Acquired Forms of Chronic Polyneuropathy
Polyneuropathy Associated With Paraproteinemia
The occurrence of a chronic sensorimotor polyneuropathy in association with an abnormality of serum immunoglobulins is recognized with increasing frequency, but its boundaries are still not well established as will be apparent in the following discussion. The excess blood protein, called a paraprotein or "M-spike," is usually in the form of a monoclonal immunoglobulin. It may be an isolated abnormality or a by-product of a plasma cell malignancy, specifically multiple myeloma, plasmacytoma, or Waldenström macroglobulinemia. Several lines of evidence suggest that a pathogenetically active antibody against components of myelin or axon is present in at least some of these cases. Special forms of neuropathy are also associated with amyloidosis. Both the acquired and genetic forms of amyloidosis are discussed further on.
Neuropathy With Monoclonal Gammopathy of Undetermined Significance (MGUS, Benign Monoclonal Gammopathy)
The association of a nonneoplastic IgM monoclonal protein and a neuropathy was first described by Forssman and colleagues and was treated as coincidental until Kahn established a compelling statistical association between the two conditions. A more direct relationship was established by the finding of antiperipheral nerve antibodies in some patients who had such a protein in their blood. This category of polyneuropathy is associated with a monoclonal or sometimes polyclonal excess of immunoglobulin (IgG, IgM, or IgA, rarely others, mainly with a kappa light chain components; see Kyle and Dyck). These cases are far more common than those caused by a malignant plasma cell disorder. In our experience, monoclonal proteins underlie the largest group of otherwise unexplained neuropathies in adults.
The polyneuropathy associated with monoclonal gammopathy affects mainly, but not exclusively, males in the sixth and seventh decades of life. The onset is insidious over weeks and months or more, with numbness and paresthesias of the feet and then of the hands, followed by a relatively symmetrical weakness and slight wasting of these muscles. In some patients, sensory signs predominate. The tendon reflexes, eventually lost or diminished, may be preserved in the early phases of the illness. The course is usually slowly progressive, sometimes static after a year or so, and rarely remitting and relapsing. The CSF typically shows an elevation of the protein in the range of 50 to 100 mg/dL, and this is not due to passive diffusion of the excess paraprotein into the CSF.
The majority of cases of polyneuropathy with monoclonal gammopathy have a demyelinating or mixed axonal–demyelinating pattern on the EMG and nerve conduction study, but once the illness is well established, most will have predominantly axonal features. With few exceptions we have been unable to distinguish the axonal and demyelinating groups on clinical grounds or by their response to therapy (Gorson et al, 1997). Sural nerve biopsies show a loss of myelinated fibers of all sizes; unmyelinated fibers are mostly spared; hypertrophic changes, reflecting cycles of demyelination and remyelination with fibrosis are present in about half the cases according to Smith and colleagues. They found the monoclonal IgM antibody bound to surviving myelin sheaths and Latov and coworkers have shown that the serum IgM fraction often displays antimyelin activity.
Typically, the monoclonal protein in the blood is present in a concentration much less than 2 g/dL and there is no evidence of multiple myeloma or other malignant blood dyscrasia. It should be emphasized that routine serum protein electrophoresis (SPEP) fails to detect the majority of these paraproteins; immunoelectrophoresis (IEP) or the more sensitive immunofixation testing is required. The bone marrow aspirate shows a normal or only mildly increased proportion of plasma cells, which are the source of the paraprotein and the plasma cells are not morphologically atypical as they are in myeloma. Insofar as myeloma becomes manifest in perhaps one-quarter of patients many years after the gammopathy has been recognized, the condition is termed monoclonal gammopathy of undetermined significance (MGUS), although the older term benign monoclonal gammopathy is less cumbersome.
The importance of excess immunoglobulin as a cause of neuropathy can be appreciated by noting that 6 percent of patients referred to the Mayo Clinic with chronic polyneuropathy of unknown cause and as many as 20 percent in our clinical material and in other series have proved to have a monoclonal paraproteinemia (of course, the majority of patients with a blood paraprotein do not develop neuropathy).
Despite the fact that IgG is the most frequent paraprotein in adults, a polyneuropathy is associated somewhat more often with the IgM class. Combining three large series of patients with neuropathy and monoclonal paraproteinemias (62 patients of Yeung et al, Gosselin et al, and our patients as reported by Simovic et al), 60 percent had IgM, 30 percent IgG, and 10 percent with IgA subclass paraproteins. An identical but infrequent condition exists in which only the light chain component of an immunoglobulin is overproduced by the plasma cells and is found exclusively in the urine (similar to the Bence Jones protein of multiple myeloma).
Four-fifths of patients have had a kappa light chain component, as mentioned previously, although lambda light chain has special significance as discussed further on in relation to plasmacytoma and the polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome. In our experience and in that of others, patients with IgM paraprotein more often have severe sensory findings and a demyelinative type of nerve conduction abnormality when compared with the IgG group. However, with the exception of the special anti-MAG syndrome (see later), we have not found the extent of difference in clinical features and response to treatment between the immunoglobulin subclasses that has been reported by others (Simovic et al).
Although more than a dozen specific antibodies against myelin and other components of nerve have been identified among the paraproteins, the ones that give rise to the most distinctive clinical syndromes, present in 50 to 75 percent of patients with IgM-associated neuropathies, are those that react with a MAG, related glycolipids, or sulfatide components of myelin (the latter are referred to as sulfate-3-glucuronyl paragloboside [SGPG] and related sulfatides). Proprioceptive sensory loss with gait imbalance, tremor, and the Romberg sign are typical findings in the group with anti-MAG activity, while weakness and atrophy tend to appear later in the illness. Other IgM antineural antibodies have a more tentative connection to polyneuropathy. It is reasonable to assume that IgG monoclonal gammopathies are also capable of causing chronic neuropathies, but the evidence is less compelling and based mainly on the frequency of their presence in cases of otherwise unexplained polyneuropathy. Indeed, it has been suggested that in many reported instances the association with neuropathy with IgG paraproteinemia is coincidental. The anti-MAG illnesses are relentlessly progressive at various rates in most patients at various rates but in about 15 percent of our patients with anti-MAG antibody the illness has been mild and static for years at a time, even without treatment.
Because of the risk of myeloma or Waldenström disease, bone marrow examination is generally performed some time in the course and particularly if the concentration of the paraprotein exceeds 3 g/dL or climbs progressively over years, or if other hematologic changes such as unexplained anemia or thrombocytopenia develop.
In most cases of uncomplicated monoclonal gammopathy with polyneuropathy that are associated with IgG or IgA paraproteins, particularly if not of long standing, plasma exchange may produce transient improvement for several weeks to months (Dyck et al, 1991). The treatment regimen generally is a total volume of approximately 200 to 250 mL/kg exchanged in each of 4 to 6 treatments over about 10 days and the removed plasma replaced with a mixture of albumin and saline.
In patients who have IgM serum activity against specific components of myelin (particularly anti-MAG), the results of treatment have been inconsistent and generally less favorable. Plasma exchange alone has effected transient improvement in half of cases but sustained improvement in only 10 to 20 percent of our patients. Series of plasma exchanges every 2 to 4 months has sometimes resulted in transient responses. According to some reports, the response to immunosuppression with intravenous cyclophosphamide or fludarabine, mycophenolate, or oral chlorambucil, when coupled with plasma exchanges, has been somewhat better, at times allowing a reduction in the frequency of exchanges but our experience has generally not affirmed this. Rituximab, which has the appeal of having a preferential effect on the B-cell lymphocyte population, after initial enthusiasm based on small series, has given conflicting and generally negative results in several trials but may be reasonable to try in intractable cases. A listing of the applicable trials that have been reported up to 2009 has been given by Brannigan.
Improvement with high-dose infused immune globulin (IVIg) has been transiently effective in half of our cases with typical paraproteinemia and in 20 percent of those with anti-MAG neuropathy but the illness nonetheless progresses in most patients. In almost all instances, immunosuppression and plasma exchanges or IVIg, if used, must be repeated indefinitely at intervals of 1 to several months as determined by the clinical course. An indwelling catheter is then usually required to allow repeated venous access. This group of neuropathies responds poorly or not at all to corticosteroids.
POEMS Syndrome, Osteosclerotic Myeloma, and Multiple Myeloma
A neuropathy associated with multiple myeloma has already been mentioned; it complicates 13 to 14 percent of cases of multiple myeloma and has a disproportionately high association with the osteosclerotic form of the disease. An abnormal monoclonal globulin (mainly with the kappa light chain component in multiple myeloma but lambda in the osteosclerotic type) is found in the serum of more than 80 percent of patients with myelomatous neuropathy.
In a special and small group of patients with osteosclerotic myeloma, there is a predominantly demyelinating sensorimotor polyneuropathy and systemic disease termed POEMS (i.e., polyneuropathy of moderate severity is associated with organomegaly, endocrinopathy, elevated M protein, and skin changes, mainly hypertrichosis and skin thickening). The same process has been referred to as the Crow-Fukase syndrome in Japan, where the disease is prevalent. In many cases there is lymphadenopathy attributable to the angiofollicular hyperplasia of Castleman disease. Another characteristic feature of the osteosclerotic-related polyneuropathy is a greatly elevated CSF protein.
The presence of the disease can be suspected from the presence of demyelinating features on the nerve conduction studies, an immunoglobulin spike in the blood, sometimes polyclonal or biclonal rather than monoclonal and, as mentioned, possessing a lambda light chain component. The diagnosis requires the demonstration of one or more osteosclerotic lesions by a radiographic survey of the long bones, pelvis, spine, and skull as well as a PET study, which usually shows the osteosclerotic lesions as highly active (a bone scan is insensitive) and a bone marrow examination, which shows a moderate increase in the number of well-differentiated plasma cells. In most of our patients there have been several discrete bone lesions concentrated in the ribs and spine; the skull and long bones may harbor such lesions as well, or there may be a single lesion, which is often situated in the spinal column. Biopsy of a bone lesion is justified. The organomegaly and skin changes are apparently the result of high levels of circulating VEGF that is produced by the tumor and is useful in confirming the diagnosis.
The neuropathy that complicates a solitary plasmacytoma may improve markedly following irradiation of the bone lesion. Multiple lesions, including those in the POEMS syndrome, when treated with chemotherapy (melphalan and prednisone) or focused radiation, may lead to some improvement or stabilization in the neuropathy. Treatment with plasma exchange has yielded uncertain but generally positive short-term results in our patients. Autologous stem cell transplantation or bevacizumab (a monoclonal antibody directed against VEGF) have been tried with mixed results (Kuwabara et al, 2008).
Macroglobulinemia was the term applied by Waldenström to a systemic condition occurring mainly in older persons and characterized by fatigue, weakness, and a bleeding diathesis. Immunoelectrophoretic examination of the blood disclosed a marked and mostly monoclonal increase in the IgM plasma fraction. About half of patients with Waldenström disease and polyneuropathy will have specific anti-MAG antibodies, similar to the approximately one-third of patients with nonmalignant IgM paraproteins. (An uncertain proportion of patients with a "benign" IgM paraprotein will, over the years, develop Waldenström disease.) A few patients with Waldenström hyperproteinemia have a hyperviscosity state manifest by diffuse slowing of the retinal and cerebral circulations, giving rise to episodic confusion, coma, impairment of vision, and sometimes strokes (Bing-Neel syndrome). Most reports attribute this syndrome to infiltration of neural by malignant plasma cells rather than to hyperviscosity.
The polyneuropathy, when present, evolves over months or longer and may be asymmetrical, particularly at the onset, but becomes bilateral, mainly sensory, and distal. The pattern in our patients has been very slowly progressive, and initially limited to the feet and legs with sensory ataxia and loss of knee and ankle jerks. The CSF protein is usually elevated and the globulin fraction increased. In a case recorded by Rowland and colleagues, the polyneuropathy was purely motor and simulated motor neuron disease. Treatment is discussed further on.
As mentioned in the section on vasculitic neuropathies, cryoglobulin, a serum protein that precipitates on cooling, is usually of the IgG or IgM type and most often polyclonal. While cryoglobulinemia may occur without any apparent associated condition (essential cryoglobulinemia), it also accompanies a wide variety of disorders such as multiple myeloma, lymphoma, connective tissue disease, chronic infection, and particularly, hepatitis C. Peripheral neuropathy occurs in a small proportion both of the essential and symptomatic cases. Occasionally the neuropathy evolves over a period of a few days and remits rapidly. More often it takes the form of a distal symmetrical sensorimotor loss, which develops insidiously (76 percent of the cases in the series reported by Gemignani et al) in association with the Raynaud phenomenon and purpuric eruptions of the skin. Initially, the neuropathic symptoms may consist only of pain and paresthesias that may be precipitated by exposure to cold (as often, there is no cold sensitivity). Later, weakness and wasting develop, more in the legs than in the arms, and more or less in the same distribution as the vascular changes. In some cases there may be a mononeuropathy multiplex with severe denervation in the territory of the involved nerves (9 percent of the series reported by Gemignani et al; see also Garcia-Bragado et al). In a few cases, the two neuropathic syndromes have been combined. As remarked earlier, detection of cryoglobulin requires special handling of the blood sample. The specimen should be carried to the laboratory in a bath of warm water to prevent precipitation of the protein.
Any of the paraproteinemic states may be associated with an amyloid polyneuropathy, a subject accorded a separate section later in the chapter.
The pathology of the cryoglobulinemic and macroglobulinemic neuropathies has been incompletely studied and the mechanisms by which these disorders cause neuropathy are uncertain. One presumes that some component of the paraprotein acts as an antineural antibody or that deposition of the protein is in some way toxic to the nerves or to the endoneurial vessels. In our most thoroughly autopsied case, there was widespread distal axonal degeneration of nonspecific type without amyloid deposition or inflammatory cells; yet in other reported cases, amyloid has been found in the nerve and the neuropathy has been attributed directly to it. Immune deposits of IgM had impregnated the inner layers of the perineurium in the case reported by Ongerboer de Visser and colleagues. Dalakas and Engel (1981b) have made similar observations. In yet other instances, the neuropathy of cryoglobulinemia is a result of the intravascular deposition of cryoglobulins, causing a more acute vasculitic mononeuropathy multiplex, as discussed earlier (Chad et al).
In the macroglobulinemic neuropathies, the use of prednisone, the alkylating agent chlorambucil, cyclophosphamide, and repeated plasma exchange has at times led to improvement both in the systemic and neuropathic symptoms, although recovery has been incomplete. The monoclonal antibody rituximab has been effective in small studies. The optimal treatment of cryoglobulinemic neuropathy has not been settled. We have used plasma exchange and added immunosuppression in the vasculitic variety of this disease.
Acquired Primary (Nonfamilial, AL) Amyloid Neuropathy
A heredofamilial type of amyloidosis (familial amyloidosis [FA]) is well known and is described further on. In addition, there are numerous sporadic instances of a peripheral neuropathy caused by amyloid deposition. As in the familial variety, the heart, kidneys, and gastrointestinal tract may be involved. This acquired type of amyloid disease has also been called primary systemic amyloidosis to distinguish it from the variety associated with chronic diseases. The term is misleading in that in most cases the amyloid is derived from a circulating paraprotein, but the proportion of "benign" and malignant plasma cell sources of the protein varies from one report to another. For example, in the large series collected by Kyle and Bayrd, only 26 percent of patients with primary amyloidosis had a malignant plasma cell dyscrasia. This agrees with our own experience, but other series have found rates of myeloma as high as 75 percent. In any case, 90 percent of primary amyloidosis is the result of a monoclonal protein in the blood (rarely polyclonal). Macrophage enzymes cleave the larger immunoglobulin molecules and the light chains aggregate to form amyloid deposits in tissue, or the plasma cells may produce light chains directly ("light chain disease"). Lambda light chain predominates in the idiopathic variety of amyloidosis and kappa light chain is more common in myeloma. In a few cases, the light chain is found only in the urine (as Bence Jones protein).
In primary amyloidosis there is no evidence of preceding or coexisting disease (except the association with paraproteinemia or multiple myeloma). Secondary amyloidosis (AA), an infrequent occurrence nowadays, is the result of chronic infection or other chronic disease outside the nervous system and, as a rule, is not associated with neuropathy (e.g., it is not cited in the large recent series by Lachmann and colleagues ). In contrast, familial amyloidosis, a third variety, is almost invariably associated with neuropathy but is associated with a paraprotein in only a small proportion of cases and the amount of immunoglobulin is small (see "Inherited [Familial Amyloidosis] Amyloid Neuropathies" later).
Primary amyloidosis is mainly a disease of older men, the median age at the time of diagnosis being 65 years. In our clinical material, the majority of the patients have had peripheral neuropathy, but this may reflect a referral bias as in other series, less than one-third were so affected (Kyle et al). The neuropathic symptoms and signs are similar to those of hereditary amyloid polyneuropathy discussed further on, but the progress of the disease is considerably more rapid.
The initial syndrome is primarily sensory—numbness, paresthesias, and very often, acral pain—signs that are mainly characteristic of involvement of small-diameter sensory fibers (loss of pain and thermal sensation). It is the painful aspect and the autonomic features discussed later that distinguish this disease from the other paraproteinemic neuropathies and indeed, from most other polyneuropathies. Weakness follows, initially limited to the feet but becoming more extensive as the disease progresses and eventually spreads to the hands and arms. Only later is there loss of mainly large fibers that mediate sensations of touch, pressure, and proprioception. Twenty-five percent of patients have carpal tunnel syndrome from infiltration of the flexor retinaculum. Exceptionally, patterns other than the painful and sensory predominant polyneuropathy have been associated with amyloidosis; preferential involvement of motor nerves, lumbar roots, plexopathy, and amyloidomas involving single nerves (sciatic, facial, trigeminal) have been reported. Unusual cases of mononeuritis multiplex are difficult to explain.
Autonomic involvement can be severe in amyloid neuropathy (familial or primary) and may become evident early in the course of the illness; several of our patients presented with disturbances of gastrointestinal motility such as episodic diarrhea and orthostatic dizziness or erectile dysfunction and bladder disturbances. The pupils may show a slow reaction to light, or there may be a reduction in sweating. An infiltrative amyloid myopathy also occurs as a rare complication of the disease; it presents as an enlargement and induration of many muscles, particularly those of the tongue (macroglossia), pharynx, and larynx.
Progression of the illness is relatively rapid, the mean survival being 12 to 24 months. An indolent neuropathy that evolves over years is unlikely to be a result of amyloidosis, although we have seen such a case. Death is a result of the renal, cardiac, or gastrointestinal effects of amyloid deposits, the manifestations of which are already evident in more than half of the patients who present with neuropathy. A nephrotic syndrome is also characteristic.
Analysis of the serum and urine, searching for an abnormal paraprotein, is the most useful screening test for amyloid neuropathy. Next in value is a microscopic examination of a biopsy of the abdominal fat pad, gingiva, or rectal mucosa for deposition of amyloid in tissue or blood vessels. Biopsy of the sural nerve or of the involved viscera has a high diagnostic yield; muscle tissue gives variable results. The liver biopsy is positive in virtually all cases of primary amyloid and the kidney shows amyloid infiltration in 85 percent. In several of our patients with a clinical syndrome typical of amyloid neuropathy but in whom amyloid was absent in the sural nerve, the diagnosis was established only after sequential biopsy of numerous sites (fat pad, kidney, liver). If the sural nerve is severely depopulated of nerve fibers, the amount of congophilic staining and the characteristic amyloid birefringence may be meager and yield a spuriously negative result. It is also critical to ensure the accuracy of congophilic staining by comparison with positive and negative control tissue from the same laboratory. The CSF has a normal or mildly elevated protein concentration, but this does not distinguish the neuropathic process from many others.
Lachmann and colleagues (2002) emphasized that 10 percent of patients who appear by all the usual criteria to have primary amyloidosis will be found to have a genetic type. However, as mentioned, only a small proportion of the latter group has a monoclonal gammopathy and it tends to be of low concentration (it has been estimated to occur in one-quarter of familial cases but we have not encountered it). This difference and the rapid progression of the primary acquired form assist in distinguishing it from the genetic type that is discussed further on.
In addition to the more slowly evolving familial types, the differential diagnosis of acquired amyloid neuropathy includes the myelomatous varieties, toxic and nutritional small-fiber neuropathies, diabetic polyneuropathy, paraneoplastic polyneuropathy, Sjögren disease, and an idiopathic small-fiber sensory neuropathy, all of which cause pain and which we have encountered more frequently than amyloidosis.
Treatment of Amyloid Neuropathy
The prognosis of primary amyloidosis and its associated neuropathy are dismal. Attempts at immunomodulation, immunosuppression (which may help the renal disease), or removal of amyloid by plasma exchange have been marginally effective. Another approach has been bone marrow suppression with high doses of melphalan followed by stem cell replacement (previously harvested from the patient). Several such patients have survived for years with marked improvement in the neuropathy. Recently, several small molecules designed to prevent the aggregation of amyloid fibrils have shown preliminary benefit as evidenced by biologic markers and in some clinical features. (In the familial type due to a transthyretin mutation discussed further on, liver transplantation has stabilized the process in the majority of patients, particularly those with the Val30Met mutation.)
Pain is a serious problem in the amyloid neuropathies that may be treated with transcutaneous fentanyl patches or with oral narcotic medications. Orthostatic hypotension responds to the use of leg stockings, midodrine, and mineralocorticoids, as well as sleeping with the bed elevated at the head so that the patient's entire body is angled down toward the feet.
Chronic Inflammatory Demyelinating Polyradiculoneuropathy
This form of polyneuropathy was separated from acute inflammatory polyradiculopathy, or GBS, by Austin in 1958 on the basis of a prolonged and relapsing course, enlargement of nerves, and responsiveness to corticosteroids. Excluding the duration of evolution, the acute and chronic forms are similar in many ways. Both are widespread polyradiculoneuropathies, usually with cytoalbuminologic dissociation of the CSF (raised protein concentration with few or no cells); both exhibit nerve conduction abnormalities characteristic of a demyelinating neuropathy (reduced conduction velocity and partial conduction block in motor nerves), and pathologically, both show similar multifocal perivenous inflammatory infiltrates. But there are also important differences, the most evident of which are the modes of evolution, responses to treatment, and prognosis. As a rule, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) begins insidiously and evolves slowly, either in a steadily progressive or stepwise manner, attaining its maximum severity after several months. From the beginning it may be asymmetrical or involve the arms predominantly. However, in a small proportion of patients (16 percent in the series of McCombe et al [1987b] and a smaller proportion in our own series) the disease at first emerges from a mild or moderate case of GBS, in which case the illness becomes relapsing or simply worsens slowly and progressively.
An antecedent infection is usually not identified in patients with CIDP as it is in GBS. Furthermore, CIDP may be distinct immunologically from GBS, insofar as certain HLA antigens occur with greater frequency in patients with CIDP than they do in the normal population, whereas there are no clear HLA propensities in patients with GBS. Finally, in contrast to acute GBS, many cases of CIDP respond favorably to the administration of prednisone. An ambiguity is introduced here because, as mentioned in the section on GBS, Hughes (1992) has described a group of patients with polyneuritis in whom weakness progressed steadily for 4 to 12 weeks and who responded to corticosteroids (subacute GBS), in such cases, blurring the distinction between GBS and CIDP.
Chronic symmetric sensorimotor loss and areflexia coupled with nerve conduction findings of demyelination essentially defines the illness. Elevated spinal fluid protein concentration is so frequent that it might be added as a diagnostic criterion. The typical findings in nerve conduction studies are of multifocal conduction block as described in Chap. 45; prolonged distal latencies ("distal block"); nerve conduction slowing to less than 80 percent of normal values in several nerves; loss of late responses; and dispersion of the compound muscle action potentials—all reflecting demyelination in motor nerves. One or several of these changes have been present in 75 percent of our patients (Gorson et al, 1997). In the early stages of the disease, demyelinating features must be carefully sought by testing multiple nerves at several sites along their courses. After several months there is often some degree of axonal change (30 percent of our series), but the fundamental process continues to be one of multiple foci of demyelination. A fairly dependable finding is the absence of denervation changes early in the illness despite weakness and reduced amplitude of the motor action potential (indicative of a demyelinating block to conduction at a proximal site).
Several large series of CIDP cases are available for review. Dyck and colleagues (1975) studied 53 patients in whom the neuropathy progressed for more than 6 months. The clinical course was monophasic and slowly progressive in about one-third, stepwise and progressive in another third, and relapsing in the remaining third. The periods of worsening or improvement were measured in weeks or months. Weakness of the limbs, particularly of the proximal leg muscles, or numbness, paresthesias, and dysesthesias of the hands and feet were the initial symptoms. In 45 of the 53 patients, the signs were those of a mixed sensorimotor polyneuropathy with weakness of the shoulder, upper arm, and thigh muscles in addition to motor and sensory loss in the distal parts of the limbs. In 5 patients the neuropathy was purely motor, and in 3, purely sensory. Cranial nerve abnormalities were distinctly unusual. Enlarged, firm nerves were found in 6 patients. Not emphasized in their series is the common occurrence of a cerebellar-like tremor in cases of long standing.
In the series reported by McCombe et al (1987b) comprising 92 patients, two major subgroups were recognized: relapsing (corresponding to the relapsing and stepwise progressive cases of Dyck et al ) and nonrelapsing ones. In our own series of now over 100 patients, we have been impressed with several variant patterns of clinical presentation. In approximately 10 percent, numbness and weakness of the hands preceded involvement of the feet, which is unusual in other polyneuropathies, and a sensory ataxic form, a purely motor form, and mononeuropathies superimposed on a mild generalized polyneuropathy each accounted for approximately 5 percent.
As mentioned earlier, a small proportion of cases began as acute GBS but continue to progress or relapse in the following months (Gorson et al, 1997). Other comprehensive accounts of the disease have been given by Barohn, Cornblath, Dyck (1975), and Hughes and their associates. All of these studies have included cases with clinical progression for longer than 8 or 12 weeks; thus CIDP has come to be defined in part by a progressive polyneuropathy of this duration.
As might be imagined from the experience with GBS, there are variant syndromes that align with CIDP but have special clinical characteristics. The best characterized of these is multifocal conduction block (called multifocal acquired demyelinating motor and sensory neuropathy; MADSAM), but these are also described a polyradicular process that presents as an ataxic illness with large fiber attributable sensory loss and spared sensory nerve action potentials (see Sinnreich et al), and a slowly progressive distal neuropathy (distal acquired demyelinating symmetrical neuropathy; DADS). Regarding the last of these, there are distal sensory and sometimes motor, disturbances and greatly prolonged distal latencies in most patients, and two-thirds have an associated IgM monoclonal gammopathy with kappa light chain component; the illness responds poorly to treatment, aligning it clinically in some respects with the anti-MAG neuropathies but in most clinical and electrophysiologic features appearing to be a variant of CIDP (see Katz et al).
The status of a predominantly axonal polyneuropathy that clinically simulates CIDP and responds to some extent to the same immunomodulating treatments has been described by Uncini and colleagues and by Gorson and Ropper. The present authors have the impression that it is an immune-mediated neuropathy comparable to CIDP but with preferential destruction of axons rather than of myelin. Its frequency as a cause of acquired polyneuropathy is unknown, but we see several new cases every year.
Also recognized is the frequency (up to 25 percent of the patients in some series, less often in our experience) with which there was a parallel systemic condition such as paraproteinemia, lymphoma, an undifferentiated reactive adenopathy or lupus, in association with an inflammatory demyelinating polyneuropathy (even aside from the rare DADS process mentioned above). These associations create problems in nosology that can be reconciled by labeling a given instance as, for example, "CIDP with paraproteinemia" or "CIDP with lupus," thus separating such cases from the idiopathic variety. These symptomatic inflammatory polyneuropathies respond to corticosteroids, albeit unpredictably, and to treatment of the underlying disease.
The CSF protein is elevated in more than 80 percent of patients with CIDP, typically in the range of 75 to 250 mg/dL. In rare instances there is papilledema and a pseudotumor cerebri syndrome (see Chap. 30) in relation to extremely high levels of CSF protein (usually >1,000 mg/dL). Elevation of the CSF gamma globulin fraction and a mild lymphocytic pleocytosis are found in 10 percent of patients (often in those who are HIV-seropositive), a considerably higher percentage than in our series.
In sural nerve biopsy material, half are found to have interstitial and perivascular infiltrates of inflammatory cells, although one expects that most nerves would show these changes if a sufficient number could be sampled. Some specimens show only demyelination, or in cases of long standing, severe depletion of all nerve fibers. As in GBS, the demyelination appears to be affected by T cells and macrophages within the endoneurium and perineurium. The loss of myelinated fibers is variable and many of the remaining fibers are seen to be undergoing wallerian degeneration or show changes of segmental demyelination or demyelination-remyelination. Onion-bulb formations are conspicuous in recurrent and relapsing cases. The few adequate autopsy studies have shown only minimal or patchy inflammation and a considerable degree of axonal damage, probably reflecting the long duration of illness before examination. The presence of endoneurial and subperineurial edema has been emphasized by Prineas and McLeod.
Several trials have shown a short-term benefit from the intravenous infusion of high doses of gamma globulin (IVIg, total 2 g/kg in divided infusions over 2 to 5 days). More than half of our patients have responded to this treatment, albeit for only several weeks or months, after which the infusions must be repeated to maintain clinical improvement. A desire to spare patients the side effects of indefinite prednisone administration (see later) makes this mode of therapy a reasonable alternative, in some cases for almost 10 years without ill effects. Patients who require treatment at such short intervals as to be impractical have benefited from the addition of small doses of prednisone or of an immunosuppressive drug as described below. The main drawbacks of IVIg are its expense and the several hours required for its infusion. Rare instances of nephrotic syndrome, aseptic meningitis, serum sickness, thrombolic venous, or arterial occlusion, including stroke and hypotension, have been reported, particularly if the infusion is too rapid.
Half of patients with CIDP also respond well to plasma exchanges. In a prospective double-blinded trial, Dyck and colleagues (1986a) found that plasma exchange administered twice weekly for 3 weeks had a beneficial effect on both neurologic disability and nerve conduction. The response to plasma exchange in our patients has been comparable to that obtained with IVIg and with steroids, but we have discerned that some patients respond to one type of treatment and not another. The effects of plasma exchanges in most patients subside in 10 to 21 days, or even less; in some, the response lasts longer as found by Dyck and colleagues (1986a) and in the series reported by Hahn and colleagues (1996a). For these reasons we prefer to try plasma exchange or immune globulin before committing a patient to long-term treatment with prednisone. The relative ease of administering IVIg favors its use first, followed by a series of plasma exchanges if there is no improvement. When there is a clear response, 3 or 4 brief series of plasma exchanges or repeated infusions of immune globulin may suffice to bring the patient to an improved level of function. These treatments can be supplemented by small doses of prednisone when frequent infusions or exchanges become impractical. It has been our experience that in about one-third of cases, IVIg and plasma exchange cease to have benefit after repeated use for 1 or more years.
Corticosteroids were formerly the mainstay of therapy, but many patients become dependent on the medication and correspondingly suffer side effects. Our approach has been to use corticosteroids as an adjunct to one of the previously mentioned treatments, but other centers use them first. The usual regimen begins with 60 to 80 mg of prednisone daily that is tapered over months to the lowest effective dose, typically 25 to 40 mg. Without substantiation by a controlled trial, we have found that corticosteroids can be withdrawn without relapse in some patients by slow tapering over many months or a year. Attempts to withdraw the steroids more quickly have led to further cycles of relapse.
A number of patients will have no response to corticosteroids within the first 1 or 2 months but will improve if treatment is continued. Barohn and colleagues (1989) have found that the earliest improvement occurs only after 2 months of treatment and is maximal at approximately 6 months. In addition to all the well-known side effects, the drug may produce tremor or exaggerate the tremor caused by the neuropathy. Long remissions lasting several years have been reported with the use of pulses of orally administered high-dose or daily corticosteroids, for example, by Eftimov and colleagues, who used dexamethasone 40 mg per day for 4 days, repeated for 6 cycles, or daily prednisolone, 60 mg for 6 weeks. Should a sustained trial of prednisone therapy prove unsuccessful, a course of azathioprine (for at least 3 months), 3 mg/kg in a single daily dose, has been recommended (Dalakas and Engel, 1981a), but a controlled trial has failed to show benefit from this combination and we have had little success with it.
When the preceding measures prove unsatisfactory, cyclophosphamide, mycophenolate, rituximab, or another similar immunosuppressive medication can be added, but we have been unable to draw any firm conclusions as to the effectiveness of these combined regimens.
Some patients who have failed to benefit from the aforementioned treatments have seemingly improved in response to the administration of alpha-interferon; however, in larger trials, interferon allowed an increase in the interval between infusions of IVIg but was not an effective primary therapy. High-dose cyclophosphamide has proven helpful in several cases under our care, although it has often failed (see Brannagan et al and the review by Brannagan that lists the applicable clinical trials). The usual regimen is 50 mg/kg IV daily for 4 days followed by granulocyte-stimulating factor beginning on the tenth day until the absolute neutrophil count recovers. Individual reports of successful treatment by autologous stem cell transplantation after high-dose chemotherapy have appeared but 1 patient relapsed after 5 years (Vermuelen and van Oers). This may become an option in severe and treatment-resistant cases. We have no explanation for the remarkable improvement and continued good health of a few of our patients after a severe toxic bacterial infection (Ropper, 1996).
One of the most difficult problems in this field is the lack of useful clinical measurements to guide treatment with IVIg and plasma exchange and even the proper adjustment of the dose of corticosteroid. Often, one may be influenced by the patient's fear of losing any ground and even slight changes in sensory or motor symptoms.
It has been stated that patients with discrete relapses have a better prognosis than those with a progressive course. In McCombe's series (1987b), 73 percent were said to have eventually recovered, but the long-term outcome has generally been poor. In fewer than 10 percent of patients has the disease finally remitted; additionally, unexplained remission occurs occasionally. The 5-year followup of 38 patients by Kuwabara and colleagues gives a figure of 49 percent with full or partial remission, far higher than in our series.
Multifocal Motor Neuropathy and Multifocal Conduction Block
Several polyneuropathies that share many of the features of CIDP have been delineated on the basis of unique clinical, immune, or electrophysiologic attributes. These include particularly multifocal motor neuropathy (MMN) and multifocal conduction block (also called MADSAM as mentioned earlier). The latter has as its main feature a block of mixed nerve conduction at focal sites in a limited number of nerves as described earlier. In multifocal motor neuropathy, only blocks in motor nerve conduction are evident.
The distinction between these two entities has been difficult. There are similarities in clinical features and response to treatment (see Delmont et al), but there is utility in separating them. Multifocal motor neuropathy, but not multifocal conduction block, is associated in half of cases with a particular IgM antibody, anti-GM1, directed against a ganglioside component of peripheral myelin (Pestronk et al). For this reason, some view this illness as belonging to the class of paraproteinemic neuropathies (see earlier and Simmons et al) and it is certainly distinctive enough clinically to be categorized separately. Its importance as a clinical entity lies in the similarity of the clinical picture to a purely lower motor neuron type of amyotrophic lateral sclerosis (ALS) and, unlike ALS, its potential responsiveness to treatment. The pathophysiologic role of anti-GM1 antibodies is further displayed by a case of transplacental transmission of a motor neuropathy to a neonate (Attarian et al).
Multifocal motor neuropathy and motor conduction block predominate in men. They usually begin with an acute or subacute motor mononeuropathy, manifest, for example, as weakness of the wrist or foot-drop, and are often joined insidiously by another focal motor palsy. The process is painless, unlike vasculitic mononeuritis multiplex, involves the nerve incompletely, and, in its usual form, is unaccompanied by any sensory symptoms such as paresthesias or numbness. Despite the initially demyelinating character of the disorder, there is almost always atrophy of the weakened muscle within months and there may be a few fasciculations, thus simulating ALS. Nevertheless, the weakness tends to be disproportionate to atrophy. Usually, the tendon reflex is lost or muted in an affected region, but for unexplained reasons, some patients have one or more brisk reflexes. Our experience has been that this latter reflex change does not reach the point of appearing "pathologic" and that clonus and Babinski signs are categorically not part of the illness, as they are in ALS.
When there is an association of the motor features with sensory symptoms or sensory loss and there is slowing of sensory conduction in regions of motor conduction block (multifocal conduction block), the acronym MADSAM (multifocal acquired demyelinating sensory and motor neuropathy) has been used as noted earlier, but the disorder, while similar to multifocal conduction block, more resembles CIDP. This conforms to what has been called Lewis-Sumner syndrome based on the description by these authors and their colleagues of subacute, painless asymmetric, distal multiple mononeuropathies. The ulnar and median nerves were involved in their patients and there was motor conduction block and sensory slowing in affected nerves. Curiously, 2 of their 5 original patients had optic neuritis, a feature not reported subsequently. The disease is not directly connected to antibodies against GM1, but a few patients with the sensorimotor disorder will display them.
For multifocal motor conduction block and motor neuropathy, with or without anti-GM1 antibodies, IVIg infusions have been effective, albeit temporarily, in more than half of patients. Some authoritative clinicians favor the early addition of rituximab in treatment-resistant cases or when the frequency of infusions is unsustainable and if that fails, cyclophosphamide. Other immune-modulating drugs have been tried in small series with various results. There is no response to corticosteroids. The MADSAM illness responds similarly to corticosteroids, IVIg, or plasma exchange, similar to the effects of these approaches in CIDP.
Polyneuropathy is among the most common complications of chronic renal failure. Robson has estimated that neuropathy complicates end-stage renal failure in two-thirds of patients who are about to begin dialysis therapy. Bolton's figures are much the same; 70 percent of his patients being dialyzed regularly had polyneuropathy and in 30 percent of all his patients, it was moderate or severe in degree. As described originally by Asbury and associates (1963), the neuropathy takes the form of a painless, progressive, symmetrical sensorimotor paralysis of the legs and then of the arms. In some patients, the syndrome begins with burning dysesthesias of the feet or with sensations of creeping, crawling, and itching of the legs and thighs, which tend to be worse at night and are relieved by movement (comparable to "restless legs" syndrome described in Chap. 19). Renal failure that is accompanied by diabetes gives rise to a particularly severe form of polyneuropathy.
The combination of muscle weakness and atrophy, areflexia, sensory loss, and the graduated, distally predominant distribution of the neurologic deficit in the limbs leaves little doubt about the neuropathic nature of the disorder. Usually the neuropathy evolves slowly over many months. Infrequent instances of a more acute sensorimotor polyneuropathy that have been reported occur mainly in diabetic patients receiving peritoneal dialysis as discussed earlier (Ropper, 1993; Asbury et al, 1963). A rare uremic polymyositis with hypophosphatemia has also been described (Layzer). The neuropathy has been observed with all types of chronic kidney diseases. More important to the development of chronic neuropathy than the nature of the renal lesion are the duration and severity of the renal failure and symptomatic uremia.
With long-term hemodialysis, the neuropathic symptoms and signs stabilize but improve in relatively few patients. In fact, rapid hemodialysis may worsen the polyneuropathy (or perhaps its symptoms) temporarily. Peritoneal dialysis appears to be more successful than hemodialysis in improving the neuropathy, but this observation has not been firmly established. Complete recovery, occurring over a period of 6 to 12 months, usually follows successful renal transplantation for reasons given later.
The pathologic findings are those of a nonspecific and noninflammatory axonal degeneration. In rapidly progressive cases, there is a tendency for the large fibers to be more affected; this is evident particularly on electrophysiologic testing that shows slowing of nerve conduction velocities, but there is no conduction block as occurs in other acquired demyelinating polyneuropathies. In all types of uremic polyneuropathies, pathologic changes are most intense in the distal segments of the nerves with the expected chromatolysis of their cell bodies.
The cause of uremic polyneuropathy is unknown. What has been called the "middle molecule" theory is plausible. The end stage of renal failure is associated with the accumulation of toxic substances in the range of 300 to 2,000 kDa molecular weight. Furthermore, the concentration of these substances, which include methyl guanidine and myoinositol, has been shown to correlate with the degree of neurotoxicity (Funck-Brentano et al). These toxins (and the clinical signs of neuropathy) are not greatly reduced by hemodialysis. In contrast, the transplanted kidney effectively eliminates substances of wide-ranging molecular weights, which would account for the almost invariable improvement of neuropathy after transplantation. As is the case with uremic encephalopathy, urea alone given to experimental animals and in controlled studies of humans, does not seem capable of inducing a metabolic neuropathy.
As described at length in Chap. 41, in virtually all patients with alcoholic–nutritional polyneuropathy who for some reason remain untreated with vitamin and protein restoration, the weakness and atrophy of the legs, and to a lesser extent the arms, may reach an extreme degree. Thus this disease, although subacute in its evolution as described earlier in the chapter, becomes a frequent cause of chronic polyneuropathy. There are usually prominent sensory features and considerable acral pain and allodynia. Certain cases of diabetic neuropathy behave similarly.
This is the best example of an infectious neuritis, caused by the direct invasion of nerves by the acid-fast Mycobacterium leprae. The disease is still frequent in India and Central Africa and there are many lesser endemic foci, including parts of South America and Florida, Texas, and Louisiana, which border the Gulf of Mexico. Limited outbreaks have been reported during treatment for AIDS, with armadillos as the probable intermediate host.
The initial lesion in leprosy is an innocuous-appearing skin macule or papule, which is often hypopigmented and lacking in sensation; it is caused by the invasion of cutaneous nerves by M. leprae. In patients with a degree of immunologic resistance to infection, the disease progresses no further than this stage, which is spoken of as indeterminate leprosy, or it may evolve in several ways, depending mainly upon the resistance of the host. The bacilli may be locally invasive, producing a circumscribed epithelioid granuloma that involves cutaneous and subcutaneous nerves and results in a characteristic hypopigmented patch of superficial numbness and sensory loss (tuberculoid leprosy). The underlying subcutaneous sensory nerves may be palpably enlarged. If a large nerve in the vicinity of the granuloma is invaded (the ulnar, median, peroneal, posterior auricular, and facial nerves are most frequently affected), a sensorimotor deficit in the distribution of that nerve is added to the patch of cutaneous anesthesia.
In contrast to the limited tuberculoid variety of leprosy, lack of resistance to the organism permits the proliferation and hematogenous spread of bacilli and the diffuse infiltration of skin, ciliary bodies, testes, lymph nodes, and nerves (lepromatous leprosy). Widespread invasion of the cutaneous nerves produces a symmetrical pattern of pain and temperature loss involving the pinnae of the ears (earlobes) and nose, as well as the dorsal surfaces of hands, elbows, forearms, and feet and anterolateral aspects of the legs—a distribution that is determined by the relative coolness of these parts of the skin. This temperature-dependent pattern is the most characteristic feature of the disease, as pointed out by our colleague T. Sabin. The sensory maps he has drawn (Fig. 46-4) are typical of established cases. The process evolves over years. Eventually, the anesthesia spreads to involve most of the cutaneous surface. Extensive sensory loss is followed by impaired motor function owing to invasion of muscular nerves where they lie closest to the skin (the ulnar nerve is the most vulnerable). There is loss of sweating in areas of sensory loss but otherwise the autonomic nervous system is unaffected. In distinction to other polyneuropathies, tendon reflexes are usually preserved in leprosy despite widespread sensory loss. Probably this is the result of sparing of most of the muscular and larger sensory nerves. Because of widespread anesthesia, injuries may pass unrecognized, with resultant infections, trophic changes, and loss of tissue. Variations in host immunity result in patterns of disease having both tuberculoid and lepromatous characteristics (dimorphous leprosy). Erythema nodosum occurs in a few cases. The diagnosis can be made from a skin scraping or biopsy, but multiple samples are often required.
Patterns of sensory loss in leprosy. The localization of these areas to cooler portions of the body is unique to this disorder. There is almost universal analgesia but sparing of warmer regions such as the midline of the back, popliteal and antecubital spaces, lower abdomen and groin, and the head and neck. (From Sabin TD: Preservation of sensation in a cutaneous vascular malformation in lepromatous leprosy. N Engl J Med 282:1084, 1970, with permission.)
The findings on nerve conduction studies are varied, but they usually include findings that are consistent with a generalized but heterogeneous sensorimotor polyneuropathy that includes features of demyelination such as slowed nerve conduction velocities, temporal dispersion and occasionally, conduction block.
All forms of leprosy require long-term treatment with sulfones (dapsone being the most commonly used), rifampin, and clofazimine. The skin lesions of lepromatous leprosy are responsive to thalidomide, which itself may cause a sensory neuropathy (Barnhill and McDougall). Reactivation of disease, or a conversion from the tuberculoid to the lepromatous pattern, may occur during times of reduced immunity.
Polyneuropathy With Hypothyroidism
The status of this disorder is uncertain and the authors have not encountered a definite case. Although characteristic disturbances of skeletal muscle are known to complicate hypothyroidism, the demonstration of a definite polyneuropathy has been infrequent. However, a number of elderly myxedematous patients complain of weakness and numbness of the feet, legs, and, to a lesser extent, hands, for which no other explanation can be found. Loss of reflexes, diminution in vibratory, joint-position, and touch-pressure sensations, and weakness in the distal parts of the limbs are the usual findings. The neuropathic manifestations are seldom severe. Nerve conduction velocities are slowed and the protein content of the CSF is usually increased to more than 100 mg/dL. Possibly the latter finding is a reflection of the increased protein content of the serum in the hypothyroid state. The subjective improvement and complete or near-complete reversibility of neuropathic signs following treatment with thyroid hormones provides evidence of a hypothyroid etiology. In biopsies of nerve, an edematous protein infiltration of the endoneurium and perineurium, a kind of metachromatic mucoid material, has been seen. Dyck and Lambert (who should be credited for drawing attention to this neuropathy) noted segmental demyelination in teased fiber preparations. In electron-microscopic sections, a slight increase in glycogen, acid mucopolysaccharides, and aggregates of glycogen and cytoplasmic laminar bodies in Schwann cells have been observed by others.
Polyneuropathy of sensorimotor type has also been observed in association with a syndrome of chronic lymphocytic thyroiditis and alopecia (Hart et al).