Chapter 27: Peripheral Neuropathy

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 Versus Demyelinating Neuropathies

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).

Small Fiber 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).

Autonomic Neuropathy

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

Clinical Features of Guillain-Barré Syndrome

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.

Since AIDP is a demyelinating neuropathy, symptoms and signs are non–length-dependent, and patients can present with distal paresthesias and proximal weakness (e.g., gluteal and/or hip flexor causing gait abnormalities) simultaneously. Pain in the back and/or feet may be an early feature. The pattern of a slightly abnormal gait due to proximal weakness and nonspecific sensory complaints and/or pain in the feet may lead initial examiners to question a neurologic etiology, especially since reflexes may still be present early in the disease. With progression of deficits and loss of reflexes, the diagnosis becomes clearer. Maximal disability is usually reached at 2–3 weeks into the illness.

Facial weakness is common in GBS, occurring in over half of patients and usually bilateral (facial weakness is in a lower motor neuron pattern since GBS affects peripheral nerves, including the cranial nerves). Autonomic instability is also common, mostly commonly manifesting as fluctuations in heart rate and blood pressure. Hyponatremia may occur and is likely due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Bladder involvement in GBS is rare, and if present, should prompt consideration of spinal cord pathology (e.g., epidural abscess, transverse myelitis), which is the main differential diagnosis for rapidly progressive symmetric weakness and sensory changes.

Beyond the core features of areflexia and symmetric sensory and motor deficits, there is considerable variation in the spectrum and severity of GBS. Pure sensory, pure motor, and pure autonomic variants exist. The Miller Fisher variant presents with ophthalmoplegia, ataxia, and areflexia but with no or minimal weakness, and is associated with anti-GQ1B antibodies. In a variant referred to as facial diplegia with acral paresthesias, patients present with isolated bilateral lower motor neuron-pattern facial weakness accompanied by paresthesias in the distal extremities and decreased or absent reflexes, but without extremity weakness. The pharyngeal-cervical-brachial variant causes dysphagia, neck weakness, proximal upper extremity weakness, and areflexia that is often limited to the upper extremities, and may also cause ptosis; anti-GT1a antibodies may be seen with this variant.

Severity of GBS may be mild with patients remaining ambulatory throughout the illness, or may be severe with progression to complete quadriplegia with respiratory failure requiring intubation and mechanical ventilation.

Diagnosis of Guillain-Barré Syndrome

Cerebrospinal fluid (CSF) analysis in GBS demonstrates an inflammatory pattern of elevated protein and no or few white blood cells (although CSF can be normal early in the disease). This dissociation between elevated protein and minimal or no elevation in white blood cells is referred to as albuminocytologic dissociation. Although this pattern of CSF findings is usually taught/learned in the context of GBS, it is a nonspecific pattern seen in inflammatory disorders of the nervous system. If there is a CSF pleocytosis in a patient with GBS, the possibilities of HIV seroconversion (see “HIV Seroconversion Syndromes Involving the Nervous System” in Chapter 20), Lyme disease, and neurolymphomatosis as the cause of an acute polyneuropathy should be considered. Lumbar puncture may be normal early in the course of GBS.

In AIDP, nerve conduction studies show a demyelinating pattern with slowed velocities/increased latencies, conduction block, and absent F waves (reflecting proximal demyelination in the roots; see “F Wave” in Ch. 15). It should be noted that very early in the disease course, EMG/nerve conduction studies may be normal.

MRI in GBS, if obtained due to clinical concern for spinal cord pathology, may show enhancement of nerve roots.

Management of Guillain-Barré Syndrome

Vital capacity and negative inspiratory force should be assessed upon presentation and monitored serially. This should be done even in patients with no respiratory symptoms, so early respiratory weakness can be detected by these measures before it becomes clinically apparent. In patients with significant facial weakness, there may be difficulty making a seal on the instruments used to test respiratory parameters, leading to falsely alarming values. A rough bedside measure of vital capacity can be obtained and followed serially by asking the patient to inhale maximally and then count as high as possible while exhaling on one breath—every 10 accounts for roughly 1 liter of vital capacity (i.e., patient counts to 20 on one breath— equivalent to about 2 liters of vital capacity, 30 approximately 3 liters). Neck flexion and extension musculature is supplied by C3-C5 as is the phrenic nerve, so evaluating for neck flexion/extension weakness can serve as a measure of muscles innervated by the same roots as the diaphragm. Patients with clinically apparent respiratory failure or a trajectory of worsening respiratory parameters generally require intubation.

GBS that progresses rapidly and/or causes gait impairment is treated with IV immunoglobulin (IVIg) or plasmapheresis, which appear to be equivalent in efficacy. Treatment usually does not lead to any noticeable improvement in the acute setting, but can lessen the ultimate severity of the disease and shorten the time to recovery. Treatment requires intensive supportive care, usually in an intensive care setting except in mild cases. The prognosis is related to the severity of the disease, but the majority of patients without respiratory failure will recover completely or with minor sensorimotor deficits.

Critical Illness Polyneuropathy and Critical Illness Myopathy

Patients hospitalized in intensive care units for sepsis or other critical illnesses can develop an axonal sensorimotor polyneuropathy and/or a myopathy over an acute to subacute period. Critical illness polyneuropathy and myopathy are part of the differential diagnosis for unexplained failure to wean from a ventilator (the differential diagnosis also includes myasthenia gravis and prolonged neuromuscular blockade).

Critical illness polyneuropathy and myopathy both cause diffuse symmetric weakness of the extremities. Facial weakness may be present in some cases, but extraocular weakness usually does not occur. Critical illness polyneuropathy will cause impaired sensation in addition to weakness. Although sensation is spared in critical illness myopathy, sensation can be difficult to assess in critically ill patients, and patients may have preexisting sensory loss from an underlying preexisting neuropathy. Reflexes may be spared in critical illness myopathy, but are typically absent in critical illness polyneuropathy. Serum creatine kinase (CK) may be elevated in critical illness myopathy. If EMG/nerve conduction studies are performed, both conditions show diminished compound motor action potentials (CMAPs) (due to axonal loss in critical illness neuropathy; due to muscle fiber loss in critical illness myopathy). However, sensory nerve action potentials (SNAPs) are only diminished in critical illness polyneuropathy as opposed to critical illness myopathy, in which they should be normal. Neuromuscular blockade and high-dose steroids used to treat the underlying critical illness may increase the risk of the development of critical illness myopathy.

Although a distinction can sometimes be made clinically/electrophysiologically between critical illness polyneuropathy and critical illness myopathy, patients may have both, and there is no treatment for either aside from rehabilitation. Medication-induced causes of neuropathy or myopathy should be searched for before making the diagnosis of critical illness myopathy or polyneuropathy. Many patients who recover from the underlying critical illness will recover to some degree from critical illness neuropathy/myopathy over subsequent months.

Causes of Peripheral Polyneuropathy

The differential diagnosis for chronic symmetric polyneuropathy is extensive, as noted at the beginning of the chapter. The most common cause in higher-income countries is diabetes mellitus, and neuropathy may be the presenting feature of the disease. Leprosy is one of the most common causes of polyneuropathy worldwide (see “Leprosy” in Chapter 20).

When evaluating a patient with a suspected polyneuropathy, the history should assess for:

• Types of symptoms: pain, paresthesia, numbness, weakness, incoordination

• Distribution of symptoms: non–length-dependent (demyelinating) versus length-dependent (axonal)

• Medication exposures: chemotherapy, antibiotics, antiretrovirals, antimyocbacterials, amiodarone

• Toxic exposures: alcohol, heavy metals

• HIV risk factors

• Diet: vegetarian diet can cause vitamin B12 deficiency; history of gastric bypass can cause multiple vitamin and mineral deficiencies if patients are not taking supplementation

The American Academy of Neurology guidelines (England et al., 2009) recommend the following initial laboratory tests for the evaluation of distal symmetric polyneuropathy:

1. Fasting blood glucose or hemoglobin A1c to evaluate for diabetes

2. Vitamin B12 and methylmalonic acid (MMA) levels to assess for vitamin B12 deficiency

3. Serum protein electrophoresis/immunofixation (SPEP/IFE) to evaluate for a monoclonal gammopathy as a cause of paraprotein-associated neuropathy

Even in patients with a clear potential cause of neuropathy (e.g., exposure to chemotherapy known to cause neuropathy), it can be useful to check serum vitamin B12, hemoglobin A1c, and SPEP with immunofixation to evaluate for additional common and potentially reversible underlying etiologies as possible contributors to the patient’s neuropathy. In a patient with known diabetes, vitamin B12 deficiency, or myeloma, one should consider sending laboratory tests to evaluate for the other two potentially contributing causes.

If no etiology is determined with this first-pass laboratory screening, additional testing depends on the clinical context and can include EMG/nerve conduction studies to further characterize the neuropathy, autoimmune serologies (ANA, Ro, La), cryoglobulins, HIV, celiac antibodies, paraneoplastic antibodies (anti-Hu), heavy metals, and genetic testing for Charcot-Marie-Tooth disease (see “Charcot-Marie-Tooth Disease” below).

Diabetes most commonly causes a distal symmetric sensory or sensorimotor polyneuropathy, but can also cause painful small fiber neuropathy, autonomic neuropathy, lumbosacral radiculoplexus neuropathy (see Ch. 17), mononeuropathy (see Chs. 16–17), and mononeuropathy multiplex (see Ch. 15).

Vitamin B12 deficiency can cause myelopathy and/or cognitive changes in addition to peripheral neuropathy. A mixed picture of myeloneuropathy can be seen (e.g., absent reflexes with Babinski sign; absent reflexes in one region with brisk reflexes in another). The differential diagnosis for myeloneuropathy also includes copper deficiency, adrenomyeloneuropathy (see Ch. 31), and the combination of myelopathy and neuropathy caused by different etiologies (e.g., cervical stenosis and diabetic neuropathy). Myelopathy and neuropathy can also occur concurrently in HIV (see “Neurologic Complications of Advanced HIV Infection” in Ch. 20).

The type of neuropathy and systemic features of paraprotein-associated neuropathies vary based on the underlying condition (Table 27–1). Screening for monoclonal gammopathy (SPEP/immunofixation) is part of the initial evaluation for patients with peripheral neuropathy so as not to miss the opportunity for potential early detection of a hematologic malignancy. If a monoclonal gammopathy is discovered by a neurologist in the evaluation of a peripheral neuropathy, further evaluation and management is best undertaken in collaboration with a hematologist/oncologist.

Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) and Its Variants

Like acute inflammatory demyelinating polyradiculoneuropathy (AIDP), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated, symmetric, non–length-dependent sensorimotor polyradiculoneuropathy with demyelinating features on nerve conduction studies and albuminocytologic dissociation. However, CIDP usually presents insidiously over months compared to the acute presentation of AIDP, and is not usually preceded by an antecedent infection as is common in AIDP. There are sensory, motor, and sensorimotor variants of CIDP (Table 27–2). Cranial nerve involvement in CIDP can occur but is extremely rare. The course can be either slowly progressive or relapsing. Some patients present acutely/subacutely and initially may appear to have AIDP, but either relapse or continue to progress beyond the usual course expected with AIDP. For the classic symmetric proximal/distal sensorimotor CIDP, steroids (daily or pulsed), IVIg, or plasma exchange may be used for treatment.

Variants of CIDP

A symmetric but distal-predominant variant of CIDP known as distal acquired demyelinating symmetric (DADS) neuropathy is important to recognize since it can be associated with a monoclonal protein (anti-MAG IgM) and generally responds poorly to immunotherapy (Table 27–2). A rare purely sensory form of CIDP called chronic immune sensory polyradiculoneuropathy (CISP) presents similarly to sensory ganglionopathy (sensory deficits including sensory ataxia with preserved strength; see “Diseases of Dorsal Root Ganglia: Ganglionopathy (Sensory Neuronopathy)” in Ch. 15).

Two CIDP variants of asymmetric onset are multifocal acquired demyelinating sensory and motor neuropathy (MADSAM; also called Lewis-Sumner syndrome) and multifocal motor neuropathy (MMN). The “multifocal” aspect of these names refers to the fact that these variants tend to present asymmetrically, with multiple focal neuropathies as opposed to the more confluent symmetric presentation of classic CIDP. MADSAM affects both sensory and motor nerve fibers as the name suggests. MMN is purely motor and should be considered in the differential diagnosis for motor neuron disease (e.g., amyotrophic lateral sclerosis [ALS]; see “Amyotrophic Lateral Sclerosis (ALS) And Its Variants” in Chapter 28) and vice versa. MMN can be associated with anti-GM1 antibodies. MMN does not respond to treatment with steroids (and may worsen when steroids are administered), but usually responds to treatment with IVIg.

Hereditary Neuropathies

Neuropathy can occur as the primary or only feature of a genetic disease (e.g., some variants of Charcot-Marie-Tooth disease), or may be one component of a genetic syndrome affecting multiple levels of the nervous system (e.g., Fabry’s disease, familial amyloidosis, porphyria, some of the spinocerebellar ataxias, some of the leukodystrophies) (Table 27–3).

Charcot-Marie-Tooth Disease (Hereditary Motor and Sensory Neuropathies)

The most common presentation of Charcot-Marie-Tooth disease (CMT) is a slowly progressive distal-predominant sensorimotor neuropathy with hammer toes and high arches of the feet. These classic features occur in the most common variants of CMT1 and CMT2. Most patients present in adolescence or early adulthood but may have noted clumsiness and poor performance in sports in childhood. Rarer forms of CMT may have diverse features in addition to neuropathy. Many of the most common forms of CMT are dominantly inherited, so there is typically a family history of the disease. Nerve conduction studies in CMT may reveal a demyelinating (CMT1, CMT3, CMT4) or an axonal (CMT2) pattern. If genetic testing is performed, it is targeted based on the most common mutations seen for the electrophysiologic/pathologic subtype (demyelinating versus axonal), and the inheritance pattern (dominant versus recessive versus X-linked). The most common mutations are:

• Demyelinating CMT: PMP22 and MPZ

• Axonal CMT: MFN2

• X-linked CMT: GJB1

Dejerine-Sottas disease (CMT3) is a rare infantile-onset severe form of the disease, and should be included in the differential of the “floppy (hypotonic) baby.”

Treatment of CMT is supportive, aimed at maintenance of ambulation with orthoses and physical therapy.

Hereditary Sensory and Autonomic Neuropathies

The hereditary sensory and autonomic neuropathies (HSAN) are a group of very rare diseases that cause sensory loss (most commonly loss of pain and temperature sensation) and/or autonomic dysfunction, as the name suggests. Most subtypes of HSAN are infantile-onset and autosomal recessive, with the exception of HSAN1, which is adult-onset and autosomal dominant. Most subtypes of HSAN cause profound loss of pain and temperature sensation, which can result in unnoticed injuries and subsequent complications such as skin ulceration leading to infection. Supportive management therefore focuses on prevention and treatment of these complications.

Hereditary Neuropathy With Liability to Pressure Palsies

Caused by a deletion in the same gene that is duplicated in CMT1A (PMP22), hereditary neuropathy with liability to pressure palsies (HNPP) is a dominantly inherited condition that causes increased risk of focal neuropathies at common sites of compression (median at carpal tunnel, ulnar at medial elbow, peroneal at fibular head; see Chs. 16–17). A symmetric polyneuropathy may also be present.

Other causes of polyneuropathy discussed elsewhere in this book include infections (leprosy, HIV; see “HIV-Associated Distal Symmetric Neuropathy” and “Leprosy” in Ch. 20), chemotherapy-induced neuropathy (see “Chemotherapy-Induced Peripheral Neuropathy” in Ch. 24), and paraneoplastic neuropathy (see Paraneoplastic Syndromes of the Nervous System” in Ch. 24).