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:
Fasting blood glucose or hemoglobin A1c to evaluate for diabetes
Vitamin B12 and methylmalonic acid (MMA) levels to assess for vitamin B12 deficiency
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.
TABLE 27–2Variants of CIDP. ||Download (.pdf) TABLE 27–2 Variants of CIDP.
| ||Clinical ||Treatment ||Associated antibody |
|“Classic” CIDP ||Sensorimotor ||Symmetric ||Proximal and distal || |
|MADSAM (Lewis-Sumner syndrome) ||Sensorimotor ||Asymmetric ||Multifocal || |
|DADS ||Sensorimotor ||Symmetric ||Distal ||Responds poorly when associated with anti-MAG ||Anti-MAG |
|MMN ||Motor ||Asymmetric ||Multifocal ||IVIg ||Anti-GM1 |
|CISP ||Sensory ||Symmetric ||Proximal and distal || |
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.
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).
TABLE 27–3Hereditary Neuropathies. ||Download (.pdf) TABLE 27–3 Hereditary Neuropathies.
| ||Clinical features || || || || |
| ||Type of Neuropathy ||Other Features ||Onset ||EMG/NC Studies ||Inheritance ||Gene |
|CMT || |
|CMT1 ||Distal sensorimotor ||Nerve enlargement ||Teens–20s ||Demyelinating ||Autosomal dominant || |
|CMT2 ||Distal sensorimotor || ||20s–30s ||Axonal ||Autosomal dominant ||Various; MFN2 most common |
|CMT3 (Dejerrine-Sottas) ||Distal sensorimotor & proximal weakness ||Nerve enlargement ||Infantile ||Demyelinating ||Autosomal recessive or dominant || |
|CMT4 ||Distal sensorimotor || ||Childhood ||Demyelinating ||Autosomal recessive ||Various |
|CMTX ||Distal sensorimotor ||Transient CNS events ||Childhood ||Demyelinating ||X-linked ||GJB1 |
|HSAN || |
|HSAN1 ||Loss of pain/temperature sensation ||Weakness ||20s and older ||Axonal ||Autosomal dominant ||SPTLC1 |
|HSAN2 ||Loss of sensation in all modalities || ||Infantile ||Axonal ||Autosomal recessive ||WNK1 |
|HSAN3 || |
Loss of pain/ temperature
| ||Infantile ||Axonal ||Autosomal recessive ||IKBKAP |
|HSAN4 || |
Complete pain insensitivity
|Mental retardation ||Infantile ||Axonal ||Autosomal recessive ||NKRT1 |
|HSAN 5 ||Complete pain insensitivity || ||Infantile ||Axonal ||Autosomal recessive ||NGFB |
|Others || || || || || || |
|HNPP ||Focal neuropathies at sites of compression || ||20s or older ||Demyelinating ||Autosomal dominant ||PMP22 deletion |
|Fabry’s disease ||Painful small fiber neuropathy || |
Angiokeratomas on abdomen
|Childhood or older ||Small fiber ||X-linked ||Alpha-galactosidase |
|Refsum’s disease ||Sensorimotor || |
|Infantile or older ||Demyelinating or axonal ||Autosomal recessive ||Phytanoyl–CoA alpha hydroxlase |
|Tangier disease || |
Painful small fiber neuropathy
Recurrent mononeuropathy multiplex
Large, orange tonsils
Low HDL/elevated triglycerides
|Childhood or older || |
Demyelinating or axonal
|Autosomal recessive ||ABCA1 |
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:
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).