Neuropathies are associated with a number of systemic disorders (Table 16-1). Neuropathies related to vasculitis, infection, endocrinopathies, cancer, and medications are discussed in other chapters. The neuropathies discussed in this chapter may be directly or indirectly related to the systemic disorder (e.g., nutritional deficiency due to malabsorption in gastrointestinal disease).
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Sjögren syndrome is characterized by the sicca complex: xerophthalmia (dry eyes), xerostomia (dry mouth), and dryness of other mucous membranes. It is more common in women and typically presents in middle adult life. Sjögren syndrome can be complicated by central nervous system (CNS) and peripheral nervous system (PNS) involvement. The CNS manifestations can mimic transverse myelitis or multiple sclerosis. Peripheral neuropathy occurs in 2–22% of patients with Sjögren syndrome.1–13 Furthermore, peripheral neuropathy can be the presenting feature of Sjögren syndrome and develop in patients without the typical sicca symptoms.
The most common form of peripheral neuropathy is a length-dependent axonal sensorimotor neuropathy characterized by numbness and tingling in the distal portions of the limbs.1,2,6,7,9–11 Mild distal muscle weakness may also be seen. A pure small fiber neuropathy characterized by burning discomfort and tingling is also common.14,15 Signs of autonomic nervous system dysfunction involving the cardiovascular system are often evident.16,17 Necrotizing vasculitis may be responsible for as many as one-third of the cases of neuropathy associated with Sjögren syndrome.8 Vasculitis should be suspected in patients with an asymmetric, multiple mononeuropathy pattern of involvement. Cranial neuropathies, particularly involving the trigeminal nerve, can also be seen.18
Sjögren syndrome is also associated with sensory neuronopathy/ganglionopathy.1–3,7,10,19–21 Patients with sensory ganglionopathies develop progressive numbness and tingling of the limbs, trunk, and face. Although the symptoms may seem length-dependent, a careful history and examination typically uncovers a non–length-dependent pattern. Symptoms can involve the arms more than the legs, and involvement can be quite asymmetric or even unilateral. Patches of numbness may occur in unusual locations like the perioral regions, back of the head, or the trunk. The onset can be acute or insidious. Sensory examination demonstrates severe vibratory and proprioceptive loss leading to sensory ataxia. Romberg sign is noted in patients with lower limb involvement. The lack of proprioception may lead to pseudoathetotic posturing of affected arms and legs. There can also be diminished sensation in the face. Signs of autonomic neuropathy also may be appreciated: Adie pupil, anhidrosis, fixed tachycardia, and orthostatic hypotension. Muscle stretch reflexes are often reduced or absent. Muscle strength is usually normal.
Patients with neuropathy due to Sjögren syndrome may have antinuclear antibodies (ANA), SS-A/Ro, and SS-B/La antibodies in the serum, but many do not.7 Cerebrospinal fluid is usually normal. Schirmer test and Rose-Bengal stain are useful for diagnosing keratoconjunctivitis. The diagnosis can be confirmed by parotid gland or lip biopsies demonstrating a lymphocytic invasion of salivary glands. Salivary gland biopsies can demonstrate histopathological features of Sjögren syndrome even in patients without complaints of dry mouth.7
Nerve conduction studies (NCS) in patients with distal sensorimotor polyneuropathy demonstrate absent or reduced amplitudes of sensory nerve action potentials (SNAPs) with normal or only mildly slow conduction velocities.1,2,6,12 Motor conduction studies are less affected but may show slightly reduced amplitudes. Abnormal blink reflexes and cutaneous masseter inhibitory reflexes may be appreciated in patients with trigeminal neuropathy.18
NCS in patients with sensory neuronopathy/ganglionopathy demonstrate absent or reduced amplitudes of the SNAPs in a non–length-dependent manner such that these may be abnormal in the arms while normal in the legs.1–3,5,12,19–21 In addition, there may be asymmetric involvement. Motor conduction studies and electromyography (EMG) are usually normal. If the trigeminal nerve is affected, blink reflexes may also be abnormal.22 An important clinical and electrophysiological feature that can help distinguish length-dependent sensory neuropathy from a sensory neuronopathy/ganglionopathy is the preservation of the masseter reflex or jaw jerk in the latter.23 The masseter reflex is unique amongst the stretch reflexes in that the cell bodies of the afferent limb lie in the mesencephalic nucleus within the CNS as opposed to the dorsal root ganglia where the sensory cell bodies innervating the extremities lie. Thus, the mesencephalic nucleus is often spared in ganglionopathies and so the associated masseter reflex is preserved. In contrast, the Gasserian ganglion, which is responsible for conveying sensory nerves responsible for facial sensation and the blink reflex, reside outside the CNS, and thus the blink reflex may be abnormal.
Peripheral nerve biopsies in patients with the more common sensorimotor polyneuropathy demonstrate axonal degeneration and some degree of secondary segmental demyelination (Fig. 16-1).1,2,6 Nonspecific perivascular inflammation involving perineurial or endoneurial blood vessels is occasionally seen. Rarely, necrotizing vasculitis is appreciated.
Biopsy of sensory nerves in patients with sensory neuronopathy/ganglionopathy may reveal a loss of large myelinated fibers and perivascular lymphocytic (CD8 T cells) inflammation involving endoneurial or perineurial vessels.1–3 Biopsy of the dorsal root ganglion have shown lymphocytic (mainly CD8 T cells) infiltration and degeneration of cell bodies.3
Reduced epidermal nerve fiber density or abnormal morphology may be demonstrated on skin biopsies in a non–length-dependent manner, suggesting that patients with painful small fiber neuropathies commonly have a small fiber sensory neuronopathy/ganglionopathy rather than a “dying-back” axonopathy.14
The pathogenic basis of the distal sensory or sensorimotor polyneuropathy is unknown but is presumably autoimmune in nature. Some cases may caused by vasculitis. The sensory neuronopathy/ganglionopathy appears to be the result of cell-mediated autoimmune attack directed against the sensory ganglia. The specific antigen(s) and trigger of the autoimmune attack are not known.
There are no proven therapies for the neuropathies related to Sjögren syndrome. When vasculitis is suspected, immunosuppressive agents may be beneficial. IVIG may be useful in nonvasculitic sensory and sensorimotor neuropathies, however the benefit of such therapy in sensory neuronopathy/ganglionopathy is much less clear.3,11,19,24–26
Peripheral neuropathy occurs in at least 50% of patients with rheumatoid arthritis (RA).13,27–32 Vasculitic neuropathy develops in 40–50% of patients with RA, making it the third most common cause of vasculitic neuropathy following polyarteritis nodosa (PAN) and isolated peripheral nervous system vasculitis. Neuropathic symptoms usually manifest 10–15 years after manifestations of other symptoms of RA, although rarely the neuropathy can be the presenting feature. Rheumatoid vasculitis can present with multiple neuropathies or generalized symmetric pattern of involvement. In addition, the neuropathy associated with RA may be secondary to amyloid deposition.27 Carpal tunnel syndrome is not uncommon, occurring in 10% of patients in one series.27
Demyelinating neuropathies (sensorimotor or pure sensory chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy) may develop as a complication of drugs used to treat the RA [e.g., antitumor necrosis factor-alpha (TNF-α) therapy and leflunomide].33,34 These neuropathies may or may not improve after discontinuation of the TNF-α blocker. In cases in which the neuropathy does not get better, treatment with other immunotherapies (e.g., corticosteroids or IVIG) may be warranted.
ANA, elevated ESR, and rheumatoid factor are often detected in the serum. NCS in patients with vasculitic neuropathy demonstrate absent or reduced amplitudes of SNAPs and compound muscle action potentials (CMAPs), often in an asymmetric, non–length-dependent pattern with normal or only mildly slow conduction velocities. Those with neuropathy related to medications typically have features of demyelination.
Nerve biopsies often reveal thickening of the epineurial and endoneurial blood vessels as well as perivascular inflammation, perhaps related to the so-called microvasculitis (Fig. 16-2). Occasionally, there is necrotizing vasculitis with transmural inflammatory cell infiltration and fibrinoid necrosis of vessel walls. In a retrospective series of 108 patients with RA, 23 underwent sural nerve biopsies.27 Abnormalities included perineurial thickening (n = 5), amyloid deposits (n = 4), perivascular infiltrate (n = 4), loss of myelin fibers (n = 2), and necrotizing vasculitis (n = 1).
In most cases, the neuropathy is presumably autoimmune in nature and may respond to immunomodulating therapies. Of course, those with demyelinating polyneuropathy secondary to TNF-α blockage should first go off the medication. If the neuropathy does not improve they may need to be treated as well with IVIG or corticosteroids; they should also avoid treatment with other TNF-α blockers in the future.
Systemic lupus erythematosus (SLE) is a common connective tissue disease with prevalence in adults of approximately 1 in 2,000. SLE can be associated with multiple organ system involvement and associated laboratory abnormalities. CNS complications are more common than peripheral neuropathies, although 2–27% of individuals with SLE clinically develop a peripheral neuropathy.13,35–43 Most of the time the neuropathy manifests as slowly progressive sensory loss beginning in the feet. Some patients develop burning pain and paresthesia with normal reflexes and NCS suggestive of a pure small fiber neuropathy.40,41 Less common are mononeuropathies, cranial neuropathies, and multiple mononeuropathies. The longer the disease progresses, the more likely the multiple mononeuropathies are to fuse and overlap, creating an increasingly symmetric pattern that mimicks a length-dependent axonal sensorimotor polyneuropathy. Of 1,533 patients in a large SLE database, 207 (14%) had a peripheral neuropathy.35 Of these, 40% were non–SLE-related. Polyneuropathy was diagnosed in 56%, multiple mononeuropathies in 9%, cranial neuropathy in 13%, and mononeuropathy in 11% of patients. Most presentations were asymmetric (59%) and distal weakness occurred in 34%. Rarely, patients manifest with generalized sensorimotor polyneuropathy meeting clinical, laboratory, electrophysiological, and histological criteria for either acute or chronic inflammatory demyelinating polyneuropathy (AIDP or CIDP).44–46
ANA, anti–double-stranded DNA, and anti-Ro antibodies may be demonstrated in the serum. Abnormal NCS occur in 24–56% of patients with SLE.38,39 Most commonly, the NCS reveal a length-dependent, axonal sensory polyneuropathy.47 However, as many as 20% of patients may have features of demyelination on NCS.35,44–46
Nerve biopsies may demonstrate endoneurial mononuclear inflammatory infiltrates and increased expression of class II antigens within nerve fascicles and on endothelial cells, suggesting an autoimmune pathogenesis.37 Upregulation of matrix metalloproteinase-3 and matrix metalloproteinase-9 within the vessel walls has also been observed.48 Skin biopsies may reveal decreased density of epidermal nerve fibers suggestive of a small fiber neuropathy.40,41
The pathogenic basis of the associated neuropathy is likely multifactorial. Neuropathy may be related to the underlying vasculopathy characteristic of SLE, which however is rare associated with histological evidence of necrotizing vasculitis. Some patients may develop neuropathy due to other systemic complications of SLE (i.e., renal failure and uremic neuropathy).
Immunosuppressive therapy is beneficial in patients with vasculitic neuropathy. Immunosuppressive agents are less likely to be effective in patients with a generalized sensory or sensorimotor polyneuropathy without evidence of vasculitis. Patients with an AIDP- or CIDP-like neuropathy should be treated accordingly (see Chapters 13 and 14).
Scleroderma is associated with progressive fibrosis of the skin, gastrointestinal tract, kidney, and lung.13,49–53 A distal symmetric, mainly sensory, polyneuropathy complicates 5–67% of cases. Cranial mononeuropathies can also develop, most commonly affecting the trigeminal nerve, leading to numbness and dysesthesias in the face. Occasionally, seventh and ninth cranial neuropathies develop.
The CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) is considered a limited form of scleroderma. Multiple mononeuropathies have been described in a small percentage (1–2%) of patients with CREST syndrome.54 The electrophysiological and histological features of nerve biopsies are those of an axonal sensory greater than motor polyneuropathy.
Sarcoidosis, a systemic granulomatous disorder, can affect the CNS, peripheral nerves, and muscle.56–59 The etiology is unknown. Women are more commonly affected than men. Nonspecific constitutional symptoms of fever, weight loss, arthralgias, and fatigue are usually the presenting complaints of most patients. Erythematous subcutaneous nodules about the anterior shin and enlarged peripheral lymph nodes may be noted. Granulomatous uveitis can lead to significant visual impairment and even blindness. Pulmonary involvement as well as mucosal lesions of the nose and sinuses are common.
The peripheral nervous system or CNS is involved in about 5% of patients with sarcoidosis and may be the presenting manifestation.56–59 In the CNS, granulomas most typically involve the meninges, hypothalamus, and pituitary gland. Cranial nerves are also frequently involved. The most common cranial nerve to be involved is the seventh nerve, which can be affected bilaterally. Any cranial nerve may be affected however, particularly the second and eighth. Often the neuropathy is relapsing and remitting in nature. Some patients develop a radiculopathy or a polyradiculopathy. With a generalized root involvement, the clinical presentation can mimic AIDP or CIDP. Rarely, patients may present with an acute sensory ataxia with sphincter dysfunction.60 Patients can also present with mononeuropathies, multiple mononeuropathies, or a generalized, slowly progressive, primarily sensory greater than motor polyneuropathy.61,62 Some have features of a pure small fiber neuropathy or a non–length-dependent neuronopathy/ganglionopathy pattern.61–66
Hilar adenopathy is often but not always appreciated on chest radiographs. MRI scans may demonstrate enhancement of the meninges in the brain, particularly in the posterior fossa, and of affected spinal roots in patients with radiculopathy (Fig. 16-3).61 PET and gallium scans can also demonstrate abnormalities. CSF may reveal pleocytosis and an elevated white blood cell count.61 Angiotensin converting enzyme (ACE) levels may be elevated in those with lung disease, but it is neither a very sensitive test nor a specific test. In patients with subclinical neuropathy, the most common finding is an absence or reduction in SNAP amplitudes in a mononeuropathy multiplex pattern.59,67 In patients with the symmetric sensorimotor peripheral neuropathy, the SNAPs may be absent or reduced in amplitude.59,68 Motor NCS also reveal reduced or absent CMAP amplitudes in the lower limbs, with decreased or borderline normal CMAPs in the upper limbs. Patients may also show EMG changes suggestive of a radiculopathy or polyradiculopathy.57 Quantitative sensory testing often reveals abnormal thermal thresholds, and autonomic testing may be abnormal indicative of small fiber involvement.64,66
Nerve biopsies can reveal noncaseating granulomas infiltrating the endoneurium, perineurium, and epineurium along with lymphocytic necrotizing angiitis (Fig. 16-4).59,62,69 There is a combination of axonal loss as well as demyelination. Muscle biopsies likewise can demonstrate noncaseating granulomas in the endomysium even in patients without an underlying myopathy.59 Skin biopsies may reveal reduced intraepidermal nerve fiber density suggestive of a small fiber neuropathy in some patients.63,65
Sarcoidosis is an autoimmune disorder, although the etiology and pathogenic mechanism of the disorder is unclear. Neuropathies may result from invasion or direct compression by granulomas or as a result of ill-defined factors associated with inflammation such as cytokine toxicity, or ischemic damage.62 One also needs to consider neuropathy associated with TNF-α blockade (in cases of demyelinating polyneuropathy).33,34
Neurosarcoidosis, particularly of the cranial nerves, may respond well to corticosteroid treatment.57,61 If patients are resistant to corticosteroids, other immunosuppressive/immunomodulating therapies can be tried (e.g., cyclosporine, methotrexate, IVIG, and TNF-α blockers).70 A few patients with small fiber neuropathy have responded to IVIG as well.71
Intolerance to gluten, which is a protein found in wheat and wheat products, results in a malabsorption syndrome (weight loss, abdominal distention, and steatorrhea). Diagnosis of celiac disease is based on the documentation of (1) malabsorption, (2) demonstration of blunting and flattening of jejunal villi, and (3) clinical and histological improvement following the institution of a gluten-free diet.72 A causal relationship between celiac disease and potential neurological complications remains somewhat controversial. The prevalence of neurological complications is variable and is estimated to occur in 10–40% of affected patients, with ataxia and peripheral neuropathy being the most common problems.73–75 The neuropathy associated with celiac disease usually manifests as distal sensory loss, paresthesias, and imbalance. Generalized sensorimotor polyneuropathy, motor neuropathy, multiple mononeuropathies, autonomic neuropathy, and neuromyotonia have also been reported in association with celiac disease or antigliadin/antiendomysial antibodies.72–85 Neurological examination often demonstrates loss of large fiber sensory modalities, mild distal muscle weakness, reduced or absent muscle stretch reflexes, and an ataxic gait. Signs of a small fiber neuropathy or autonomic neuropathy may be evident.81,82
Antigliadin and endomysial antibodies are often detected in the serum of patients with celiac disease but are nonspecific. NCS usually demonstrate reduced SNAP amplitudes with only mildly reduced nerve conduction velocities (NCVs) or prolonged distal latencies.73,74,79,80,83,84 Motor conduction studies demonstrate a mild reduction in the NCVs with preservation of distal motor latencies and CMAP amplitudes. Autonomic studies may be abnormal in patients with autonomic neuropathy.82 Rare cases with neuromyotonic discharges have been appreciated.79
Nerve biopsy may reveal a loss of large myelinated fibers.73 Skin biopsies can demonstrate loss of epidermal nerve fibers suggestive of a small fiber neuropathy in some patients.81 In one small series, autopsy of three patients revealed inflammation in the dorsal root ganglia with degeneration of the posterior columns of the spinal cord.76 In another report, a loss of Purkinje cells in the cerebellum was described along with degeneration of the posterior columns and corticospinal tracts, cortical atrophy and loss of neurons in the thalamus, basal ganglia, and brainstem.78
The neuropathy may be secondary to malabsorption of vitamins B12 and E. However, some patients have no appreciable vitamin deficiencies. The pathogenic basis for the neuropathy in these patients is unclear but may be autoimmune in etiology.73,83
Some patients may improve with gluten-free diet,76 many others do not.72,85 In patients with vitamin B12 or E deficiency, replacement therapy may improve or stabilize the neuropathy.
Ulcerative colitis and Crohn disease are inflammatory disorders of the bowel and are associated with various neurological abnormalities including peripheral neuropathy. Acute or chronic demyelinating neuropathies (including multifocal motor neuropathy),86–91 generalized axonal sensory or sensorimotor polyneuropathy,91,92 small fiber neuropathy,91 brachial plexopathy,89,93 multiple mononeuropathies,89 and cranial neuropathies89 can complicate ulcerative colitis and Crohn disease. The neuropathies in these cases may be autoimmune in nature, secondary to toxicity of treatment (e.g., metronidazole), nutritional (e.g., vitamin B12 deficiency), or idiopathic. An acute neuropathy with multifocal demyelination and conduction blocks on NCS has been reported in patients with inflammatory bowel disease treated with TNF-α blockers.94 In addition, patients can develop weakness secondary to myasthenia gravis or myositis (including polymyositis, dermatomyositis, and granulomatous myositis).89
Primary biliary cirrhosis (PBC) is an autoimmune disorder directed against the biliary ducts in the liver. Peripheral neuropathy is the most common neurological complication of PBC. The neuropathy usually manifests with distal numbness and tingling.95–99 Large fiber sensory modalities are predominantly affected, leading to reduced or absent muscle stretch reflexes. Muscle strength is typically normal but may be reduced in patients with a CIDP-like neuropathy. The neuropathy may be immune-mediated, or caused by anti–TNF-α therapy or metronidazole.33,34,98 Myasthenia gravis, Lambert–Eaton syndrome, and myositis can also complicate PBC.
Liver function tests are elevated, and antimitochondrial antibodies can be detected in the sera of some patients with PBC. NCS demonstrates reduced or absent SNAPs. The motor conduction and needle EMG portions of the evaluation are typically normal.
Nerve biopsies usually reveal a loss of large myelinated fibers without evidence of segmental demyelination.
The neuropathy could have an immunological basis or may be related to unknown toxins that might be accumulating secondary to the liver failure. In addition, the neuropathy may be associated with treatments (e.g., TNF-α blockade or metronidazole).98
PBC is treated with immunosuppressive therapy and ultimately liver transplantation. Whether or not transplantation affects the peripheral neuropathy has not been adequately addressed.
The hypereosinophilic syndrome is characterized by eosinophilia associated with various skin, cardiac, hematologic, and neurological abnormalities.100–102 Multiple mononeuropathies or a generalized, symmetric polyneuropathy occurs in 6–14% of patients. In addition, some develop an inflammatory myopathy. NCS reveal features suggestive of axonal sensorimotor peripheral neuropathy. The pathogenic basis for the neuropathy is not known but may be autoimmune in nature. The multiple organ dysfunction, including the peripheral nervous system, is believed to occur as a result of the eosinophilia or some by-products of the eosinophils.
Renal failure is associated with both CNS and peripheral nervous system complications.103–107 At least 60% of patients with renal failure (usually with glomerular filtration rates below 12 mL/min) develop neuropathy characterized by length-dependent numbness, tingling, and allodynia. Muscle cramps in the distal legs and restless legs syndrome are also common. Reduced sensation, particularly large fiber modalities, and diminished muscle stretch reflexes are appreciated on neurological examination. Mild distal greater than proximal muscle weakness may be noted. Rarely, patients develop rapidly progressive weakness and sensory loss very similar to AIDP, which improves with an increase in renal dialysis or transplantation.103,104,107
Mononeuropathies can also occur, the most common of which is carpal tunnel syndrome. These neuropathies are often related to hemodialysis equipment that uses a Cuprophan membrane. This is because this membrane fails to completely remove a small β2-microglobulin, that is normally catabolized by the healthy kidney. β2-Microglobulin can deposit throughout the body, including the transverse carpal ligament. Individuals who are affected are also prone to developing ulnar neuropathy at the elbow and peroneal nerve injury about the fibular head. Damage to the brachial plexus or the peripheral nerves may also occur secondary to improper limb positioning or traction during renal transplant surgery. Ischemic monomelic neuropathy affecting the median, ulnar, and radial nerves can complicate arteriovenous shunts created in the arm for dialysis.108
NCS in patients with uremia reveal features of a length-dependent, primarily axonal, sensorimotor polyneuropathy.105,106,109,110 Sensory studies are reduced in amplitude, if obtainable, distal latencies prolonged and conduction velocities slowed. Most patients have either prolonged or absent H-reflexes, and somatosensory-evoked potential studies reveal both peripheral and central slowing of conduction. Motor conduction studies reveal normal or mildly reduced amplitudes. Distal latencies and conduction velocities can be normal or reflect moderate slowing of conduction. F-waves are usually absent or demonstrate delayed latencies. The posterior tibial and peroneal motor studies are affected earlier than the median and ulnar studies.
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