TABLE 16-1. NEUROPATHIES ASSOCIATED WITH SYSTEMIC DISORDERSNeuropathies 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).
TABLE 16-1. NEUROPATHIES ASSOCIATED WITH SYSTEMIC DISORDERS
Connective tissue disease
Sjögren syndrome or sicca complex
Rheumatoid arthritis
Systemic lupus erythematosus
Scleroderma
Mixed connective tissue disease
Sarcoidosis
Celiac disease
Inflammatory bowel disease
Ulcerative colitis
Crohn disease
Hypereosinophilic syndrome
Uremia
Primary biliary sclerosis
Liver disease
Whipple disease
Gout
Critical illness polyneuropathy
Amyloidosis
Acquired
Familial
Vasculitis
Isolated peripheral nerve vasculitis
Vasculitis associated with systemic disease
Granulomatosis with angiitis
Polyarteritis nodosa
Churg–Strauss syndrome
Microscopic polyangiitis
Infection
HIV
HTLV1
CMV
EBV
Lyme
Syphilis
Cancer
Direct tumor infiltration of nerves
Paraneoplastic
NEUROPATHIES ASSOCIATED WITH CONNECTIVE TISSUE DISEASESSjögren 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.
Figure 16-1. Sjögren syndrome. Sural nerve biopsy demonstrates a moderate reduction of large and small myelinated nerve fibers and evidence of axonal degeneration. Plastic section stained with toluidine blue.
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).
Figure 16-2. Rheumatoid arthritis. Sural nerve biopsy reveals an epineurial vessel with perivascular inflammation and scattered perineurial and endoneurial dilated capillaries with thickened walls. Paraffin section stained with Hematoxylin & Eosin (H&E).
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.
Mixed connective tissue disease represents an overlap syndrome of SLE, scleroderma, and myositis. A mild distal axonal sensorimotor polyneuropathy reportedly occurs in approximately 10% of patients.13,55 Trigeminal neuropathy is also a recognized complication of this syndrome.
OTHER PRESUMABLY IMMUNE-MEDIATED NEUROPATHIESSarcoidosis, 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
Figure 16-3. Sarcoidosis. MRI scan of the brain with contrast demonstrates enhancement of the meninges around the cerebellum (A) and of the cauda equina (B) in a patient who presented with multiple cranial neuropathies and a polyradiculopathy.
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
Figure 16-4. Sarcoidosis. Superficial peroneal nerve biopsy reveals a noncaseating granuloma and perivascular inflammation in the epineurium. Paraffin section stained with H&E.
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.
OTHER NEUROPATHIES ASSOCIATED WITH SYSTEMIC DISEASERenal 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.
Patients with mononeuropathies often have NCS compatible with superimposed focal demyelination or axonal loss. With ischemic monomelic neuropathy, the EMG and NCS abnormalities reveal severe axonopathy in the territory of the ischemic insult.108 The median, radial, and ulnar SNAPs may be absent or reduced in amplitude, depending on the degree and time period of ischemia. If CMAPs are elicited, the distal motor latencies are relatively normal as are the conduction velocities. Pseudoconduction block or actual conduction block may be seen across the ischemic segments, particularly within the first week of injury before complete Wallerian degeneration of the affected nerve distal to the nerve infarct can occur. Needle EMG demonstrates a marked reduction in motor unit action potentials (MUAPs) with abundant positive sharp waves and fibrillation potentials along with decreased recruitment. The pattern of EMG abnormalities is typically length dependent, affecting distal more than proximal muscles innervated by the same peripheral nerve.
In uremic neuropathy, sural nerve biopsies demonstrate a loss of nerve fibers, particularly the large myelinated nerve fibers; active axonal degeneration; and segmental and paranodal demyelination.111 At autopsy, chromatolysis of anterior horn cells and degeneration of the fasciculus gracilis have been noted in the spinal cord.
It is unclear what the primary pathophysiological mechanism of uremic neuropathy is and equally unclear whether the Schwann cell or the axon is the primary target of the essential metabolic or toxic abnormality.
The sensorimotor polyneuropathy may be stabilized by hemodialysis and improved upon successful renal transplant, if performed prior to the loss of large numbers of axons.106,107,112–116 Patients with carpal tunnel syndrome can be treated with surgical release. Median neuropathy at the wrist related to amyloid deposition in the form of β2-microglobulin is much less common nowadays with newer dialysis techniques currently in use. Patients with ischemic monomelic neuropathy should undergo revision of their shunt so as to allow more blood flow to the nerves. If treated early enough, the motor and sensory symptoms can resolve quickly, indicating an ischemic-induced conduction block rather than peripheral nerve infarction. Severe ischemia resulting in infarction is associated with a delayed and incomplete recovery.
Generalized sensorimotor peripheral neuropathy, characterized by numbness, tingling, and minor weakness in the distal aspects of primarily the lower limbs, commonly occurs in patients with chronic liver failure.96,117–121 In addition, autonomic dysfunction is present in approximately 50% of patients with severe liver disease.121 The cause of the neuropathy is quite variable. Neuropathy may be directly related to the underlying cause of the liver disease (e.g., alcoholism, viral infection, porphyria, amyloidosis, mitochondrial cytopathy), associated nutritional deficiencies, and complications of treatment such as transplantation (e.g., toxic effect of drugs or altered immunity related to immunosuppression). It is not known if hepatic failure in and of itself can cause peripheral neuropathy. Perhaps, toxins may accumulate secondary to the liver disease that could damage peripheral nerves. Electrophysiological abnormalities are thus variable and dependent on the cause of the liver failure. Most often, NCS demonstrate reduced SNAP amplitudes, while motor NCS are usually normal or show only slightly diminished amplitudes. Quantitative sensory and autonomic tests are abnormal in most patients.96,121 Sural nerve biopsies reveal both segmental demyelination and axonal loss.
Whipple disease is characterized by abdominal pain, diarrhea, malabsorption, weight loss, arthralgias, fever, and peripheral lymphadenopathy, accompanied by enlargement of the celiac, mesenteric, and periaortic lymph nodes.72,122–125 CNS involvement can lead to dementia, supranuclear ophthalmoparesis, convergence nystagmus, myoclonus, oromandibular myorhythmia, insomnia, hyperphagia, and polydipsia. Rarely, patients develop a sensorimotor polyneuropathy.122–125
The cerebrospinal fluid examination in patients with CNS involvement typically demonstrates polymorphonuclear cells and macrophages.72 MRI scans reveal gadolinium enhancement suggestive of ependymitis/meningitis. Sensory and motor NCS may demonstrate reduced amplitudes with mild impairment of conduction velocities.122
Small bowel biopsies demonstrate PAS-positive macrophages containing the gram-positive rod-shaped bacterium, Tropheryma whippeli, in the mucosa. The organism can also be identified in the CNS, but there have been no reports of peripheral nerve or muscle histopathology in patients with suspected neuropathy or myopathy.
Whipple disease is caused by the actinomycete—T. whippeli. The pathogenic basis of the neuropathy is not known, but some symptoms of the polyneuropathy may be the result of malabsorption of necessary vitamins. Another possibility is that the neuropathy may be caused by bacterial infiltration and subsequent inflammatory involvement of the peripheral nerves.
Whipple disease can be treated with chloramphenicol and trimethoprim-sulfamethoxazole.72
GOUTSome patients with gout have been reported to develop a sensorimotor peripheral neuropathy, characterized by length-dependent sensory loss or mononeuropathies at the usual sites of compression at the wrist and elbow.126 Sensory and motor NCS may reveal reduced amplitudes with normal or only mild alterations of conduction velocities or distal latencies.
The most common causes of acute generalized weakness leading to admission to a medical intensive care unit (ICU) are Guillain–Barré syndrome (GBS) and myasthenia gravis. However, weakness developing in patients who are critically ill while in the ICU is usually caused by critical illness polyneuropathy (CIP),127–130 critical illness myopathy (CIM) (also known as acute quadriplegic myopathy),131–137 or, much less commonly, prolonged neuromuscular blockade.138 From a clinical and electrophysiological standpoint, it can be quite difficult to distinguish these disorders. Although a few authorities feel that CIP is more frequent than CIM,129 most specialists and the authors’ own anecdotal experiences suggest that CIM is more common than CIP.134,136,139 In a series of 88 patients who developed weakness while in an ICU, CIM was three times as common as CIP (42% vs. 13%); prolonged neuromuscular blockade occurred in only one patient who also had CIM.134 In patients who survive the underlying sepsis and multiorgan failure, muscle strength recovers slowly over several months.
CIP can develop as a complication of sepsis and multiple organ failure.127–130 Neuropathies are common in the subset of critically ill patients due to extensive burn surfaces.140,141 Often, CIP presents as an inability to wean a patient from a ventilator. Concomitant encephalopathy may limit the neurological examination, in particular the sensory examination; however, generalized weakness can still be appreciated. Cranial nerves are relatively spared, although mild facial weakness can occur. Muscle stretch reflexes are absent or reduced.
Serum creatine kinase (CK) is usually normal. An elevated serum CK would point to CIM as opposed to CIP.
The electrophysiological hallmark is markedly reduced amplitudes or absent CMAPs with preserved motor conduction velocities and distal motor latencies.128–130,142 Repetitive stimulation studies should be normal. The SNAPs are significantly diminished in amplitude or absent. Importantly, it is important to recognize that low-amplitude SNAPs do not necessarily implicate CIP as the cause of weakness. Patients may have an age-related decrease in SNAP amplitudes or the SNAPs may be abnormal secondary to an underlying coincidental condition (e.g., diabetes mellitus and uremia). In addition, lower extremity edema is common in these patients potentially obscuring SNAPs on a technical basis. Thus, the patients could still have CIM rather than CIP even if the SNAPs are abnormal. Lastly, CIP and CIM are not mutually exclusive and may occur concurrently.
Needle EMG in CIP usually reveals profuse positive sharp waves and fibrillation potentials. It is not unusual for patients with severe weakness to be unable to recruit MUAPs. When MUAPs are recruited, these are often small and polyphasic in morphology. These small units have been attributed to early reinnervation, but may occur because there is degeneration of distal motor nerve terminals without reinnervation early in the course. Thus, MUAP morphology may resemble what is commonly seen in myopathies. Most published studies fail to discuss the recruitment pattern of MUAPs. One would expect to see decreased recruitment of these small MUAPs in a neurogenic process. However, decreased recruitment can also be seen in severe myopathies when all the muscle fibers of a motor unit have degenerated. Nevertheless, if one sees early recruitment of small duration, polyphasic MUAPs, CIM is most likely.
Direct muscle stimulation may help distinguish CIP from CIM, as it bypasses the distal motor nerve and neuromuscular junction.135,136 In a neuropathic process or prolonged neuromuscular blockade, the muscle membranes should retain its excitability and the direct muscle stimulation CMAP amplitude should be near normal compared to the low or absent nerve stimulation–evoked CMAP. In contrast, in CIM in which there is reduced muscle membrane excitability, both the nerve stimulation–evoked and the direct muscle stimulation CMAPs are reduced. The ratio of nerve stimulation–evoked CMAP to direct muscle stimulation CMAP should be close to 1:1 (greater than 0.9) in CIM and should approach zero (0.1 or less) in a CIP or neuromuscular junction disorder.116,117
Nerve biopsies demonstrate axonal degeneration.130 On autopsies, chromatolysis of anterior horn cells, loss of dorsal root ganglion cells, and axonal degeneration of motor and sensory nerves have been observed.130 Muscle biopsies may reveal atrophic and targetoid or core-like lesion fibers suggestive of acute neurogenic process.130 However, these light microscopic features can be seen in myopathies. Other studies have found loss of myosin thick filaments on muscle biopsy and morphology of intramuscular nerves and those of multiple nerve roots and proximal nerves to be normal on autopsy, suggesting that these cases may all be CIM.139
The pathogenic basis of CIP is not known. Perhaps, circulating toxins and metabolic abnormalities associated with sepsis and multiorgan failure impair axonal transport or mitochondrial function, leading to axonal degeneration.130 As mentioned, some have questioned the existence of CIP and suggested that most, if not all, such cases are CIM.143
There is no specific therapy for critical illness neuropathy other than supportive care and treatment of the underlying sepsis and organ failure.
AMYLOID POLYNEUROPATHYAmyloid comprises 10–20 nm, nonbranching protein fibrils, which aggregate to form three-dimensional β-pleated sheets that are resistant to proteolytic decomposition.144,145 Amyloidosis can be hereditary or acquired and is associated with systemic proteinaceous deposition in multiple organs (e.g., kidney, liver, heart, and GI tract) including peripheral nerves and muscle (Table 16-2). Familial forms of amyloidosis are inherited in an autosomal-dominant fashion and can be caused by mutations in the transthyretin (TTR), apolipoprotein A1, or gelsolin genes. In primary or AL amyloidosis, the abnormal protein deposition is composed of immunoglobulin light chains. AL amyloidosis occurs in the setting of multiple myeloma, Waldenström macroglobulinemia, lymphoma, other plasmacytomas or lymphoproliferative disorders, or in the absence of identifiable disease.146 Approximately 10% of patients with a presumptive diagnosis of systemic AL amyloidosis actually have hereditary amyloidosis with genetic testing.147 Secondary amyloidosis (AA) can complicate RA and other chronic inflammatory diseases and is associated with the accumulation of protein A but is not associated with a polyneuropathy.
TABLE 16-2. AMYLOID NEUROPATHY
Acquired
Primary or AL amyloidosis
Secondary amyloidosis
Familial amyloid polyneuropathy (FAP)
Transthyretin-related amyloidosis (FAP types I and II)
Apolipoprotein A1-related amyloidosis (type III FAP or Van Allen type)
Gelsolin-related amyloidosis (FAP type IV, Finnish)
Amyloid deposits have a characteristic apple-green birefringence when stained with Congo red and observed under polarized light and bright red under rhodamine fluorescence. Amyloid is also metachromatic when stained with methyl violet or crystal violet and also stains with Alcian blue. On nerve biopsy, amyloid deposition may be demonstrated in the endoneurium, perineurium, or epineurium and around blood vessels (Fig. 16-5).148 Chronic inflammatory cell infiltrate may be appreciated. Concomitant muscle biopsy may also reveal amyloid deposits encasing muscle fibers or around blood vessels. The appearance of the Congo red or metachromatic staining does not distinguish between the various subtypes of amyloidosis. Immunohistochemistry using antibodies directed against light chains, apolipoprotein A, gelsolin, and TTR and genetic testing is required to distinguish between the various forms of amyloidosis. Proteomic analysis of nerve tissue using laser microdissection (LMD) and mass spectrometric (MS)-based proteomic analysis can distinguish specific types of amyloid independent of clinical information.149
Figure 16-5. Superficial radial nerve biopsy (A–D, paraffin sections and E and F, epoxy sections). Serial paraffin cross sections show (A, hematoxylin and eosin stain) areas of eosinophilic amorphous deposits in the endoneurium and in the walls of endoneurial microvessels. The deposits react to lambda light chain preparations (B), stain salmon-pink on Congo red stain (C), and, when viewed under polarized light (D), show apple-green birefringence in the areas of amorphous material. The semithin epoxy sections (E and F) show a moderately reduced density of myelinated fibers. Unlike the clinical symptoms and findings (that are large fiber predominant), the biopsy shows relatively more severe reduction of small myelinated fibers in comparison to large myelinated fibers. The arrow shows a region of amyloid infiltration of an endoneurial microvessel. These findings are diagnostic of primary amyloidosis from a lambda light chain. (Reproduced with permission from Tracy JA, Dyck PJ, Dyck PJ. Primary amyloidosis presenting as upper limb multiple mononeuropathies. Muscle Nerve. 2010;41(5):710–715.)
Patients with primary (AL) amyloidosis can present with nephrotic syndrome, congestive heart failure, cardiac arrhythmia, purpura, bruises, sicca syndrome, dyspnea due to pleural effusions, gastrointestinal dysmotility (nausea/constipation/diarrhea/pain), splenomegaly, hepatomegaly, lymphadenopathy, fatigue, weight loss, myopathy, carpal tunnel syndrome, or polyneuropathy.150,151 It is more common in men over 50 years of age, which may help distinguish AL from familial amyloidosis, which usually presents earlier in adult life. However, AL amyloidosis can develop in people in their thirties and hereditary amyloidosis can present later in life.
Polyneuropathy develops in as many as 30% of patients with AL amyloidosis and can be the presenting manifestation.151–154 There is an early predilection for small fiber modalities resulting in painful dysesthesias and burning sensations along with diminished pain and temperature sensation and allodynia on examination. The legs are usually affected in a symmetric, length-dependent fashion; however, the trunk can be involved and as many as 20% or more present asymmetrically in a multifocal neuropathy pattern.153 Carpal tunnel syndrome occurs in 25% of patients and may be the initial complication. Cranial nerves may be affected. The neuropathy is slowly progressive, and eventually weakness develops along with large fiber sensory loss. Generalized proximal and distal weakness can develop such that it resembles CIDP.153 Most patients develop autonomic involvement with postural hypertension, syncope, impotence, bowel and bladder incontinence, constipation, and impaired sweating. Occasionally, enlarged peripheral nerves are appreciated by an astute clinician. The general physical examination can demonstrate limb edema, hoarse voice, hepatomegaly, and macroglossia. Patients generally die from their systemic illness (renal failure and cardiac disease).
The monoclonal protein can be composed of IgG, IgA, IgM, or only free light chain. Lambda (λ) is more common than κ light chain (>2:1) in AL amyloidosis, in contrast to multiple myeloma in which κ light chains are more common. Immunoelectrophoresis (IEP) or immunofixation (IFE) of the serum and urine is more sensitive in identifying monoclonal proteins than serum or urine protein electrophoresis (SPEP or UPEP); but serum-free light-chain assay is even more sensitive and thus should be performed on patients with possible amyloid neuropathy. Hypogammaglobulinemia, anemia, renal failure, proteinuria, and transaminitis due to liver involvement may be seen. The serum CK levels can also be elevated in patients with concurrent amyloid myopathy. The cerebrospinal fluid protein is often increased (with normal cell count), and thus the neuropathy may be mistaken for CIDP.153
Sensory nerve action amplitudes are usually reduced or absent in involved nerves. When obtainable, the distal sensory latencies can be normal or only moderately prolonged and the conduction velocities are similarly normal or moderately slow. Motor conductions are less involved than the sensory conduction but, nonetheless, are frequently abnormal. Motor NCVs can be normal or moderately reduced.151–158 The distal motor latencies are normal or only moderately prolonged in the upper limbs and usually prolonged in the lower limbs. CMAP amplitudes are normal or only mildly reduced during the early course of the disease and not as severely affected as the SNAP. The motor and sensory conduction abnormalities are usually symmetric but can be asymmetric in patients with multifocal neuropathies.153 Electrophysiological evidence of superimposed median neuropathy at the wrist (carpal tunnel syndrome) is common.
Needle EMG examination usually reveals positive sharp waves and fibrillation potentials along with reduced recruitment of long-duration, high-amplitude, polyphasic MUAPs in affected muscles. Myotonic discharges and myopathic MUAPs, particularly in more proximal muscles, may be seen in patients with superimposed amyloid myopathy.
Nerve biopsies reveal axonal degeneration and severe loss of small myelinated and unmyelinated fibers. There is a less pronounced but obvious degeneration of the large myelinated nerve fibers as well. Congo red staining reveals amyloid deposition in a globular or diffuse pattern within the perineurial, epineurial, and endoneurial connective tissue as well as in and around blood vessel walls (Fig. 16-5).152 Amyloid deposition can also be demonstrated in the sympathetic and dorsal root ganglion. Because of the patchy, multifocal pattern of amyloid deposition, biopsies are not always diagnostic. Other sites commonly biopsied include the kidney, rectal mucosa, stomach, abdominal fat pad, salivary glands, muscle, and skin. Abdominal fat pad biopsies seem to be the most sensitive method to detect amyloid deposits and these are abnormal in 85% of patients. Immunohistochemistry is helpful in demonstrating that the amyloid is composed of λ, or less frequently κ, light chains.
The pathogenic basis for the neuropathy associated with amyloidosis is unclear and may be multifactorial. Amyloid deposition in the epineurial and endoneurial connective tissue may lead to compression of nerve fibers with focal demyelination and axonal degeneration. Deposition around blood vessels might cause ischemic damage to nerve fibers.159 Transport of nutrients into and waste products out of the nerves may also be affected by amyloid deposition within the endoneurium and epineurium and around blood vessels.
The prognosis of patients with primary amyloidosis is poor, with a median survival of less than 2 years. Death is generally secondary to progressive congestive heart failure or renal failure. Chemotherapy with melphalan, prednisone, colchicine that reduces the concentration of monoclonal proteins, and autologous stem cell transplantation may prolong survival and improve the neuropathy.160–162 The severity of baseline cardiac and renal involvement, number of organs involved, and presence of autonomic neuropathy may be independent, adverse determinant of survival in these patients.162
FAMILIAL AMYLOID POLYNEUROPATHIESAlthough frequently clinically indistinguishable from primary amyloidosis, familial amyloid polyneuropathy (FAP) is phenotypically and genetically heterogeneous. It is caused by mutations in the genes for TTR (prealbumin), apolipoprotein A1, or gelsolin.146,157,163–168 Diagnosis of familial amyloidosis is made by detection of amyloid deposition in abdominal fat pad, rectal, or nerve biopsies or with genetic testing (Fig. 16-6). Unlike, the nonhereditary forms of amyloidosis, monoclonal gammopathies are not present and the abnormal amyloid deposits do not immunostain for immunoglobulin light chains. In contrast, these amyloid deposits may stain for TTR, apolipoprotein A1, or gelsolin.
Figure 16-6. Familial amyloid polyneuropathy. Sural nerve biopsy in a patient with mutations in the transthyretin gene reveals large globular deposition of amyloid in the endoneurium that is appreciated using Congo red stain. (A) The amyloid stains pinkish-red under routine light microscope without polarization, and under rhodamine fluorescence (B) the amyloid deposition appears bright red. The amyloid deposit stains blue with Alcian blue (C).
Nerve biopsies in the different forms of FAP reveal findings similar to that seen in AL amyloidosis. Amyloid deposition can be multifocal or diffuse within the endoneurium, epineurium, or perineurium, as well as around blood vessels in autonomic ganglia and in peripheral nerves.157,165 Importantly, in approximately 50% of FAP, nerve biopsies do not demonstrate amyloid deposits perhaps secondary to sampling error.169 As mentioned previously, immunohistochemistry and even LMD and MS-based proteomic analysis can be used to distinguish specific types of amyloid.142
There is a loss of myelinated nerve fibers, particularly small myelinated and unmyelinated nerve fibers. These deposits encroach upon the nerve fibers, resulting in axonal degeneration and segmental demyelination. The clinical features, histopathology, and electrophysiological studies reveal abnormalities consistent with a generalized or multifocal, predominantly axonal but occasionally demyelinating, sensorimotor polyneuropathy.155,161–171 Cerebrospinal fluid can reveal elevated protein levels with normal cell count again mimicking CIDP. The pathogenic bases for the FAP neuropathies are likely similar to that noted with AL neuropathy.
The majority of patients with FAP have mutations in the TTR gene. There appear to be two somewhat different clinical phenotypes associated with TTR-related amyloidosis: FAP I and a less severe FAP II. FAP I was originally reported in the Portuguese,172 but it affects multiple ethnic groups with particularly large foci in Sweden and Japan.143,163,166–168,173–177 Patients usually develop insidious onset of numbness and painful paresthesia in the distal lower limbs in the third to fourth decade of life, although some patients develop the disorder later in life.173,174 Pain and thermal sensation are the most common modalities affected. Carpal tunnel syndrome is uncommon. Autonomic involvement can be severe, leading to postural hypotension, constipation or persistent diarrhea, erectile dysfunction, and impaired sweating. Distal and later proximal muscle atrophy and weakness develop over time such that the patients may be mistaken for having CIDP.155,177 Occasional cranial neuropathies, leading to pupillary changes, decreased saliva secretion, diminished facial (including corneal) sensation, dysphonia, dysphagia, and facial weakness occur. Amyloid deposition also occurs in the heart, kidneys, liver, and the corneas. Patients usually die by 10–15 years after the onset of symptoms from cardiac failure or complications from malnutrition.
A milder form of TTR-associated FAP (Type II FAP) was initially described in families in Indiana and Switzerland and is characterized by the development of carpal tunnel syndrome and later by a mild generalized sensorimotor polyneuropathy.143,145,166 Although erectile dysfunction can be seen, severe autonomic dysfunction is unusual. As with FAP I, vitreous opacities may be appreciated. Although there can be systemic involvement, severe nephropathy or cardiomyopathy usually does not develop. Thus, most patients with FAP II have a relatively long survival, with little morbidity related to the amyloidosis. The symptoms of carpal tunnel syndrome can be relieved with surgical decompression.
More than 100 different mutations within the TTR gene located on chromosome 18q11.2–12.1 have been associated with FAP types I and II.146,166,170,175,178 A mutation involving a methionine to valine substitution at position 30 (Val30Met) in the TTR gene is the most common mutation associated with type I FAP, while serine substitutions at position 84 and histidine at position 58 are the most common mutations associated with FAP type II. There can be variability in the age of onset and severity even within families with the Val30Met mutations. TTR functions as a transport protein for vitamin A and thyroxin. Over 90% of the body’s TTR is synthesized in the liver. The amino acid substitutions lead to the formation of the β-pleated sheet structure of the protein and its resistance to degradation by proteases, thus its amyloidogenic properties.
Because the liver produces much of the body’s TTR, liver transplantation has been used to treat FAP related to TTR mutations. Serum TTR levels decrease after transplantation and improvement in clinical and neurophysiological features has been reported.170,175,178,179 However, abnormal TTR can continue to be synthesized in the CNS (by the choroid plexus) and within the eyes, potentially resulting in progressive deficits from local accumulation in these areas. Oral administration of tafamidis meglumine, which prevents misfolding and deposition of mutated TTR, is under evaluation in patients with TTR FAP.174 There is an ongoing clinical trial of diflunisal in TTR-related FAP.180 Both of these medications are hypothesized to decrease the fibril-forming ability of mutant TTR protein.
FAP type III was originally described by Dr. Van Allen in a family from Iowa.181,182 The neuropathy usually manifests as numbness and painful dysesthesias in the lower limbs in the fourth decade of life. Gradually, the symptoms progress to the distal upper limbs and proximal muscle weakness and atrophy develop. Although autonomic neuropathy is not severe, some patients develop diarrhea, constipation, or gastroparesis. Most patients die from systemic complications of amyloidosis (e.g., renal failure) 12–15 years after the onset of the neuropathy.
FAP type III is caused by mutations leading to arginine for glycine substitution at position 26 (Arg26Gly) in the apolipoprotein A1 gene on chromosome 11q23–qter.183 Apolipoprotein A1 is a major component of high-density lipoproteins. As with TTR mutations, the amino acid substitution probably impairs its degradation by proteases.
There are no specific medical therapies.
FAP IV was initially described in Finland and is characterized by the combination of lattice corneal dystrophy, multiple cranial neuropathies (e.g., facial palsies and bulbar weakness), and cutis laxa.184–188 Onset of symptoms is usually in the third decade of life. Over time, a mild generalized sensorimotor polyneuropathy develops. Autonomic dysfunction does not occur. Cutis laxa manifests as loose or hanging skin affecting the scalp and face (Fig. 16-7).
Figure 16-7. Clinical characteristics in hereditary gelsolin amyloidosis. (A) The drooping face of a 79-year-old male patient, after corrective facial surgery. Note also the loss of frontotemporal hair and thinning of the eyebrows. (B) The tongue is morel-like and macroglossic. (C) Drooping ears and abnormally lax, folded, and unelastic skin of the scalp with thinning of scalp hair. Cutis laxa affecting (D) the thumb and (E) the back. (D and F) The thumb and scalp skin retain their deformed state after pressure for 2–5 minutes. (Reproduced with permission from Kiuru-Enari S, Keski-Oja J, Haltia M. Cutis laxa in hereditary gelsolin amyloidosis. Br J Dermatol. 2005;152(2):250–257.)
Autopsy studies have demonstrated a different distribution of amyloid deposition in FAP type IV than the other types of amyloidosis.189 Histological, immunohistochemical, and electron microscopic studies reveal deposition of gelsolin amyloid, particularly in the vascular walls and perineurial sheaths. Nerve roots are more severely affected than distal nerves. The marked proximal nerve involvement with gelsolin-related angiopathy is a characteristic feature of FAP type IV. There was also preferential large fiber loss, not generally seen in other forms of amyloid neuropathy.
Type IV amyloidosis is caused by mutations in the gelsolin gene.190–192 Gelsolin is an actin-binding protein found in plasma, leukocytes, and other cells. The resultant mutations and amino acid substitutions lead to a charge change on the protein, which may render the molecule resistant to proteases.
There are no specific medical therapies. However, facial plastic surgical procedures can help fix the cosmetic problems associated with cutis laxa.184
SUMMARYAs discussed, neuropathies may complicate many different systemic disorders. It is important to distinguish neuropathies that may be directly related to the underlying disorder, caused by treatment (toxic neuropathy), or just be coincidental occurrence as management may differ according to the etiology. Thus, as discussed in Chapter 1, it is always important to take a detailed medical history and examination to assess for an underlying systemic disorder that may be associated with the neuropathy.
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