syndrome) can often be repaired by surviving Schwann cells in about 6 to 12 wk.

After axonal damage, the fiber regrows within the Schwann cell tube at about 1 mm/day once the pathologic process ends. However, regrowth may be misdirected, causing aberrant innervation (eg, of fibers in the wrong muscle, of a touch receptor at the wrong site, or of a temperature instead of a touch receptor).

Regeneration is impossible when the cell body dies and is unlikely when the axon is completely lost.

Evaluation

  • Deficits defined by history and examination

  • Attention to clinical clues to peripheral nervous system disorders

  • Usually nerve conduction studies and electromyography

  • Sometimes nerve or skin punch biopsy

  • Genetic testing (for hereditary neuropathies)

Clinical evaluation

History should focus on type of symptom, onset, progression, and location, as well as information about potential causes (eg, family history, toxic exposures, past medical disorders). Physical and neurologic examination (see Evaluation of the Neurologic Patient : Neurologic Examination) should further define the type of deficit (eg, motor deficit, type of sensory deficit, combination). Sensation (using pinprick and light touch for small fibers; using vibration and proprioception tests for large fibers), motor strength, and deep tendon reflexes are evaluated. Cranial nerve as well as central and peripheral nerve function is evaluated. Whether motor weakness is proportional to the degree of atrophy is noted, as are type and distribution of reflex abnormalities. Autonomic function is evaluated (see Autonomic Nervous System).

Physicians should suspect a peripheral nervous system disorder based on the pattern and type of neurologic deficits, especially if deficits are localized to particular nerve roots, spinal nerves, plexuses, specific peripheral nerves, or a combination. These disorders are also suspected in patients with mixed sensory and motor deficits, with multiple foci, or with a focus that is incompatible with a single anatomic site in the CNS.

Physicians should also suspect peripheral nervous system disorders in patients with generalized or diffuse weakness but no sensory deficits; in these cases, peripheral nervous system disorders may be overlooked because they are not the most likely cause of such symptoms. Clues that a peripheral nervous system disorder may be the cause of generalized weakness include the following:

  • Patterns of generalized weakness that suggest a specific cause (eg, predominant ptosis and diplopia, which suggest early myasthenia gravis)

  • Symptoms and signs other than weakness that suggest a specific disorder or group of disorders (eg, cholinergic effects, which suggest organophosphate poisoning)

  • Deficits in a stocking-glove distribution, which suggest diffuse axonal disorders or polyneuropathy

  • Fasciculations

  • Hypotonia

  • Muscle wasting without hyperreflexia

  • Weakness that is progressive, chronic, and unexplained

Clues that the cause may not be a peripheral nervous system disorder include hyperreflexia and hypertonia. These deficits suggest an upper motor neuron disorder as the cause of weakness. Hyporeflexia is consistent with peripheral nervous system deficits but is nonspecific. For example, cervical spinal cord compression can mimic Guillain-Barre syndrome, particularly in patients with preexisting neuropathy.

Although many exceptions are possible, certain clinical clues may also suggest possible causes of peripheral nervous system deficits (see Table: Clinical Clues to Causes of Peripheral Nervous System* Disorders).

Clinical Clues to Causes of Peripheral Nervous System* Disorders

Finding

Cause to Consider

Symmetric, diffuse deficits

Diffuse disorders (eg, toxic-metabolic, hereditary, infectious, or inflammatory disorders; most immune-mediated disorders)

Unilateral deficits

Focal disorders (eg, mononeuropathies, plexopathies)

Deficits localized to one or more peripheral nervous system structures (eg, nerve root, spinal nerve, nerve plexus, single peripheral nerve, ≥ 2 discrete nerves in separate areas [multiple mononeuropathy])

Lesion in a peripheral nervous system structure

Stocking-glove distribution of deficits

Diffuse peripheral polyneuropathies, possibly axonal

Disproportionate weakness of proximal muscles (eg, difficulty climbing stairs or combing hair) with no sensory deficits

Diffuse muscle dysfunction, as occurs in diffuse myopathies

Possibly disorders of the neuromuscular junction if the eyes are affected

Chronic, progressive weakness affecting mostly distal muscles with no sensory deficits

Motor neuron disease

Buzzing and tingling with motor weakness and decreased reflexes

Demyelination

Profound proximal and distal motor weakness with minimal atrophy

Acquired demyelinating polyneuropathy

Deficient pain and temperature sensation; painful, often burning sensations

Weakness proportional to atrophy; disproportionately mild reflex abnormalities, usually more distal than proximal

Vascular disorders (eg, vasculitis, ischemia, hypercoagulable states)

*Upper motor neuron disorders (eg, spinal muscular atrophies) technically involve the CNS because the cell body of the motor neuron (anterior horn cell) is located in the spinal cord.

Clinical assessment narrows diagnostic possibilities and guides further testing.

Testing

Usually, nerve conduction studies and electromyography (collectively called electrodiagnostic testing) are done (see Electromyography and nerve conduction studies). These tests help identify level of involvement (nerve, plexus, root) and distinguish demyelinating disorders (very slow conduction) from axonal disorders. Other testing, such as imaging, depends on whether a CNS lesion must be ruled out (eg, if all limbs are affected, to rule out cervical spinal cord compression).

Nerve biopsy is occasionally done to help differentiate demyelinating from vasculitic large-fiber neuropathies. If vasculitis is a consideration, the biopsy specimen should include skin and muscle to increase the likelihood of a definitive diagnosis. If a small-fiber neuropathy is suspected, skin punch biopsy can be done; loss of nerve endings supports that diagnosis.

Pearls & Pitfalls

  • If clinical findings and electrodiagnostic test results are inconclusive, do a biopsy (nerve biopsy for suspected large-fiber neuropathy or skin punch biopsy for suspected small-fiber neuropathy).

  • If all limbs are affected, consider MRI to rule out cervical spinal cord compression.

Genetic testing is indicated if a hereditary neuropathy is suspected.

Patients with weakness but no sensory deficits are evaluated for weakness (see Weakness). Electrodiagnostic testing helps differentiate peripheral nervous system disorders from other causes of weakness and helps differentiate among peripheral nervous system disorders (eg, root, plexus, peripheral nerve, neuromuscular junction, muscle fiber). It also helps differentiate between axonal and demyelinating peripheral neuropathies.

Treatment

  • Treatment of underlying disorder

  • Supportive care, often by a multidisciplinary team

Treatment is directed at the underlying disorder when possible. Otherwise, treatment is supportive. A multidisciplinary team approach helps patients cope with progressive neurologic disability:

  • Physical therapists may help patients maintain muscle function.

  • Occupational therapists can recommend adaptive braces and walking devices to help with activities of daily living.

  • Speech and language therapists may provide alternative communication devices.

  • If pharyngeal weakness develops, a speech therapist or a multidisciplinary team that specializes in swallowing problems can help assess risk of aspiration and recommend measures for prevention (eg, precautions for oral feeding and/or need for tube feedings).

  • A gastroenterologist may recommend percutaneous endoscopic gastrostomy.

  • If respiratory weakness develops, forced vital capacity is measured, and pulmonary or intensive care specialists help assess whether intensive care, noninvasive respiratory support (eg, bilevel positive airway pressure), and tracheostomy with full ventilatory support are needed.

Early in fatal disorders, health care practitioners must talk frankly with patients, family members, and caregivers to determine the level of intervention acceptable (see The Dying Patient). These decisions should be reviewed and confirmed at various stages of the disorder.

Key Points

  • Peripheral nervous system disorders are often suspected based on clinical findings (eg, stocking-glove distribution, hyporeflexia, distal muscle weakness and wasting, localization to a peripheral nerve distribution).

  • If patients have profound motor weakness with minimal atrophy and areflexia, consider acquired demyelinating polyneuropathy.

  • If patients have abnormal pain and temperature sensation and atrophy in proportion to weakness (sometimes with disproportionate preservation of reflexes), consider a vasculitic or ischemic neuropathy.

  • If patients have chronic progressive muscle weakness, fasciculations, muscle atrophy, and no sensory deficits, consider motor neuron disease.

  • Nerve conduction studies and electromyography help identify level of involvement (root, plexus, peripheral nerve, neuromuscular junction, muscle fiber) and help distinguish demyelinating from axonal disorders.

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