Peripheral neuropathies can be classified as mononeuropathy (affecting one nerve), mononeuropathy multiplex (affecting multiple individual nerves), and polyneuropathy (affecting peripheral nerves diffusely). Mononeuropathies of the upper and lower extremities are discussed in Chapters 16 and 17, and mononeuropathy multiplex is discussed in Chapter 15. This chapter focuses on polyneuropathy.
Polyneuropathies can be classified by:
Modality affected: sensory, motor, sensorimotor, autonomic
Fiber type affected: large fiber (proprioception/vibration) versus small fiber (pain/temperature)
Pathophysiology: axonal versus demyelinating
Sensory symptoms can include negative symptoms (numbness), positive symptoms (paresthesias, pain), and/or sensory ataxia due to impaired proprioception (see “Distinguishing Cerebellar Ataxia From Sensory Ataxia” in Chapter 8). Neuropathies affecting motor fibers lead to weakness with lower motor neuron features (see “Upper Motor Neuron Lesions Versus Lower Motor Neuron Lesions” in Chapter 4). Autonomic neuropathy can lead to orthostatic hypotension, bowel/bladder dysfunction, impaired sweating, erectile dysfunction, and/or pupillary abnormalities.
The etiologies of peripheral polyneuropathy include:
Metabolic causes: diabetes, uremia, vitamin B12 deficiency
Medications:
Chemotherapy: platins, taxanes, bortezomib (see “Chemotherapy-Induced Peripheral Neuropathy” in Chapter 24)
Antiretrovirals: didanosine, stavudine, zalcitabine (see “Antiretroviral-Associated Neuropathy” in Chapter 20)
Antibiotics: metronidazole, linezolid, quinolones, nitro-furantoin
Antimycobacterials: isoniazid, dapsone
Amiodarone
Toxins: heavy metals (e.g., mercury, arsenic, lead), alcohol
Inflammatory processes:
Primary neurologic inflammatory disorders: acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and chronic inflammatory demyelinating polyneuropathy (CIDP)
Inflammatory neuropathies secondary to systemic inflammatory disease: Sjögren’s syndrome, lupus, sarcoidosis
Malignancy:
Paraprotein-associated neuropathies: myeloma, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes), secondary amyloidosis (see Table 27–1)
Paraneoplastic (see “Paraneoplastic Syndromes of the Nervous System” in Chapter 24)
Infections: HIV, leprosy (see “HIV-Associated Distal Symmetric Neuropathy” and “Leprosy” in Chapter 20)
Hereditary diseases: Neuropathy may be the only (or predominant) feature of hereditary conditions (e.g., Charcot-Marie-Tooth disease) or may be one component in a multisystem hereditary disease (e.g., Tangier disease, Fabry’s disease, acute intermittent porphyria) (see Table 27–3)
Axonal neuropathies affect the longest nerves first since these are the most sensitive to dysfunction in axonal physiology. This causes symptoms in a length-dependent pattern. The longest nerves are those that lead from the spinal cord to the toes. Therefore, patients with axonal neuropathies typically present first with sensory changes and/or weakness in the feet and loss of the ankle reflexes, but with preserved reflexes and sensorimotor function elsewhere. As an axonal neuropathy progresses, the symptoms and signs can ascend the legs and ultimately begin to involve the distal upper extremities over time. The hands are generally not affected in axonal neuropathies until the neuropathy has progressed to the level of the mid-calves in the lower extremities.
In contrast, demyelinating neuropathies affect myelin throughout the peripheral nervous system, so short and long nerves can be affected simultaneously. This causes both proximal and distal symptoms and signs, and can lead to involvement of both the hands and the feet simultaneously at presentation, a non–length-dependent pattern. Since the longest nerves have the most myelin, they have the most possible territory to be demyelinated by a demyelinating process, so symptoms may still begin in the distal extremities. However, the hands and feet may be affected simultaneously at presentation, and diminution or loss of tendon reflexes may be more diffuse at presentation than in axonal neuropathies.
The clinical distinction between axonal and demyelinating neuropathies is important because it guides the differential diagnosis: The majority of axonal neuropathies are caused by toxins, medications, or metabolic etiologies, whereas the majority of demyelinating neuropathies are caused by immune/inflammatory etiologies, although exceptions exist in all categories. This broad pathophysiologic distinction is logical because toxins, medications, and metabolic dysfunction alter axonal metabolism, leading to axonal dysfunction (axonal neuropathy), whereas myelin is affected in most immune-mediated inflammatory neuropathies (e.g. acute inflammatory demyelinating polyradiculoneuropathy [AIDP] and chronic inflammatory demyelinating polyneuropathy [CIDP]).
Nerve conduction studies in axonal neuropathies primarily demonstrate decreased amplitudes, whereas demyelinating neuropathies primarily demonstrate slowing of conduction velocities (and prolonged distal latencies). In most inherited demyelinating neuropathies, slowing of conduction velocity tends to be diffuse; in most acquired demyelinating neuropathies (e.g., traumatic or inflammatory), demyelination causes focal/multifocal conduction block (see “Nerve Conduction Studies” in Chapter 15 for further discussion). Additionally, evaluation of multiple nerves with EMG/nerve conduction studies can demonstrate whether longer nerves are preferentially affected (length dependence, suggestive of axonal neuropathy) or whether shorter nerves are affected alongside longer nerves that are not affected (non–length dependence, suggestive of demyelinating neuropathy).
The small unmyelinated nerve fibers that carry pain and temperature sensation may be affected in isolation or in conjunction with large fiber involvement. Small fiber neuropathy is characterized by pain that is typically burning in character with allodynia (pain response to a nonpainful stimulus; e.g., the bed sheets touching the feet). Symptoms are most commonly length-dependent, beginning in the feet.
Examination of patients with small fiber neuropathy may be normal, or may demonstrate diminished pain and temperature sensation in affected areas, allodynia, and/or hyperalgesia (disproportionate response to painful stimulus). If there is isolated small fiber neuropathy with no concurrent large fiber involvement, reflexes will be normal.
EMG/nerve conduction studies are usually normal in small fiber neuropathy (unless large fibers are also affected), since small unmyelinated fibers cannot be assessed by EMG/nerve conduction studies. The diagnosis can be confirmed by skin biopsy to evaluate the density of nerve fibers in the epidermis, but if the clinical picture is clear, an evaluation for an underlying cause may be pursued without biopsy. Etiologies of small fiber neuropathy include:
Metabolic: diabetes
Toxic: alcohol
Infectious: HIV, hepatitis C
Inherited: Fabry’s disease, hereditary sensory and autonomic neuropathy (HSAN), amyloidosis
Inflammatory: Sjögren’s syndrome, sarcoid, celiac disease, paraneoplastic (most commonly associated with anti-Hu antibodies)
Some cases of small fiber neuropathy are idiopathic.
As with any cause of neuropathic pain, symptomatic management includes antidepressants (amitriptyline, nortriptyline, duloxetine), antiepileptics (gabapentin, pregabalin), and topical treatments (lidocaine patch, capsaicin cream).
The autonomic nervous system includes the sympathetic pathways and parasympathetic pathways. Dysfunction of the autonomic pathways can cause orthostatic hypotension, bowel and/or bladder dysfunction, impaired sweating, and/or erectile dysfunction. Autonomic neuropathy can occur concurrently with neuropathy affecting other modalities (i.e., sensory, motor, small fiber) such as in diabetes, Guillain-Barré syndrome, hereditary sensory and autonomic neuropathy (HSAN), Sjögren’s syndrome, amyloidosis, and paraneoplastic neuropathy. Autonomic neuropathy may also occur in isolation in any of these conditions, as well as in Chagas’ disease and autoimmune autonomic neuropathy. Autoimmune autonomic neuropathy is commonly postinfectious with antibodies against ganglionic nicotinic acetylcholine receptors.
Diagnosis of autonomic neuropathy can be made by evaluating autonomic function with tests of sweating and tests of the cardiovascular response to provocative maneuvers (e.g., Valsalva maneuver, tilt table). Treatment is directed at the underlying cause. Orthostatic symptoms may be managed with education of the patient not to move from supine to seated to standing too rapidly, compression stockings or abdominal binder, and/or fludrocortisone or midodrine.
Most polyneuropathies arise subacutely or chronically. The differential diagnosis for the etiology of an acute-onset polyneuropathy includes:
Guillain-Barré syndrome: acute inflammatory demyelinating polyradiculoneuropathy (AIDP) or acute axonal forms (see “Guillain-Barré Syndrome”)
Toxins
Organophosphates (often accompanied by cholinergic [parasympathetic] symptoms)
Thallium (may be accompanied by hair loss)
Arsenic (other heavy metals more often cause subacute neuropathy, but arsenic may cause an acute or subacute neuropathy)
Acute intermittent porphyria causes a recurrent acute motor-predominant neuropathy with abdominal pain, psychiatric disturbances, and/or seizures. Triggers include barbiturates, antiepileptics, sulfonamides, alcohol, and fasting. Diagnosis is by urine porphobilinogen, and treatment is with glucose and hematin.
Botulism presents similarly to an acute polyneuropathy, but is actually a disorder of the neuromuscular junction (see “Infection at the Neuromuscular Junction: Botulism” in Chapter 20). Viral poliomyelitis affects the anterior horn cells (acute flaccid paralysis) and can also present similarly to an acute polyneuropathy (e.g., West Nile virus, enterovirus; see “Acute Flaccid Paralysis” in Chapter 20)
An acute-onset myelopathy (e.g., transverse myelitis) can be difficult to distinguish from an acute polyneuropathy, since upper motor neuron signs may not yet be present at the time of onset of a myelopathy (see “Transverse Myelitis” in Chapter 21). The presence of bowel/bladder dysfunction and/or a spinal level on examination with acute-onset weakness is more suggestive of myelopathy than polyneuropathy. If symptoms progress in the lower extremities without any involvement of the upper extremities, this also suggests a spinal cord process (because a generalized polyneuropathy would not be expected to remain isolated to the legs).
Guillain-Barré Syndrome (GBS) is the overarching term for acute-onset and rapidly progressive immune-mediated polyneuropathy. The underlying pathophysiology can be either demyelinating (acute inflammatory demyelinating polyradiculoneuropathy [AIDP] or axonal (acute motor axonal neuropathy [AMAN] and acute motor and sensory axonal neuropathy [AMSAN]). AIDP is more common, with AMAN being most commonly seen in China. Axonal variants can be associated with anti-GM1 antibodies.
The core features of GBS are the development and rapid progression of symmetric paresthesias and/or weakness in the extremities and loss of reflexes, often preceded by a diarrheal or respiratory illness or vaccination. The notion of “ascending paralysis” in GBS is often misunderstood —it does not mean that the symptoms start in the hands and feet and progresses proximally, but rather that the symptoms typically begin in the lower extremities and progress to the upper extremities.
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