Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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The vasculitides are a group of heterogeneous disorders that present with a variable and complex clinical picture. Debates over clinical versus pathological approaches to classification abound in the literature, with recognized limitations given the variable clinical presentations and the overlap between the recognized diagnostic entities. Peripheral neuropathy is an important, and often the presenting, clinical feature of the vasculitides. Its recognition can be critical to attain an early diagnosis in these disorders where the ultimate outcome can be greatly influenced by early therapeutic intervention.
• Neuropathy related to vasculitis can occur as either a primary condition (in the setting of systemic vasculitis) or secondary to a range of diseases including infection and connective tissue disorders. Localized nonsystemic vasculitic neuropathies include diabetic lumbosacral radiculoplexus neuropathy (DLRPN) and nondiabetic lumbosacral radiculoplexus neuropathy (LRPN).
• Vasculitic neuropathies can be classified according to clinical features or histopathologically based on the size of involved vessels.
• Diagnostic tests include electrodiagnostic studies demonstrating an asymmetric non-length dependent axonal neuropathy and nerve biopsy when necessary.
• Management involves institution of immunosuppressive therapy and removal of the inciting agent when present.
Peripheral neuropathy figured prominently in the first complete description of a systemic necrotizing vasculitis (polyarteritis nodosa) by Kussmaul and Maier in 1866. For the next 80 years, essentially all vasculitic diseases, irrespective of clinical features, were called polyarteritis nodosa. Scattered descriptions of patients with peripheral neuropathy appeared in many of these early reports. Neuropathy occurring in the setting of rheumatoid arthritis was also described in the late 19th century, and one report described in detail the vascular histopathology (04).
In the 1950s, hypersensitivity vasculitis, Churg-Strauss syndrome, and Wegener granulomatosis were all described in the English language literature as entities distinct from polyarteritis nodosa, and Zeek first proposed a classification scheme for the vasculitic syndromes based on the size of involved blood vessels (01). Over the next 20 years, numerous reports appeared detailing the clinical features, histopathology, response to treatment, and prognosis of the various vasculitic syndromes; peripheral neuropathy was an important finding in many of these reports. During this time several different, and often conflicting, classification schemes for the vasculitides were proposed based on the size of involved vessels, type of vascular pathology, clinical features, or immunopathologic mechanisms. Despite several multicenter studies that have attempted to standardize the nomenclature, diagnostic criteria, and classification of the vasculitic syndromes, some confusion over these issues persists (31; 33; 01). The International Chapel Hill Consensus Conference updated their classification system in 2012, now organized primarily by vessel size and etiology (34). Additionally, in 2010, the Peripheral Nerve Society published new guidelines on the classification of vasculitic neuropathies, subdividing them into primary systemic, secondary systemic, and nonsystemic or localized vasculitides. This scheme included the entities of nondiabetic lumbar radiculoplexus neuropathy (LRPN) and diabetic lumbosacral radiculoplexus neuropathy (DLRPN), which had not been included in prior classification systems (08). In 2015, the Brighton criteria revised the diagnostic criteria for vasculitic neuropathies using the same histopathological criteria as the Peripheral Nerve society but also included several clinical features in addition (25).
In 1972, Dyck and colleagues published a seminal work detailing the sural nerve histopathology in 14 patients with various vasculitic syndromes (14). This study correlated the three-dimensional morphology of nerve fiber degeneration and vascular pathology, and provided strong support for the concept that ischemia probably accounts for the nerve damage in these syndromes. Several large series of patients with vasculitic neuropathy have defined the clinical spectrum, laboratory features, electrophysiologic findings, and immunopathology of these syndromes. An important concept to emerge from these studies is that neuropathy can be the sole manifestation of an underlying vasculitis (40; 03; 26; 13; 60; 55; 29; 52; 11). Several studies have documented a true necrotizing vasculitis associated with the syndrome of proximal diabetic neuropathy (diabetic amyotrophy/lumbosacral radiculoplexus neuropathy) (41; 15; 20; 59). A similar vasculopathy has also been found in nondiabetics presenting with lumbosacral radiculoplexopathy (16).
The peripheral neuropathy associated with vasculitis is caused by involvement of the vasa nervorum resulting in ischemic damage to the nerve and usually axonal degeneration. The extent, distribution, and severity of the vasculitic process will, therefore, determine the clinical presentation of the neuropathy. Classically, patients present with the acute or subacute onset of painful weakness and sensory loss in the distribution of individual peripheral or cranial nerves. This multiple mononeuropathy typically progresses in a stuttering, step-wise fashion so that patients are frequently able to pin-point accurately the onset of their deficits. In 10% to 15% of patients, the multiple mononeuropathy is relatively "pure," so that the involvement of large individual nerves can readily be identified clinically. More commonly (25% to 50%), the mononeuropathy is "overlapping" or "extensive" and the involvement is too severe to identify individually-affected nerves. In these patients, examination reveals significant asymmetry between sides, either in the degree or distribution of weakness, or the pattern of sensory loss (40; 52; 11).
Exceptions to this classic presentation commonly occur. Approximately 20% to 30% of patients will present with a distal, symmetric, "stocking-glove" polyneuropathy. Although some of these patients will give a history of asymmetric onset or step-wise progression of deficits to suggest the vasculitic process, about 25% to 30% of patients will have a symmetric neuropathy from the outset and a steady progression of deficits (09). This variant implies early widespread vasculitic involvement at multiple levels of the nerve trunk, producing a distal summation of deficits. Burning, dysesthetic neuropathic pain is usually a prominent part of the symptom complex, but can be absent in about 25% of cases (29; 52). Finally, although the process is usually progressive, and most patients present within a period of weeks to months of symptom onset, some individuals can have a chronic, indolent disease, with symptoms present for years before diagnosis (40; 29). Occasional patients will even have quiescent periods lasting weeks to months, where there is no apparent progression of symptoms or objective findings. The diagnosis of vasculitis in any of these clinical contexts can be particularly challenging for the clinician and requires a high index of suspicion. Nonspecific systemic symptoms such as generalized fatigue, weight loss, anorexia, arthralgias, and fever occur in up to 80% of patients with a systemic vasculitis and 50% of patients with a nonsystemic (isolated peripheral nerve) vasculitis. Occasionally, there can be cranial nerve involvement as well, more often in those patients with systemic vasculitis (09).
The clinical syndrome is identical, whether the vasculitic neuropathy occurs in isolation (nonsystemic vasculitic neuropathy), as part of a systemic vasculitic disease (such as polyarteritis nodosa, Churg-Strauss syndrome, or Wegener granulomatosis) (Table 1) or in association with another connective tissue disease (such as systemic lupus erythematosus, rheumatoid arthritis, or Sjögren syndrome) (38; 54; 04). In patients with a primary systemic syndrome the kidneys, lungs, skin, and bowel are frequently involved, and the central nervous system can also be affected. Such multi-organ involvement in the setting of a neuropathy should always raise the possibility of vasculitis. In those with nonsystemic vasculitic neuropathy (eg, diabetic radiculoplexus neuropathy), pain is a more frequent symptom and attacks tend to be less frequent and less severe. These patients progress more slowly, do not typically have other constitutional symptoms, and infrequently progress to have other systemic involvement (23).
I. Primary systemic vasculitis
A. Predominantly small vessel
• Classic polyarteritis group
B. Predominantly medium vessel
• Polyarteritis nodosa (PAN)
C. Predominantly large vessel
• Giant cell arteritis
II. Secondary systemic vasculitis
A. Vasculitis with connective tissue disease (eg, systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, Behçet disease)
• Bacterial (eg, syphilis, tuberculosis, Lyme disease)
C. Vasculitis associated with malignancy (eg, paraneoplastic with anti-Hu antibodies)
III. Nonsystemic or localized vasculitis
A. Nonsystemic vasculitic neuropathy (eg, nondiabetic radiculoplexus neuropathy)
There have been no prospective studies that have examined the long-term prognosis of patients with peripheral nerve vasculitis. What is clear from the limited data available is that there is a striking difference in prognosis depending on whether or not there is an underlying systemic necrotizing vasculitis. In the Mayo clinic series of 65 patients with vasculitic neuropathy (45 with an underlying systemic necrotizing vasculitis and 20 with nonsystemic vasculitic neuropathy), approximately one third of the systemic vasculitis patients died within a median time of 1.5 years of presentation, whereas none of the patients with nonsystemic vasculitis died during a mean follow-up of 11.5 years (13). Although treatment was not controlled in this series, the general and neurologic status was the same or better at the time of last follow-up in approximately two thirds of the systemic vasculitis patients and one half of the patients without a systemic vasculitis. A similar experience was reported by Davies and colleagues, who documented improvement (at a mean follow-up of 176 weeks) in 24 out of 25 patients with isolated peripheral nerve vasculitis (11). A series of 48 patients with nonsystemic vasculitis reported by Collins and colleagues also showed a good outcome with more than 80% of the patients showing mild to moderate or no disability on follow-up (10).
Another large series of 34 patients reported by Hawke and colleagues documented a poor prognosis in patients with a systemic necrotizing vasculitis, which was present in 32 of their cases (29). In this series, 50% of the patients died within a mean of 36 months of presentation and the 5-year survival was only 37%. All of the surviving patients, however, had responded to therapy, and at 36-month follow-up, approximately one half of the patients had no or only mild neurologic deficits; 4 patients had ceased therapy altogether. Taken together, these studies strongly support the use of aggressive immunosuppression in these patients, particularly because the untreated 5-year survival rate for most types of systemic necrotizing vasculitis is less than 15%.
A 56-year-old man with a history of chronic sinusitis and asthma presented to the emergency department with chills and rapidly progressive pain and numbness in the left leg and right arm. Soon after, he developed acute onset weakness in the right hand and left leg and was soon unable to walk unassisted. On examination, there was distal greater than proximal weakness in the right arm, a complete foot drop on the left, and sensory deficits in the right hand and in the left leg in a fibular distribution. Both erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were elevated, and perinuclear antineutrophil cytoplasmic antibodies (ANCA) titers were positive. Nerve conduction studies demonstrated a severe non-length dependent sensorimotor neuropathy with features consistent with mononeuritis multiplex, including nondemyelinating conduction block. A sinus biopsy showed small necrotizing granulomas with eosinophilic infiltration, and he was diagnosed with Churg-Strauss syndrome. Treatment with cyclophosphamide and prednisone was initiated, and after several weeks he had marked improvement in both pain and motor function.
The vasculitic syndromes, including those involving the peripheral nerve, must be considered idiopathic, in that little is understood concerning their etiology. Approximately 50% of vasculitic neuropathy cases occur in the setting of a primary systemic vasculitis (such as polyarteritis nodosa or Wegener granulomatosis) or as a secondary systemic vasculitis associated with collagen vascular disease, most commonly rheumatoid arthritis (40; 54). Another 10% are associated with some other systemic illness or process such as infection, malignancy, or drug ingestion (See Table 1). In these patients, some antigen related to the systemic illness presumably triggers the immunologic processes that result in vessel damage. In the remaining 40% of patients, the neuropathy occurs in isolation (nonsystemic vasculitic neuropathy), at times associated with diabetes mellitus, though often with no other associated condition or etiology identified.
Although all of the vasculitic syndromes are presumed to be autoimmune diseases, the pathogenic mechanisms responsible for mediating the vessel damage are unclear, and the antigens that trigger the immunologic processes are unknown. It is unlikely that a single mechanism can explain the differing clinical and pathologic findings of the various syndromes. More likely, different mechanisms trigger and perpetuate the sequence of immunologic events depending on whether the vasculitis is primary or secondary to some other illness or insult (65; 06).
Immune complex formation has traditionally been considered a unifying mechanism for many of the vasculitides, and most of the early understanding of vasculitis came from studies of serum sickness in animals. In this type of vasculitis, antibodies bind to some endogenous or exogenous antigen, forming circulating complexes that are then deposited in blood vessel walls. The complexes initiate a number of immunologic processes, including activation of the classical complement pathway and generation of neutrophil chemotactic factors C3a and C5a. Neutrophils are then recruited to the site, infiltrate the blood vessel walls, and discharge proteolytic enzymes in the leukocytoclastic reaction. Terminal complement membrane attack complex is also generated and deposited in the vessel walls, and the coagulation system is activated (39). The end result of all of these processes is inflammatory necrosis of the vessel wall and thrombosis of the vessel.
Immune complex formation is probably important in most types of hypersensitivity vasculitis related to infection, malignancy, cryoglobulinemia, and many types of therapeutic and illicit drugs. Many of the secondary vasculitides seen in the setting of various connective tissue diseases, such as systemic lupus erythematosus and rheumatoid arthritis, may also be mediated by immune complex mechanisms, where the inciting antigen is an endogenous protein. Finally, immune complexes may be important in the 30% of polyarteritis nodosa patients who have circulating hepatitis B antigen-antibody complexes (in which cases the hepatitis B infection is thought to trigger the vasculitis). Vasculitis can also occur in the setting of hepatitis B infection with associated cryoglobulinemia, which is typically a mixed essential cryoglobulinemia. In diabetic lumbosacral radiculoplexus neuropathy (DLRPN), microvasculitis leads to ischemic injury. Nerve biopsy in these cases may show fiber loss, neovascularization, and perineural thickening (15).
Antibody-induced vasculitis need not necessarily involve circulating immune complexes because antibodies could be generated directly against microvascular or other cellular antigens. Antiendothelial cell antibodies have been detected in many autoimmune disorders, including systemic vasculitis, and there is some evidence that the level of antiendothelial cell antibodies may correlate with disease activity in these patients (47). Similarly, antibodies directed against neutrophil cytoplasmic antigens have been demonstrated in Wegener granulomatosis, classic and microscopic polyarteritis, Churg-Strauss syndrome, and small vessel vasculitis (22). Antineutrophil cytoplasmic antibodies have a broad spectrum of activity and regulate a wide range of neutrophil functions that could result in endothelial cell damage.
The role of both antiendothelial cell antibodies and antineutrophil cytoplasmic antibodies (ANCAs) in the pathogenesis of vasculitic neuropathy is uncertain. Although a prospective study documented the presence of detectable antineutrophil cytoplasmic antibodies titers in 4 of 6 patients with vasculitic neuropathy, positive titers were also detected in 14% of patients with other immune-mediated neuropathies, as well as in other patients with nonimmunologic disorders (05). One thought is that ANCAs lead to granulomatous inflammation via activation of extravascular neutrophils leading to necrosis and fibrin formation, subsequently causing an influx of monocytes and other inflammatory cells (35). Perinuclear ANCAs are known to be associated most strongly with microscopic polyangiitis and Churg-Strauss syndrome, whereas cytoplasmic ANCAs are found in Wegener granulomatosis.
A growing body of persuasive evidence indicates that other immune mechanisms besides immune complex formation must be important in many types of peripheral nerve vasculitis. Immunohistochemical analyses of the peripheral nerve vasculitic lesions have revealed that T-cells and macrophages are the predominant cell types in the cellular infiltrates of these lesions (39; 55; 07), suggesting that primary cellular immunity involving cytotoxic T-cells may be particularly important. In this scenario, circulating T-cells recognize antigen in association with endothelial cells, which can serve as antigen presenting cells and express class II major histocompatibility complex antigens. This recognition leads to the activation or up-regulation of an amazingly complex system of cell-adhesion molecules and soluble mediators that results in the adherence of selected lymphocyte and other effector cell populations to the endothelial surface.
This, in turn, activates an equally complex system of cytokines, chemotactic agents, inflammatory regulators, and effector molecules that eventually leads to damage of the vessel wall through several mechanisms, including degradative enzyme release, free radical production, perforin-mediated cytolysis, and induced apoptosis (65; 06). One study suggests that cyclooxygenase-2 may be an important mediator of cell damage (62). Another demonstrated that macrophages effecting axonal damage and demyelination express tumor necrosis factor-alpha (53). Activation of nuclear factor kappaB, mediated by the receptor for advanced glycation (RAGE), has been postulated as an inflammation promoter in vasculitis due to the presence of these ligands in sural nerve biopsies of affected patients (28).
The end result of the various immunologic processes in all the vasculitic syndromes is inflammation and necrosis of blood vessel walls, compromise of the vessel lumen, and ischemia in the distribution of the involved vessels.
In peripheral nerve vasculitis, the 50- to 300-mm vessels of the vasa nervorum are affected by the vasculitic process. Because of the rich anastomotic blood supply to peripheral nerve, ischemic damage results only after extensive involvement of the nerve microvasculature (46; 48). The resulting ischemia causes predominantly axonal degeneration, usually in a random, focal fashion that results in axonal loss that is asymmetric between and within fascicles (14; 60; 46). Myelinated fibers are more susceptible to ischemia than unmyelinated fibers, and fibers larger than 7 Tm are particularly vulnerable (04). With extensive involvement, all cellular elements including fibroblasts, Schwann cells, and unmyelinated fibers can be involved, and entire fascicles can appear infarcted.
Accurate information concerning the incidence and prevalence of vasculitic neuropathy is unavailable. In fact, the epidemiology of the vasculitic syndromes in general is poorly understood, due in large part to the fact that most of the published clinical series are from large, tertiary referral centers and most of the conditions are relatively uncommon. An analysis suggested that the incidence of all types of vasculitis may be as high as 39 per million population, although many of these types are not commonly associated with neuropathy (68). For one of the most common primary systemic vasculitis, polyarteritis nodosa, the best available information suggests an annual incidence rate of approximately 5 to 10 cases per 1,000,000 population. Because 50% to 75% of patients with polyarteritis have peripheral nerve involvement, this would translate to 2.5 to 7.5 cases of vasculitic neuropathy per year per 1,000,000 population, a figure that approximates that reported in several clinical series (40; 13; 29).
No specific methods of prevention are known for the vast majority of idiopathic vasculitic diseases. Prevention or treatment of infections (such as HIV, Lyme disease, and hepatitis B) and avoidance of drugs (such as amphetamines and cocaine) known to be occasionally associated with vasculitis will obviously "prevent" vasculitic neuropathy in these patients. Similarly, appropriate management of systemic diseases commonly associated with vasculitis (eg diabetes, connective tissue diseases) may prevent progression of disease and onset of vasculitis in these patients.
The differential diagnosis of vasculitic neuropathy can be variable, depending on the patient's clinical presentation, the duration of the illness, and the presence or absence of an underlying systemic connective tissue disorder. The diagnosis is usually obvious, for example, in a patient with polyarteritis nodosa who develops acute, painful, multiple mononeuropathies. More difficult is the patient with a more chronic illness, atypical clinical features, or the absence of an underlying disease or other organ system involvement. In these patients, other causes of multiple mononeuropathies, including diabetes, malignant infiltration, sarcoidosis, pressure palsies, infection (especially HIV, Lyme disease, and cytomegalovirus), and multifocal motor neuropathy must be considered (05). Most difficult of all are those patients presenting with a distal symmetric sensorimotor polyneuropathy, where the differential is extensive and includes a number of toxic, infectious, metabolic, and inflammatory entities.
The syndrome of diabetic amyotrophy, also known as proximal diabetic neuropathy or lumbosacral radiculoplexopathy, has been associated with an inflammatory angitis. The various presentations, such as diabetic femoral nerve palsy or diabetic radiculopathy, seem to have the same etiology with nerve and muscle biopsy showing inflammatory infiltrates and sometimes necrotizing vasculitis (41; 15; 20; 59). An identical presentation in nondiabetics has also shown evidence of vasculitis with secondary nerve ischemia (16). Trials of immunotherapy for these diabetic neuropathic syndromes have been based on these pathological findings.
• Acute or chronic inflammatory demyelinating polyneuropathy
The initial approach in the diagnosis of vasculitic neuropathy can be organized by answering the following key questions:
(1) Is this neuropathy typical (ie, classical mononeuritis), or is it compatible (symmetrical but with probable summation of mononeuritic events) with vasculitic neuropathy?
(2) Does the patient have a collagen vascular or rheumatic disease?
(3) Does the patient have diabetes?
(4) Does the patient have other clinical findings seen in disorders with vasculitis (eg, organ involvement, eosinophilia, chronic infectious diseases, leukemia, malignancy, etc)?
(5) Do I have other supportive laboratory tests to diagnose vasculitis?
The diagnostic workup of a patient with a suspected vasculitic neuropathy involves serologic studies, electrodiagnostic evaluation, and a sensory nerve biopsy, usually with an accompanying muscle biopsy. The purpose of the serologic studies is twofold: to screen for evidence of other organ system involvement, and to detect an abnormality or pattern of abnormalities indicative of an underlying connective tissue disease or systemic vasculitis. The Peripheral Nerve Society guideline published in 2010 made a consensus recommendation regarding the appropriate laboratory investigations in cases of suspected vasculitic neuropathy. These studies include renal function studies, hepatic enzymes, urinalysis, complete blood count with differential, glycated hemoglobin, erythrocyte sedimentation rate, C-reactive protein, serum protein immunofixation electrophoresis, antinuclear antibody, extractable nuclear antigens, serum complements (C3, C4, and CH 50), rheumatoid factor, hepatitis B antigen and antibody, hepatitis C antibodies, cryoglobulins, and antineutrophil cytoplasmic antibodies titers. Other studies, such as HIV titer, Lyme titer, toxicology screen, paraneoplastic panel, and immune complex assays may be needed in individual patients, depending on the clinical presentation. All of the studies are usually normal in patients without an underlying disease (ie, nonsystemic vasculitic neuropathy), except for the erythrocyte sedimentation rate, which is often mildly elevated (40). Cerebrospinal fluid protein is elevated in 20% to 30% of patients, but the elevation is usually modest and does not contribute greatly to the diagnosis.
Electrodiagnostic studies are useful for demonstrating the distribution of involved nerves, the extent of denervation, and the most appropriate nerve to biopsy. Nerve conduction studies classically show evidence of an asymmetric non-length dependent axonal neuropathy. Electromyographic and nerve conduction velocity studies may reveal subclinical sensory or motor involvement and can indicate the presence of a multiple mononeuropathy that has escaped clinical detection. Nerve conduction velocity studies typically reveal low-amplitude sensory nerve and compound motor action potentials in a multifocal distribution (54). In severe cases the responses may be irrevocable; motor conduction block can be seen prior to Wallerian degeneration of the distal segment of the nerve studied. EMG classically reveals signs of denervation (fibrillations, sharp potentials) distributed in a non-length-dependent fashion, often with significant proximal involvement (54). Ultrasound of the peripheral nerves has been studied as a possible additional diagnostic tool in the evaluation of various neuropathies. One study was found to show an increase in cross sectional area in focal areas of nerves in axonal neuropathies secondary to vasculitis. This may ultimately have diagnostic implications as far as identifying nerve segments, which may increase the diagnostic yield of nerve biopsy (21).
Nerve biopsy. Over the years, careful studies have led to a consensus regarding the usefulness of biopsy for the diagnosis of vasculitis with peripheral nerve involvement. It seems that (1) only a percentage of diagnosed patients have a positive nerve biopsy, (2) combined nerve and muscle biopsy adds to the overall diagnostic yield than either alone, (3) the absence of a positive tissue biopsy does not exclude the disorder, (4) biopsy of “symptomatic sites” seems to improve the diagnostic yield, (5) electromyography and nerve conduction studies help in the selection of the biopsy site, and (6) whole nerve biopsy is more useful than fascicular biopsy (50; 57; 58; 20). In those patients with a known systemic vasculitis and prior biopsy of another affected organ, nerve biopsy can usually be avoided. One study of 78 patients looked at both positive negative predictive factors for a pathologically confirmed diagnosis, positive predictive factors included step-wise clinical progression, the presence of a positive serum anti-myeloperoxidase antibody, and rheumatoid factor seropositivity. Negative predictive factors included normal or primarily demyelinating nerve conduction studies (51).
The demonstration of vascular inflammation and necrosis in a biopsy specimen is the only way to definitively confirm the diagnosis of vasculitis. In most patients with vasculitic neuropathy, a combined superficial peroneal nerve/peroneus brevis muscle biopsy through a single incision on the lateral aspect of the leg is the most efficient procedure (60; 38). This combined biopsy is appropriate because diagnostic lesions can be demonstrated pathologically only in muscle in some cases of clinical peripheral nerve vasculitis (60; 67). The sural nerve can also provide a high diagnostic yield if there is electrophysiologic evidence of involvement. Rarely, patients with restricted upper extremity involvement will require a superficial radial nerve biopsy (38).
Pathologically, there must be vascular transmural inflammatory cell infiltration with vessel wall necrosis for an unequivocal diagnosis of vasculitis (44; 48). Perivascular inflammation without vessel wall invasion is not sufficient for diagnosis, but can be suggestive with the appropriate accompanying clinical and laboratory findings. In older lesions, fibrin deposition and occlusion of vessels with secondary recanalization may be seen. Immunoglobulin and complement deposits can be demonstrated by immunofluorescent staining in approximately 80% of cases, a finding that appears to be specific for vasculitis (39; 55; 29; 18; 07; 52). The nerve itself typically demonstrates various degrees of nerve fiber loss with asymmetry of involvement between and within individual fascicles. Depending on the age of the lesion, fibers undergoing Wallerian degeneration may be seen. Overall sensitivity of nerve or nerve and muscle biopsy in making a diagnosis of vasculitis is about 50% to 60% (09).
New guidelines given by the Peripheral Nerve Society on the diagnosis of vasculitic neuropathy include the following diagnostic criteria for pathologically definite vasculitic neuropathy and require that vessel wall inflammation be accompanied by vascular damage. Pathologically probable vasculitic neuropathy is suggested by the following: vascular deposits of IgM, C3, or fibrinogen by direct immunofluorescence, hemosiderin deposits, asymmetric nerve fiber loss, prominent active axonal degeneration and myofiber necrosis, regeneration, or infarcts in a peroneus brevis muscle.
The management of a patient with vasculitic neuropathy usually involves 4 main considerations: (1) removal of any possible inciting antigens and treatment of underlying causes (ie, infection); (2) institution of immunosuppressive therapy; (3) limiting, if possible, vaso-occlusive complications; and (4) providing appropriate supportive care. Unfortunately, the inciting antigen can usually be identified only in the small minority of patients with hypersensitivity vasculitis related to therapeutic or recreational drug use, various infectious diseases, or an underlying malignancy. In these patients, initial therapy should be aimed at the primary underlying process before treating the vasculitis itself. In this regard, reports on the use of antiviral agents for various hepatitis-associated vasculitides are particularly intriguing (37). Several evidence-based guidelines exist regarding the management of ANCA-associated vasculitis, including the 2016 European League Against Rheumatism guideline and the 2017 guidelines of the Japan Research Committee of the Ministry of Health, Labor, and Welfare (69; 27).
In most patients, however, vasculitis is idiopathic and consideration must be directed to immunosuppressive therapy. Typically, management of these patients should be done in conjunction with a rheumatologist or internist. Essentially all patients with an underlying systemic necrotizing vasculitis should be treated with a combination regimen that includes prednisone and a cytotoxic agent (usually cyclophosphamide) because of the documented effectiveness of this regimen in various types of systemic vasculitis (49; 30). Typically, an induction dose is given to stop the immediate inflammation followed by a maintenance dose for long-term immunosuppression. A typical regimen involves oral prednisone at 1.5 mg/kg per day given as a single morning dose and cyclophosphamide at 2.0 mg/kg per day. In particularly fulminant cases, intravenous methylprednisolone (1.0 gm in 100 cc saline infused over 4 to 6 hours every day for 5 doses) followed by the oral regimen can be used to institute therapy. Pulse cyclophosphamide at doses of 0.6 to 0.75 g/m2 can be used instead of an oral formulation, every 2 to 4 weeks. Oral prednisone is continued at a high dose for at least 1 to 2 months, after which it can be slowly tapered depending on the patient’s clinical response. The maximal clinical response may take up to 2 years after the initiation of treatment to become evident. Cyclophosphamide is typically continued for an average of 4 to 6 months and is important in any case of marked systemic vasculitis with poor prognostic factors. Inflammatory markers such as the erythrocyte sedimentation rate or C-reactive protein can be followed but are often not a sensitive marker of disease activity. In cases of ANCA-associated vasculitis, some follow serial ANCA levels, and a rise in these levels has been shown to be associated with disease relapse (66).
Patients who cannot tolerate cyclophosphamide are usually treated with azathioprine or methotrexate, although the effectiveness of these agents and other immunosuppressive agents is uncertain in peripheral nerve vasculitis.
In those patients on combination therapy with cyclophosphamide, 1 of these agents is typically substituted for cyclophosphamide once the patient is thought to be in remission. In cases of mild systemic vasculitis (non-life-threatening with no organ-threatening damage), methotrexate or azathioprine can be used instead of cyclophosphamide in combination with prednisone. In cases of nonsystemic vasculitic neuropathy, the current recommendation is to treat with prednisone monotherapy because the condition is not immediately life-threatening and the neurologic prognosis is less ominous than in those with an underlying systemic necrotizing vasculitis (13; 11). If the patient has rapidly progressing symptoms or progression despite prednisone therapy, cyclophosphamide, azathioprine, or methotrexate should be added to the regimen (08). In these cases, prednisone is continued for at least 18 to 24 months and then tapered, and the patient placed on azathioprine or methotrexate maintenance. Prednisone monotherapy is also employed in most patients with neuropathy in the setting of temporal arteritis because prednisone results in complete remission of the primary disease in most patients. Similarly, some patients with vasculitic neuropathy secondary to an underlying connective tissue disorder can often be managed with prednisone alone, depending on the extent and severity of the nerve involvement.
In cases of diabetic lumbosacral radiculoplexus neuropathy (DLRPN) or nondiabetic lumbosacral radiculoplexus neuropathy (LRPN), supportive therapy is typically the standard management. However, in certain cases treatment with immunotherapy can be considered, particularly in those patients with a progressive course. One randomized, double-blind, placebo-controlled trial randomized 75 patients to intravenous methylprednisolone (1g 3 times per week for 12 weeks) or placebo. Though there was no objective improvement in primary outcomes measures, patients in the methylprednisolone group did demonstrate an improvement in neuropathic pain scores (17). There are some who argue in favor of treating these patients with 1g methylprednisolone weekly for 12 weeks (24).
Plasma exchange has not been robustly studied as a treatment in controlled trials and should be considered only in patients with cryoglobulinemia, hepatitis B-associated vasculitides, or HIV-associated vasculitides refractory to other therapies. Intravenous gammaglobulin (IVIG) has not been extensively studied in vasculitis neuropathies but has been found to be effective in a subset of patients with refractory systemic vasculitis and ANCA-associated vasculitis (32; 43; 45). In a study of 10 patients with vasculitic neuropathy, improvement or complete resolution of neuropathy was noted in 8 patients after IVIG therapy. The nonresponders included those with mixed cryoglobulinemia associated with hepatitis C and sarcoidosis (43). IVIG can, thus, be beneficial and can be considered as adjuvant therapy when conventional treatment has failed or is contraindicated.
Rituximab (anti-CD 20 monoclonal antibody) has been studied in several of the systemic vasculitides and is considered a reasonable alternative to cyclophosphamide in several of these cases. In fact, rituximab is now considered to be first line in the induction treatment of granulomatous polyangitis and microscopic polyangiitis. One study looked at 59 patients with cryoglobulinemic vasculitis (some with concurrent hepatitis C infection) randomized to conventional treatment or rituximab plus steroids; treatment with rituximab was superior to or as good as conventional therapy and was well tolerated (12). Rituximab has also been shown to be effective in cases of vasculitis associated with rheumatoid arthritis (56). Two large randomized trials looked at rituximab vs cyclophosphamide in combination with steroids in antineutrophil cytoplasmic antibody-associated vasculitis and they were similar in terms of remission rates. However, rituximab showed a favorable response in terms of remission in cases of relapse (36; 64).
The management of vaso-occlusion is an often-neglected aspect of therapy in patients with vasculitis. Concurrent conditions that may contribute to ischemia, such as diabetes, hypertension, hyperlipidemia, and tobacco use, must be aggressively treated. Antiplatelet agents and even vasodilators may be indicated in patients who seem to be progressive despite seemingly adequate immunosuppression.
All patients on prednisone must be followed closely for the development of side effects, and weight, blood pressure, electrolytes, serum glucose, and ocular status (for the development of cataracts and glaucoma) must be monitored carefully. Patients at risk should undergo tuberculin skin testing prior to immunosuppression; antituberculous prophylaxis is usually indicated in positive responders. A low sodium, low simple sugar, low calorie diet will usually minimize weight gain, and calcium (at least 1000 mg/day calcium carbonate) and calcitriol (.5 to 1.0 mg/day) supplementation will help minimize osteoporosis (61). Patients on cyclophosphamide must have a complete blood count every 4 to 6 weeks to check for myelosuppression and urinalyses should be performed every 6 months indefinitely because hemorrhagic cystitis occurs in about 15% of patients. Those on chronic immunosuppressive therapy should also be placed on PCP prophylaxis with trimethoprim and sulfamethoxazole.
Vasculitic neuropathy may occur in association with hepatitis C infection and cryoglobulinemia. Treatment options include interferon alpha2b, sometimes with ribavirin (42) and cyclophosphamide (63). Caution is required when initiating interferon alpha treatment in hepatitis C-related vasculitic neuropathy as it has been shown to exacerbate neuropathy (02). For vasculitis associated with hepatitis B infection, interferon alpha, in combination with plasma exchange, has been found to be useful (19).
Supportive care is crucial because many patients, particularly those with extensive axonal damage, will be on prolonged immunosuppressive therapy and have an extended period of neurologic impairment. Physical therapy is important in maintaining range of motion and strength, improving functional status, and maintaining activity levels to minimize the risk of developing a secondary steroid myopathy. Orthotic devices, especially custom-fit ankle-foot orthoses in patients with foot-drop, are frequently necessary to improve ambulation, and occupational therapy is useful to maximize upper extremity function. Agents such as amitriptyline, carbamazepine, gabapentin, duloxetine, pregabalin, topiramate, clonazepam, mexiletine, and even narcotics may be required to control neuropathic pain.
Although occasional patients have been reported with vasculitic syndromes that develop during pregnancy, there is no specific information available concerning vasculitic neuropathy and pregnancy. None of the large series have reported any patients who were pregnant.
No specific contraindications exist for surgery or anesthesia in patients with vasculitic neuropathy. Patients on chronic prednisone must obviously have these agents continued, intravenously if necessary, in the perioperative period.
Comana M Cioroiu MD
Dr. Cioroiu of Columbia University has no relevant financial relationships to disclose.See Profile
Louis H Weimer MD
Dr. Weimer of Columbia University has received consulting fees from Roche.See Profile
Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Jan. 18, 2022
Nerve ultrasound for neuropathy allows for the determination of peripheral nerve anatomical course, echogenicity, vascularity, and degree of mobility. Magnetic resonance neurography allows for visualization of higher soft-tissue contrast, which can depict milder abnormalities when there are subtle T2 signal abnormalities.
Jan. 13, 2022
The author reviews the clinical neurotoxicity of the antiarrhythmic agent amiodarone, an amphiphilic drug that forms intralysosomal lipid complexes in
Jan. 07, 2022
After carpal tunnel syndrome, the most common median nerve entrapment is the pronator teres syndrome. The most common features of the pronator teres syndrome are insidious proximal forearm fatigability, pain, and tenderness amplified by exercise and, at times, radiating to the shoulder. Other less common entrapment sites include the ligament of Struthers, lacertus fibrosus, and the tendinous origin of the flexor digitorum superficialis.
Jan. 02, 2022
Movement disorders are prominent in the clinical presentation of many autoimmune disorders. These abnormal motor phenomena include faciobrachial dystonic seizures, neuromyotonia, chorea, myorhythmia, stereotypies, dystonia, tremor, parkinsonism, ataxia, and stiff-person-like phenomena. Each type of autoimmune encephalitis presents with a different profile of abnormal movements, and a therapeutic response to immunomodulatory therapy suggests that these motor phenomena also have an autoimmune pathogenesis.
Dec. 30, 2021
Acquired sensory neuronopathies depend on a primary involvement of sensory neurons in dorsal root ganglia leading eventually to a definitive and irreversible degeneration of the cell body. They include toxic, infectious, and dysimmune mechanisms, although an important proportion remains idiopathic after an extensive workup. The loss of large sensory neurons results in ataxia that usually predominates in the lower limbs, resulting in ataxic gate and Romberg sign.
Dec. 02, 2021
Familial dysautonomia is an autosomal recessive hereditary sensory and autonomic neuropathy (HSAN) disorder characterized by both sensory and autonomic dysfunction, resulting in decreased pain and temperature perception as well as pervasive manifestations of autonomic dysregulation. Four unique features associated with this particular HSAN type are absence of overflow emotional tearing, afferent baroreflex failure, hyperadrenergic vomiting crises, and optic neuropathy.
Nov. 18, 2021
Neuroacanthocytosis is a neurologic syndrome characterized by a broad spectrum of movement disorders that often share acanthocytes on the blood smear. A variety of other neurologic symptoms may accompany neuroacanthocytosis, including seizures, motor neuron disease, and dementia. Chorea-acanthocytosis is an autosomal recessive disorder due to mutations in the VPS13A gene (chromosome 9q21), and is among the disorders known to cause neuroacanthocytosis.
Nov. 09, 2021