Neurology_Adams

Neurology_Adams. Some patients who have taken phenytoin for decades may lose ankle and patellar reflexes and acquire mild distal symmetrical impairment of sensation, slowed conduction velocity in the peripheral nerves of the legs and rarely, weakness of the distal musculature. The mechanism and frequency of this complication are not clear. The cholesterol-lowering statin drugs have been tentatively implicated in a painful, paresthetic distal axonal polyneuropathy with retained reflexes (Gaist et al) but the evidence for this association is not strong; sometimes a period off the drug or a change to an alternative agent is all that can be tried but it should not preclude a search for alternative causes. More often the problem with statins is one of a toxic myopathy. Colchicine has long been known to cause a myopathy, but a few cases of predominantly axonal sensory neuropathy have also been reported (neuromyopathy).


Neurology_Adams

Neurology_Adams. Among various other agents that cause neuropathy are hydroxychloroquine and colchicine are known to cause a toxic neuropathy. The anesthetic agent trichloroethylene, as with the aforementioned stilbamidine, has a predilection for cranial nerves, particularly the fifth. The neurotoxicity is apparently caused by dichloroacetylene, formed as a product of trichloroethylene. The neuropathic potential of nitrous oxide has already been mentioned. Most of the group of tumor necrosis factor-alpha (TNF-α) inhibitors may cause a polyneuropathy, including small-fiber neuropathy, but this category of agents do not appear to have a direct toxic effect on nerves but instead alter immune function in some way that results in a process that simulates chronic inflammatory demyelinating polyneuropathy (see further on).


Neurology_Adams

Neurology_Adams. Residual effects of polyneuropathy were seen in patients with the toxic eosinophilia-myalgia syndrome; the problem was traced to the ingestion of adulterated l-tryptophan, which had been used in nonprescription drugs for insomnia. One patient under our care suffered permanent areflexic quadriplegia. There may be an eosinophilic infiltrate in nerves, but the neuropathy is probably the result of a direct toxic mechanism. A sensory neuropathy, resulting from excessive pyridoxine ingestion alluded to earlier, is still seen among individuals who take huge doses of vitamin supplements. Amitriptyline is capable of producing paresthesias, but the effect seems to be idiosyncratic and infrequent.


Neurology_Adams

Neurology_Adams. Diabetes mellitus is the most common cause of polyneuropathy in general clinical practice, for which reason it is accorded a separate section. We are referring mainly to a generalized, predominantly sensory syndrome, but several focal or regional forms of peripheral nerve disease also result from diabetes and for convenience of exposition, are included here. In recent years, attention has also been directed to a possible association between a nondescript sensory polyneuropathy and impaired glucose tolerance, even without manifest diabetes, persistent hyperglycemia, or an elevation of hemoglobin A1c. The survey by Sumner and colleagues makes a case for such an association, but we remain uncertain about the relationship between glucose intolerance alone and polyneuropathy. By statistically adjusting for relevant factors such as glycemic control and glycosylated hemoglobin, Tesfaye and colleagues have suggested that some cardiovascular risk factors subsumed under the term “metabolic


Neurology_Adams

Neurology_Adams. adjusting for relevant factors such as glycemic control and glycosylated hemoglobin, Tesfaye and colleagues have suggested that some cardiovascular risk factors subsumed under the term “metabolic syndrome” (triglyceride levels, body mass, hypertension) are themselves risk factors for diabetic polyneuropathy.


Neurology_Adams

Neurology_Adams. Approximately 15 percent of patients with diabetes have symptoms and signs of polyneuropathy, but nearly 50 percent of cross-sectional population samples have evidence of peripheral nerve damage as judged by nerve conduction abnormalities. The duration of diabetes is perhaps the most important factor. Fewer than 10 percent of patients have clinically evident polyneuropathy at the time of discovery of diabetes, but this figure rises to 50 percent after 25 years. The presence of diabetic retinopathy is associated with higher incidences of neuropathy. It is not surprising, therefore, that neuropathy is most common in diabetics older than 50 years; it is infrequent in those younger than age 30 years and is rare in childhood. Dyck and colleagues (1993) studied diabetics in Rochester, Minnesota, and found that 54 percent with type 1 (insulin-deficient) and 45 percent with type 2 (insulin-resistant) had polyneuropathy. The percentages were lower when patients were selected on the basis of


Neurology_Adams

Neurology_Adams. and found that 54 percent with type 1 (insulin-deficient) and 45 percent with type 2 (insulin-resistant) had polyneuropathy. The percentages were lower when patients were selected on the basis of clinical symptoms alone rather than on the presence of changes in nerve conduction; close to 15 percent at the time of diagnosis in both groups. In the syndromes described further on, both type 1 and type 2 diabetic patients are susceptible, the duration of diabetes being a major factor.


Neurology_Adams

Neurology_Adams. Several fairly distinct clinical syndromes of diabetic neuropathy have been delineated: (1) the most common as noted is a distal, symmetrical, primarily sensory polyneuropathy affecting feet and legs in a chronic, slowly progressive manner; the others are (2) acute ophthalmoplegia that affects the third, and less often the sixth, cranial nerve on one side; (3) acute mononeuropathy of limbs or trunk including a painful thoracolumbar radiculopathy; (4) an acute or subacute painful, asymmetrical, predominantly motor, multiple neuropathy affecting the upper lumbar roots and the proximal leg muscles (“diabetic amyotrophy”); (5) a more symmetrical, proximal motor weakness and wasting, usually without pain and with variable sensory loss, pursuing a subacute or chronic course; and (6) an autonomic neuropathy involving bowel, bladder, sweating and circulatory reflexes. These forms of neuropathy often coexist or overlap, particularly the autonomic and distal symmetrical types and the subacute


Neurology_Adams

Neurology_Adams. neuropathy involving bowel, bladder, sweating and circulatory reflexes. These forms of neuropathy often coexist or overlap, particularly the autonomic and distal symmetrical types and the subacute proximal neuropathies.


Neurology_Adams

Neurology_Adams. Most of the syndromes listed here are likely to be a result of ischemia or infarction of nerves or nerve fascicles, because of a diabetic microvasculopathy. All but the first are special types of mononeuropathy multiplex. The polyneuropathy is associated with occlusion of small endoneurial blood vessels (vasonervorum) but possibly also incorporate a poorly understood metabolic abnormality; however, other theories of causation abound. In recent years, an inflammatory process has been postulated as yet another mechanism of peripheral nerve damage. These aspects are discussed further on.


Neurology_Adams

Neurology_Adams. The distal, symmetrical, primarily sensory form of polyneuropathy is the most common type. It is usually a chronic process, sometimes unnoticed by the patient. The main complaints are persistent and often distressing numbness and tingling, usually confined to the feet and lower legs and worse at night. The ankle jerks are absent and, sometimes, the patellar reflexes as well. As a rule, sensory loss is confined to the distal parts of the lower extremities, but in severe cases the hands are involved and the sensory loss may even spread to the anterior trunk, simulating a sensory level of spinal cord disease (Said et al, 1983). Trophic changes in the form of deep ulcerations and neuropathic degeneration of the joints (Charcot joints) are encountered in the most severe and long-standing cases, presumably as a result of sensory analgesia, trophic changes, and repetitive injury. (Foot ulcerations are more common simply as a result of the microvascular disease of skin in diabetic patients.)


Neurology_Adams

Neurology_Adams. presumably as a result of sensory analgesia, trophic changes, and repetitive injury. (Foot ulcerations are more common simply as a result of the microvascular disease of skin in diabetic patients.) Muscle weakness is usually mild, but in some patients a distal sensory neuropathy is combined with a proximal weakness and wasting of the types mentioned earlier. Treatment of the acral pain may be a major problem and is discussed further on.


Neurology_Adams

Neurology_Adams. In another group of patients with diabetic polyneuropathy the clinical picture may be dominated instead by loss of deep sensation, ataxia, and atony of the bladder, with only slight weakness of the limbs, in which case it resembles tabes dorsalis (hence the term diabetic pseudotabes). The similarity to tabes dorsalis is even closer if lancinating pains in the legs, unreactive pupils, abdominal pains, and neuropathic arthropathy are present. Among these, diabetic ophthalmoplegia is a common occurrence, usually in a patient with well-established diabetes. It commonly presents as isolated, painful third nerve palsy with sparing of pupillary function. In the first autopsied patient reported by Dreyfus and colleagues, there was an ischemic lesion in the center of the retroorbital portion of the third nerve. Subsequently, a similar case was described by Asbury and colleagues (1970). Slightly less often, the sixth nerve on one side is involved. The disorder was described in Chap. 13.


Neurology_Adams

Neurology_Adams. Isolated involvement of practically all the major peripheral nerves has been described in diabetes, but the ones most frequently affected are the femoral, sciatic, and peroneal nerves, in that order. Rarely is a nerve in the upper extremity affected. As mentioned, the acute mononeuropathies, both cranial and peripheral, are presumably a result of infarction of the nerve, but it is only in pathologic studies of the third nerve that this basis has been established. Recovery is the rule but may take many months.


Neurology_Adams

Neurology_Adams. This category overlaps with the mononeuropathies. A syndrome of painful unilateral or asymmetrical multiple neuropathies tends to occur in older patients with relatively mild or even unrecognized diabetes. Multiple nerves are affected in a random distribution (mononeuropathy multiplex). The mononeuropathies often emerge during periods of transition in the diabetic illness, for example, after an episode of hyperor hypoglycemia, when insulin treatment is initiated or adjusted, or when there has been rapid weight loss.


Neurology_Adams

Neurology_Adams. The most characteristic syndrome affects the lumbar roots. Pain, which can be severe, begins in the low back or hip and spreads to the thigh and knee on one side; the discomfort has a deep, aching character with superimposed lancinating jabs and there is a propensity for pain to be most severe at night. Weakness and later atrophy are evident in the pelvic girdle and thigh muscles, although the distal muscles of the leg may also be affected. The weakness can progress for days or weeks (rarely, months). The patellar reflex is lost on the affected side. Curiously, we have found the opposite patellar reflex to be absent in some patients, without explanation. Deep and superficial sensation may be intact or mildly impaired, conforming to either a multiple nerve or multiple adjacent root distribution (i.e., L2 and L3, or L4 and L5). The pain lasts for several days and then gradually abates. Motor recovery is the rule although months and even years may elapse before it is complete. The same


Neurology_Adams

Neurology_Adams. (i.e., L2 and L3, or L4 and L5). The pain lasts for several days and then gradually abates. Motor recovery is the rule although months and even years may elapse before it is complete. The same syndrome may recur after an interval of months or years in the opposite leg. The EMG shows denervation in the lumbar and sometimes adjacent myotomes.


Neurology_Adams

Neurology_Adams. This form of neuropathy has been referred to as diabetic amyotrophy, a term that draws attention to one facet of the syndrome. Garland’s name (also Bruns’s) has been attached to this diabetic lumbar radiculoplexopathy based on his thorough report (but he mistakenly attributed the condition to a spinal cord lesion). Clinical experience has shown that an identical painful lumbofemoral neuropathy may develop in nondiabetics; possibly this form is also vasculopathic or vasculitic. While lumbar disc herniation, retroperitoneal hematoma compressing upper lumbar roots, carcinomatous meningeal seeding, and neoplastic and sarcoid infiltration of the proximal lumbar plexus enter into the differential diagnosis, the diabetic type is usually so distinctive as to permit recognition on clinical grounds alone. In an informative reexamination of this syndrome, Barohn and colleagues (1991) point out that there is considerable overlap between the chronic polyneuropathy of diabetes and this rapidly


Neurology_Adams

Neurology_Adams. alone. In an informative reexamination of this syndrome, Barohn and colleagues (1991) point out that there is considerable overlap between the chronic polyneuropathy of diabetes and this rapidly evolving regional disorder. They also point out a high incidence of involvement of the L5 root, but we find this difficult to reconcile with the frequent finding of hip flexor and quadriceps weakness in our patients. As with the diabetic mononeuropathies, the upper extremities are only rarely affected by this process.


Neurology_Adams

Neurology_Adams. Also observed in diabetic patients is a relatively painless syndrome of proximal symmetrical leg weakness, wasting, and reflex loss of more insidious onset and gradual evolution as discussed by Pascoe and colleagues. The iliopsoas, quadriceps, and hamstrings are involved in varying degrees. The muscles of the scapulae and upper limbs, usually the deltoid and triceps, are affected less frequently. Sensory changes, if present, are distal, symmetrical, and usually mild. In an attempt to delineate these types of proximal diabetic neuropathies, it must be emphasized that they overlap and that distal parts of a limb may be involved to a mild degree and the evolution of symptoms varies. Whether the proximal and distal syndromes should be distinguished on pathologic or electrophysiologic grounds is not clear.


Neurology_Adams

Neurology_Adams. A syndrome of thoracoabdominal radiculopathy characterized by severe pain and dysesthesia is also well described (Sun et al). Almost always the diabetes has been of long standing (Kikta et al). The pain is distributed over one or several adjacent segments of the chest or abdomen; it may be unilateral, or less often bilateral, and, as with the lumbar radiculoplexopathy, sometimes follows a period of recent weight loss. Superficial sensory loss can be detected over the involved area in most patients. The pathology of this state is not known, but it is presumed to be an ischemic radiculopathy. The EMG changes consist of fibrillations of the paraspinal and abdominal muscles in one or more adjacent myotomes, corresponding to the painful area. With control of the diabetes, or perhaps spontaneously, recovery eventually occurs but it may be protracted. The differential diagnosis includes preeruptive herpes zoster, sarcoid infiltration of nerve roots, and thoracic disc rupture.


Neurology_Adams

Neurology_Adams. In all forms of diabetic polyneuropathy the CSF protein may be elevated from 50 to 150 mg/dL and sometimes higher. The protein concentration is usually normal in cases of diabetic mononeuropathy. Whether a slight elevation of CSF protein, discovered incidentally, can be attributed to diabetes in the absence of a polyneuropathy is uncertain. Symptoms of autonomic involvement include any combination of pupillary and lacrimal dysfunction, impairment of sweating and vascular reflexes, nocturnal diarrhea, atonicity of the gastrointestinal tract (gastroparesis) and bladder dilation, erectile dysfunction, and postural hypotension. The most striking examples in our experience include severe abdominal and limb pain in young type 1 diabetics, symptoms comparable to the crises of tabes dorsalis that required narcotics to control.


Neurology_Adams

Neurology_Adams. The basis of this type of autonomic involvement is not well understood. Duchen and associates, who studied the sympathetic ganglia in diabetic patients with autonomic symptoms, described vacuoles and granular deposits in sympathetic neurons and little if any neuronal degeneration; there was also a loss of myelinated nerve fibers in the vagus and splanchnic nerves and the rami communicantes, as well as changes in neurons of the intermediolateral columns of the spinal cord. Pathology and Pathophysiology of the Diabetic Neuropathies


Neurology_Adams

Neurology_Adams. In the typical symmetrical diabetic distal sensory polyneuropathy, loss of myelinated nerve fibers is the most prominent finding. In addition, segmental demyelination and remyelination of remaining axons are apparent in teased nerve fiber preparations. The latter findings are probably too severe and widespread to be simply a reflection of axonal degeneration. Occasionally, repeated demyelination and remyelination lead to onion-bulb formations of Schwann cells and fibroblasts, as it does in the relapsing inflammatory neuropathies. Unmyelinated fibers are also reduced in number in most specimens. Similar scattered lesions are found in the posterior roots and posterior columns of the spinal cord, and in the rami communicantes and sympathetic ganglia. Under the electron microscope, the basement membranes of intraneural capillaries are thickened and duplicated. There are changes in the microvasculature of the nerves as well, similar to what is seen in other organs and in the skin of


Neurology_Adams

Neurology_Adams. basement membranes of intraneural capillaries are thickened and duplicated. There are changes in the microvasculature of the nerves as well, similar to what is seen in other organs and in the skin of diabetics.


Neurology_Adams

Neurology_Adams. As can be surmised from this discussion, uncertainties persist about the pathogenesis of the diabetic neuropathies. Both the cranial and peripheral mononeuropathies, as well as the painful, asymmetrical, predominantly proximal neuropathy of sudden onset, have been considered by most neuropathologists to be ischemic in origin, secondary to a vasculopathy of the vasa nervorum. Obliterative microvascular lesions were well illustrated by Raff and coworkers and corresponding multiple small infarcts were found in the nerve trunks in other studies. The observations of Dyck et al (1986b) and of Johnson and their associates also suggested that all forms of diabetic neuropathy had the same microvascular basis. The latter authors described multiple foci of fiber loss throughout the length of the peripheral nerves, beginning in the proximal segments and becoming more frequent and severe in the distal. This pattern of change differs from that observed in diffuse metabolic disease of Schwann cells


Neurology_Adams

Neurology_Adams. nerves, beginning in the proximal segments and becoming more frequent and severe in the distal. This pattern of change differs from that observed in diffuse metabolic disease of Schwann cells and in the dying-back type of neuropathy. Fagerberg had earlier noted that the fascicular capillaries and epineural arterioles have thickened and hyalinized basement membranes, similar to the microvascular changes seen in the retina, kidney, and other organs. But occlusion of vessels and frank infarction of nerve has not been observed in most cases of polyneuropathy for which reason a vascular pathogenesis remains unsettled.


Neurology_Adams

Neurology_Adams. An alternative view has been offered, based largely on the work of Dyck and colleagues (2000) and of Said and coworkers (2003). They have found areas of perivascular inflammation and adjacent damage to nerve fascicles in the proximal radicular plexus syndrome. These findings, if valid, have implications for possible treatment with anti-inflammatory drugs.


Neurology_Adams

Neurology_Adams. Several biochemical findings implicated in diabetic polyneuropathy and their interpretations were reviewed by Brown and Greene, who advanced the idea that persistent hyperglycemia inhibits sodium-dependent myoinositol transport. Low levels of intraneural myoinositol reduce phosphoinositide metabolism and sodium- potassium adenosine triphosphatase (ATPase) activity. Others have emphasized a deficiency of aldose reductase and an elevation of polyols (particularly sorbitol) as being causally important. The role of factors other than hyperglycemia that are subsumed under the “metabolic syndrome” mentioned earlier is also unclear. In reviewing these studies, one can only conclude that a convincing biochemical pathogenesis for neuropathy in diabetes has yet to be formulated.


Neurology_Adams

Neurology_Adams. Another group of novel findings holds that there is a reduction in trophic factors within diabetic nerves (nerve growth factor [NGF], vascular endothelial growth factor [VEGF], erythropoietin); partial reversal of the polyneuropathy has been obtained in animals by replacement of these factors through gene therapy. Trials addressing this mode of treatment are noted later.


Neurology_Adams

Neurology_Adams. Treatment The only preventive treatment for diabetic neuropathy is the maintenance of blood glucose concentration at close to normal range. The prevailing view, derived from long-term human studies, is that there is a relationship between peripheral nerve damage and inadequate regulation of the diabetes. This is supported by the findings of the National Diabetic Complications Trial, in which 715 patients with type 1 diabetes were followed for 6 to 10 years. There was a relation between strict glucose control by means of an intravenous insulin infusion system and a reduction or delay in the occurrence of painful neuropathic symptoms, retinopathy, and nephropathy. However, this came at the price of a threefold increase in hypoglycemic reactions (see also Samanta and Burden). Whether similar protective effects of glucose control apply to type 2 diabetes is not known, but for most patients rigid control is impractical. A number of small trials have been conducted with aldose reductase


Neurology_Adams

Neurology_Adams. protective effects of glucose control apply to type 2 diabetes is not known, but for most patients rigid control is impractical. A number of small trials have been conducted with aldose reductase inhibitors based on theoretical considerations of the above-discussed metabolic changes. Some recent interest has also been directed at the therapeutic use of gangliosides, which are normal components of neuronal membranes and can be administered exogenously. These approaches have not entered routine practice.


Neurology_Adams

Neurology_Adams. Treatment using gene transfer had been pursued by our group. In experimental models of diabetic neuropathy, the intramuscular administration of VEGF has had a beneficial effect on several measures of nerve conduction and on the histologic changes of diabetic nerve damage in the treated limb (Ropper et al, 2009). Whether this was mediated by a trophic influence on nerves and Schwann cells, or is the result of angiogenesis, is not known. With similar intentions, two trials of NGF injections in almost 500 patients conducted by Apfel and colleagues gave equivocal results, the first being positive and the followup study not showing improvement. VEGF has resulted in improvement of sensory symptoms but not of nerve conduction or of the sensory examination in a trial we conducted.


Neurology_Adams

Neurology_Adams. The distressing paresthesias of the distal extremities can be managed with amitriptyline, other tricyclic antidepressants, or one of the newer generation of antidepressants, duloxitine, gabapentin, or pregablain but the response is usually incomplete. Shooting, stabbing pain also responds to some degree to anticonvulsant drugs but only modest effects can be expected. Gabapentin may give reasonable results, perhaps in part because high doses are tolerated (Gorson et al, 1999). Topical creams with capsaicin, lidocaine or other substances, or compounds with several of these (including ketorolac, gabapentin, ketamine) have been found helpful by a few patients but do not have support in randomized trials. Nerve blocks and epidural injections have been helpful in very few patients. In the proximal asymmetrical, truncal, or ophthalmoplegic neuropathies, the severe pain usually lasts for only a short period and requires the judicious use of analgesics, as outlined in Chap. 7. The course in


Neurology_Adams

Neurology_Adams. asymmetrical, truncal, or ophthalmoplegic neuropathies, the severe pain usually lasts for only a short period and requires the judicious use of analgesics, as outlined in Chap. 7. The course in patients with the distal, symmetrical sensory neuropathy is generally of slow progression, but in the other types improvement and eventual recovery may be expected over a period of months or years.


Neurology_Adams

Neurology_Adams. ASYMMETRICAL AND MULTIFOCAL POLYNEUROPATHIES (MONONEUROPATHY, OR MONONEURITIS MULTIPLEX) (TABLE 43-4)


Neurology_Adams

Neurology_Adams. In addition to diabetes, several systemic conditions are accompanied by acute or subacute involvement of multiple individual nerves serially or almost simultaneously. This configuration gives rise to the distinctive clinical picture of mononeuropathy, or mononeuritis multiplex. The most notable examples are associated with vasculitides that produce nerve infarction, the archetype being polyarteritis nodosa and other vasculitides and particularly a form of idiopathic vasculitis that is confined to the peripheral nervous system. The distinctive features of the multiple mononeuropathy syndromes are the acute or subacute evolution of complete or almost complete sensorimotor paralysis in the distribution of single peripheral nerves. In addition to vasculitis or the nerves, sarcoidosis, forms of HIV-related neuropathy, Leprosy and Lyme disease may become manifest in this fashion, probably from infiltration or inflammation of nerves rather than infarction. The diabetic mononeuropathies were


Neurology_Adams

Neurology_Adams. HIV-related neuropathy, Leprosy and Lyme disease may become manifest in this fashion, probably from infiltration or inflammation of nerves rather than infarction. The diabetic mononeuropathies were addressed in the preceding section.


Neurology_Adams

Neurology_Adams. More than half of all cases of mononeuropathy multiplex can be traced to a systemic vasculitis involving the vasa nervorum. These are the main causes of mononeuritis multiplex. Included in this category are polyarteritis nodosa, the eosinophilic granulomatosis with polyangiitis (formerly called Churg-Strauss syndrome of allergic bronchial asthma and eosinophilia), rheumatoid arthritis, lupus erythematosus, scleroderma, cryoglobulinemia, granulomatosis with polyangiitis, and the aforementioned idiopathic variety of vasculitis that is confined to the peripheral nerves and has no systemic manifestations. In Said’s series of 425 cases of vasculitis (2005) affecting the peripheral nerves, 24 percent were associated with polyarteritis nodosa, 23 percent with rheumatoid arthritis, and about 32 percent with other connective tissue diseases; in 21 percent there were no signs of vasculitis beyond the peripheral nerves. Elevation of the sedimentation rate, C-reactive protein and other serologic


Neurology_Adams

Neurology_Adams. with other connective tissue diseases; in 21 percent there were no signs of vasculitis beyond the peripheral nerves. Elevation of the sedimentation rate, C-reactive protein and other serologic abnormalities are typical features but not invariable of this group. The most recent addition to the diagnostic list has been a microscopic polyangiitis that is different from the vasculitis of medium-sized vessels that characterizes the remainder of the group. This subject has been reviewed by Collins, who summarizes guidelines for diagnosis.


Neurology_Adams

Neurology_Adams. Almost 75 percent of cases of polyarteritis nodosa include involvement of the small nutrient arteries of peripheral nerves (these figures come from autopsy series), but a symptomatic form of neuropathy develops in about half this number. Nevertheless, involvement of the peripheral nerves may be the principal or first sign of the disorder, before the main systemic components of the clinical picture—abdominal pain, hematuria, fever, eosinophilia, hypertension, vague limb pains, and asthma—have not fully declared themselves or have been misinterpreted.


Neurology_Adams

Neurology_Adams. Although characteristically a disease of multiple discrete mononeuropathies, the syndrome associated with polyarteritis nodosa may appear more or less generalized and symmetrical as a result of the accumulation of many small nerve infarctions; that is, it can simulate a polyneuropathy. In these cases, careful clinical and electrophysiologic examinations disclose elements of mononeuritis that have been engrafted on an otherwise generalized process. For example, an asymmetrical footor wrist-drop or a disproportionate affection of one nerve in a limb, such as ulnar palsy with relative sparing of function of the adjacent median nerve, are clues to the multifocal nature of the process. As often it takes form of random infarctions of two or more individual nerves. The onset is usually abrupt with symptoms of pain or numbness at a focal site along a nerve or in the distal distribution of an affected nerve, followed in hours or days by motor or sensory loss in the distribution of that nerve


Neurology_Adams

Neurology_Adams. symptoms of pain or numbness at a focal site along a nerve or in the distal distribution of an affected nerve, followed in hours or days by motor or sensory loss in the distribution of that nerve and then by involvement in a saltatory fashion of other peripheral nerves. Both the spinal and cranial nerves may be affected but far less often than the nerves in the limbs. Virtually no two cases are identical.


Neurology_Adams

Neurology_Adams. The CSF is usually normal. Nerve biopsy, usually taken from the sural nerve, will in most cases show the necrotizing arteritis in medium-size vessels (fibrinoid necrosis of all 3 coats of the vessel walls), with infiltrating eosinophils and occlusion of vessels. Muscle biopsy may also show perivascular inflammation and necrosis, but the diagnostic yield is less than for biopsy of a nerve, particularly if a sample is taken from a clinically affected nerve. On the basis of the smaller size of affected vessels and the presence of perinuclear antinuclear cytoplasmic autoantibodies (p-ANCA), Lhote and colleagues have differentiated a “microscopic” polyarteritis. Rapidly progressive glomerulonephritis and lung hemorrhage are the additional features of the latter disease, neuropathy occurring somewhat less frequently than in typical polyarteritis.


Neurology_Adams

Neurology_Adams. Treatment Based on the response to the systemic vasculitides with ANCA activity, mononeuritis multiplex caused by vasculitis has been treated with corticosteroids and either rituximab 375 mg/m2 weekly for 4 weeks, or cyclophosphamide 1 g/m2 intravenously once a month for several months, but other equivalent regimens have been suggested. For the corticosteroid regimen, we have used intravenous methylprednisolone, 1.5 mg/kg, for several days, followed by oral corticosteroid treatment. It appears from clinical experience that corticosteroids alone are often inadequate, but some clinicians have taken this approach initially. Azathioprine is a reasonable alternative if cyclophosphamide is not tolerated. Treatment usually must be continued for at least several months. In intractable cases and in those with systemic involvement, treatment with methotrexate may be indicated, or this may be used initially. Spontaneous remission and therapeutic arrest are known, but many cases have a fatal


Neurology_Adams

Neurology_Adams. in those with systemic involvement, treatment with methotrexate may be indicated, or this may be used initially. Spontaneous remission and therapeutic arrest are known, but many cases have a fatal outcome from kidney and systemic complications. The infarctive nerve palsies and sensory loss of the mononeuropathies generally persist to a large degree even when the systemic disease is brought under control.


Neurology_Adams

Neurology_Adams. Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss, Allergic Granulomatosis) and Hypereosinophilic Syndrome


Neurology_Adams

Neurology_Adams. These closely related systemic illnesses involve multiple individual peripheral nerves, much as in polyarteritis. A characteristic feature is the excess of circulating and tissue eosinophils (more so than in polyarteritis) and a tendency of the vasculitis to involve the lungs and skin, in contrast to the renal and bowel infarctions of polyarteritis nodosa. There is considerable degree of pathologic and clinical overlap between both polyarteritis and Churg-Strauss necrotizing vasculitis with the more benign hypereosinophilic syndrome that is less aggressive and has a greater tendency for eosinophilic infiltration of tissues other than nerve. One medication (zafirlukast, a leukotriene receptor antagonist) that has been used in Europe to treat asthma, has precipitated several cases of Churg-Strauss disease. Rarely, the overall illness has apparently been preceded by treatment with a macrolide antibiotic (e.g., azithromycin), estrogen, or carbamazepine, but these associations are


Neurology_Adams

Neurology_Adams. Churg-Strauss disease. Rarely, the overall illness has apparently been preceded by treatment with a macrolide antibiotic (e.g., azithromycin), estrogen, or carbamazepine, but these associations are uncertain and most cases are idiopathic.


Neurology_Adams

Neurology_Adams. In Churg-Strauss disease, rhinitis or asthma may be present for years and only later is there marked eosinophilia and organ infiltration, particularly an eosinophilic pneumonitis. The neuropathy that then develops in approximately three-quarters of patients is usually preceded by fever and weight loss and takes the form of an acute, painful mononeuritis multiplex. A granular cytoplasmic pattern of antineutrophil cytoplasmic autoantibodies (c-ANCA) of the same type that occurs in Wegener granulomatosis is found in more than half of cases (see below). The histologic feature in nerve biopsies is similar to polyarteritis nodosa, but the eosinophilic infiltration tends to be more intense. We have seen other types of cutaneous diseases with vasculitic mononeuritis, the most impressive being a massive leukocytoclastic vasculitis of the skin (necrotic polymorphonuclear cells surrounding venules) resulting in large confluent hemorrhagic lesions.


Neurology_Adams

Neurology_Adams. The idiopathic eosinophilic syndrome comprises a heterogeneous group of disorders, the common features of which are a persistent and extreme degree of eosinophilia and eosinophilic infiltration of many organ systems. Neuropathy occurs in fewer than half of the cases, taking the form of a painful diffuse sensorimotor syndrome with axonal damage or of a mononeuritis multiplex (see Moore et al). The pathologic appearance is one of diffuse infiltration of the nerves by eosinophils rather than a vasculitis. The neuropathic effects are attributable to the infiltration itself or to a postulated tissue-damaging effect of the eosinophilic cell.


Neurology_Adams

Neurology_Adams. Treatment Both the Churg-Strauss and the idiopathic hypereosinophilic syndrome are treated initially with high doses of corticosteroids, with which the peripheral eosinophilia, as well as tissue damage, may abate in several weeks or months. Further immunosuppressive treatment in the forms of rituximab as discussed previously, azathioprine, methotrexate, or cyclophosphamide has been used in fulminant or refractory cases, which includes most of the ones that we have seen.


Neurology_Adams

Neurology_Adams. This disorder gives rise to asymmetrical multiple mononeuropathy indistinguishable from the other angiopathic neuropathies described earlier and, probably based on the same mechanism, mononeuropathies of the lower cranial nerves directly as they exit the skull and pass through the retropharyngeal tissues. The frequency of peripheral nerve involvement in Wegener disease is much lower than in the other of classic vasculitides and the affected vessels are of a smaller caliber than in polyarteritis nodosa. Nonetheless, DeGroot and colleagues emphasized in a prospective analysis of 128 patients with Wegener disease that 25 had evidence of mononeuritis multiplex, with the peroneal nerve most often involved, and an even greater number had distal polyneuropathy; however, the proportion of their cases in which neuropathy was the presenting or sole manifestation of disease was higher than in other series. The finding of circulating c-ANCA is relatively specific for Wegener granulomatosis and


Neurology_Adams

Neurology_Adams. cases in which neuropathy was the presenting or sole manifestation of disease was higher than in other series. The finding of circulating c-ANCA is relatively specific for Wegener granulomatosis and for Churg-Strauss disease, as mentioned earlier (Specks et al), and helps to differentiate it from polyarteritis (which may be associated with p-ANCA) and from retropharyngeal carcinoma, chordoma, sarcoidosis, and herpes zoster. Wegener vasculitis as it affects the lower cranial nerves is discussed in Chap. 44.


Neurology_Adams

Neurology_Adams. Treatment is along the lines of corticosteroids and rituximab or cyclophosphamide as already discussed.


Neurology_Adams

Neurology_Adams. This process may be associated with a vasculitic mononeuritis multiplex as well as a more generalized polyneuropathy. In many cases, glomerulonephritis, arthralgia, and purpura are conjoined, reflecting the systemic nature of the vasculopathy, but the mononeuritis may occur in isolation. The evolution in the cases under our care has been slower than in the typical vasculitic neuropathies, sometimes taking weeks or months between attacks of mononeuropathy. The neurologic disorder may become quiescent for long periods, during which time considerable improvement may occur. There is no evident relationship between the mode of onset or severity of the neuropathy and the concentration of cryoprecipitable proteins in the serum. These proteins can be detected by cooling the serum and demonstrating a precipitation of IgG and IgM proteins that redissolve upon warming to 37°C (98.6°F). To demonstrate this phenomenon the blood sample must be carefully transported to the laboratory in a warm water


Neurology_Adams

Neurology_Adams. a precipitation of IgG and IgM proteins that redissolve upon warming to 37°C (98.6°F). To demonstrate this phenomenon the blood sample must be carefully transported to the laboratory in a warm water bath. An association of cryoglobulinemia with hepatitis C is well known, but many patients have had polyneuropathy from cryoglobulins but without the infection.


Neurology_Adams

Neurology_Adams. Treatment Garcia-Bragado and colleagues suggested that the neuropathy can be stabilized by corticosteroids and cyclophosphamide, but rituximab has been increasingly employed rather than cyclophosphamide and plasma exchange; the comparison between approaches has not been systematically tested. If the underlying problem is hepatitis C infection, pegylated alpha-interferon and ribavirin are usually administered as antiviral agents, with rituximab if the neuropathy is severe. It is too early to judge if the new protease inhibitors for the treatment of hepatitis C will reduce the occurrence and degree of polyneuropathy. Other aspects of the condition are discussed further under “Polyneuropathy Associated with Paraproteinemia” and “Other Vasculitic Neuropathies.”


Neurology_Adams

Neurology_Adams. Some 1 to 5 percent of patients with rheumatoid arthritis have vasculitic involvement of one or more nerves at some time in the course of their disease, apart from more mundane pressure neuropathies as a result of thickened tendons and destructive joint changes. The arteritis is of small-vessel fibrinoid type and immune globulins are demonstrable in the walls of vessels. Most of the affected patients under our care have had severe rheumatic disease for many years and were strongly seropositive (see Pallis and Scott). In addition to the neuropathy, such patients often have rheumatoid nodules, skin vasculitis, weight loss, and fever. There are rarer forms of chronic progressive polyneuropathy that complicate rheumatoid arthritis; they are described further on.


Neurology_Adams

Neurology_Adams. Approximately 10 percent of patients with lupus exhibit symptoms and signs of peripheral nerve involvement, but only a negligible number occur before the established and more advanced stages of the disease (i.e., rarely has it been the initial presentation). In our several patients, the polyneuropathy has taken the form of a symmetrical, progressive sensorimotor paralysis, beginning in the feet and legs and extending to the arms, evolving over a period of several days or weeks, thereby simulating GBS. In a few, weakness and areflexia were more prominent than the sensory loss; the latter involved mainly vibratory and position senses. A more common syndrome in our experience has been a progressive or relapsing disease that cannot be distinguished clinically from chronic inflammatory demyelinating polyneuropathy (discussed further on). Multiple mononeuropathies have also been reported, as has involvement of the autonomic nervous system. An elevation of CSF protein that is found in some


Neurology_Adams

Neurology_Adams. polyneuropathy (discussed further on). Multiple mononeuropathies have also been reported, as has involvement of the autonomic nervous system. An elevation of CSF protein that is found in some instances suggests nerve root involvement. Sural nerve biopsies may show vascular changes consisting of endothelial thickening and mononuclear inflammatory infiltrates in and around the small vessels for which reason the disease is included here with the other vasculitic neuropathies. Axonal degeneration is the most common change, but a chronic demyelinating pathology has also been described (Rechthand et al). Vascular injury from deposition of immune complexes is the proposed mechanism of nerve damage.


Neurology_Adams

Neurology_Adams. In contrast to the aforementioned disorders, which involve several tissues and organs in addition to the peripheral nerves, necrotizing vasculitis may be limited to the peripheral nerves. Cases of this type appear as often as all the other systemic vasculitic types together. This restricted form of mononeuritis multiplex usually presents as a subacute symmetrical or asymmetrical polyneuropathy with superimposed mononeuropathies or solely with multiple mononeuritis. Circulating antineutrophil cytoplasmic antibody (ANCA) is found in a few cases, but other tests for inflammatory and connective tissue diseases are negative. In the series reported by Collins and colleagues (2003), the sedimentation rate was mildly elevated, the mean being 38 mm/h, with only one-quarter having values greater than 50 mm/h. The main diagnostic difficulty in diagnosis arises when the EMG performed early in the course of illness shows conduction block that simulates a demyelinating polyneuropathy. Nerve biopsy


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Neurology_Adams. 50 mm/h. The main diagnostic difficulty in diagnosis arises when the EMG performed early in the course of illness shows conduction block that simulates a demyelinating polyneuropathy. Nerve biopsy should then settle the issue.


Neurology_Adams

Neurology_Adams. Treatment The neuropathy tends to be less aggressive (and nonlethal) than the systemic forms of vasculitic neuropathy and has usually responded to corticosteroids without treatment with cyclophosphamide. However, in the aforementioned series reported by Collins, the use of cyclophosphamide for 6 months with corticosteroids resulted in a more rapid remission and fewer relapses. An expert group has provided guidelines for treatment specifically of this condition that approximates this approach by adding an immunosuppressive agent to corticosteroids only if the disease behaves aggressively (Collins et al, 2010).


Neurology_Adams

Neurology_Adams. In the past, administration of pooled serum for the treatment of various infections led to brachial plexus neuritis or to an immune mononeuropathy multiplex, presumably from deposition of antibody–antigen complexes in the walls of the vasa nervorum. A similar “serum sickness” reaction occurred after certain viral infections associated with arthritis, rash, and fever. The neuropathy that arises with hepatitis C infection may be of this type, perhaps mediated by the frequently associated cryoglobulinemia as mentioned earlier. Interferon, which has been effective in treating the hepatitis, may also ameliorate the neuropathy, but greater success has been achieved with cyclophosphamide. Pooled immunoglobulin for the treatment of diverse neuromuscular diseases such as Guillain-Barré syndrome and myasthenia gravis has not, to our knowledge, led to a serum-sickness neuropathy, but one of our patients with Churg-Strauss disease developed a fulminating vasculitic skin eruption while being


Neurology_Adams

Neurology_Adams. and myasthenia gravis has not, to our knowledge, led to a serum-sickness neuropathy, but one of our patients with Churg-Strauss disease developed a fulminating vasculitic skin eruption while being treated with IVIg.


Neurology_Adams

Neurology_Adams. In 2 cases of severe systemic vasculitis related to administration of hydralazine, we observed no neuropathic features; whether this applies to other drug-induced vasculitides is not known. Minocycline is another drug that has been associated in rare instances with a vasculitis, including mononeuropathies. The increasing appearance of vasculitic neuropathy with HIV infection, including a type that is independent of CMV infection, has already been mentioned; such cases have tended to improve spontaneously or with corticosteroid therapy. In about half of these cases the CSF contains polymorphonuclear cells. From time to time a patient with a lymphoproliferative disorder such as Hodgkin disease will develop mononeuritis multiplex that is found by biopsy to be caused by vasculitis. (A chronic demyelinating, nonvasculitic polyneuropathy is more common with lymphomas of any type as discussed earlier.)


Neurology_Adams

Neurology_Adams. A rare paraneoplastic variety of vasculitic neuropathy has also been described. Oh reported 2 of his patients and reviewed 13 previous ones. The most common underlying cancer was of the small oat cell lung type. Anti-Hu antibodies that are typical of paraneoplastic neurologic diseases from this cancer are generally not detected (see Chap. 31). Other solid tumors (renal, gastric, gynecologic) have been associated with a similar neuropathy but only in a few instances. Almost all have had slightly elevated protein concentration in the CSF but few showed a pleocytosis. At autopsy, the vasculitis was limited to nerve and muscle.


Neurology_Adams

Neurology_Adams. The role of an obscure small-vessel vasculitis in otherwise idiopathic axonal polyneuropathies of elderly patients has been reported, but is in our view, controversial. We have not found, as did Chia and colleagues, an unexpected vasculitis in the nerve biopsies of such patients. The vasoocclusive and infiltrative condition of intravascular lymphoma often includes a syndrome of multiple painless mononeuropathies as part of a larger multifocal illness of the central and peripheral nervous system. Neuropathy of Critical Limb Ischemia


Neurology_Adams

Neurology_Adams. A few patients with severe atherosclerotic ischemic disease of the iliac or leg arteries will be found to have localized sensory changes or diminished reflexes. Usually, the other effects of ischemia—claudication and pain at rest, absence of distal pulses and trophic skin changes—are so prominent that the neurologic changes are minor by comparison. In experimental studies, combined occlusion of the aorta and multiple limb vessels are required to produce neural ischemia because of the profusely ramifying vasculature. In our experience of 12 patients with a critically ischemic leg, there was a neuropathy with a pronounced distal predominance; sensory loss in the feet was worse than the symptoms might suggest and there was mild weakness of the toes and depression or loss of the ankle reflex (Weinberg et al). Although paresthesias, numbness, and deep aching pain at rest were characteristic, the patients were more limited by symptoms of their vascular claudication than by the neuropathic


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Neurology_Adams. (Weinberg et al). Although paresthesias, numbness, and deep aching pain at rest were characteristic, the patients were more limited by symptoms of their vascular claudication than by the neuropathic ones. Restoration of circulation to the limb by surgical or other means resulted in some improvement of the regional neuropathy. Reviews of the literature on this subject can be found in the writings of Eames and Lange.


Neurology_Adams

Neurology_Adams. A poorly understood but presumably localized ischemic neuropathy occurs in the region of arteriovenous shunts (fistulas) that have been placed for the purpose of hemodialysis. Complaints of transient diffuse tingling of the hand are not uncommon soon after creation of the shunt but only a few patients develop persistent forearm weakness, numbness and burning in the fingers, reflecting variable degrees of ulnar, radial, and median nerve, and possibly also muscle, ischemia. The role of an underlying uremic polyneuropathy in facilitating this neuropathy has not been studied.


Neurology_Adams

Neurology_Adams. A progressive, symmetrical polyneuropathy as a result of systemic cholesterol embolism has been described by Bendixen and colleagues. An inflammatory and necrotizing arteritis surrounds embolic cholesterol material within small vessels and appears to account for the progression of symptoms. This neuropathic process is more often discovered at autopsy than it is in the clinic, being eclipsed during life by the cerebral manifestations of cholesterol embolism. The peripheral part of the illness simulates the polyneuropathy of a small-vessel polyarteritis.


Neurology_Adams

Neurology_Adams. The generalized granulomatous disease of sarcoidosis infrequently produces subacute or chronic polyneuropathy, polyradiculopathy, or mononeuropathies. A painful, small-fiber sensory neuropathy has also been described by Hoitsma and colleagues. Any of the neuropathies may be associated with granulomatous lesions in muscles (polymyositis) or with signs of CNS involvement, most often of the stalk of the pituitary with diabetes insipidus or a myelopathy (see Chap. 31).


Neurology_Adams

Neurology_Adams. Involvement of a single nerve with sarcoid most often implicates the facial nerve (facial palsy), but sometimes multiple cranial nerves are affected in succession (see Chaps. 35 and 44). Next in frequency is weakness and reflex and sensory loss, appearing sequentially (polyradiculopathy), in the distribution of several spinal nerves or roots. The occurrence of large, irregular zones of sensory loss over the trunk is said to distinguish the neuropathy of sarcoidosis from other forms of mononeuropathy multiplex. This pattern particularly when accompanied by pain, resembles diabetic radiculopathy (see earlier in “Diabetic Multiple Mononeuropathies and Radiculoplexus Neuropathy”).


Neurology_Adams

Neurology_Adams. Unlike the cases of sarcoid polyneuropathy we have reported (Zuniga et al), in the series of 11 patients with sarcoid neuropathy studied by Said and colleagues (2002), only 2 were known to have pulmonary granulomas before the onset of neuropathic symptoms; 6 had a focal or multifocal neuropathic syndrome (including 1 with a clinical and electrophysiologic pattern that simulated multifocal conduction block). The remainder had a nonspecific symmetric polyneuropathy, 1 of which had an acute onset. Facial diplegia was common in sarcoid, as is well known. The pathologic changes in nerve and muscle biopsy specimens consisted mainly of epineurial granulomas and endoneurial inflammatory infiltrates, but there were indications of necrotizing vasculitis in 7 cases. Among the cases we studied, 6 of 10 had a subacute or chronic sensorimotor polyneuropathy. It is notable that in only 2 of Said’s patients were levels of angiotensin-converting enzyme elevated in the serum.


Neurology_Adams

Lyme Neuropathies (See Also Chap. 31)

Neurology_Adams. Lyme Neuropathies (See Also Chap. 31)


Neurology_Adams

Neurology_Adams. The neuropathy that develops in 10 to 15 percent of patients with this disease takes several forms. Cranial nerve involvement is well known, unior bilateral facial palsy being by far the most frequent manifestation. Other cranial nerves may also be affected as may almost any of the spinal roots, mostly in the cervical or lumbar region. Even phrenic nerve palsy has been attributed to Lyme disease in a few cases. A concurrent mild or moderate aseptic meningoradiculitis (10 to 100 mononuclear cells/mm3) is characteristic (although this may also occur in HIV and CMV and other forms of neuritis). The CSF glucose is usually normal but has been slightly depressed in a few cases with multiple radiculopathies. Some of the CSF cells may have immature features suggesting a lymphomatous infiltration. (See further on and Chap. 31 for further details of the laboratory diagnosis.) There may be radicular pain not unlike that of cervical or lumbar disc or plexus disease.


Neurology_Adams

Neurology_Adams. The triad of cranial nerve palsies, radiculitis, and aseptic meningitis is most characteristic of Lyme disease during its disseminated phase, that is, from 1 to 3 weeks after the tick bite or from the appearance of the typical rash. The disease tends to be seasonal in the period of maximal tick exposure. The special polyradiculitis form of Lyme is discussed further on.


Neurology_Adams

Neurology_Adams. Besides the just described cranial neuropathies, the following are the main neuropathic syndromes of Lyme disease: (1) multiple mononeuropathies (involvement of a single major nerve in the limbs, resulting in an isolated footor wrist-drop—a distinctly rare pattern, or a thoracoor lumbar mononeuropathy causing sagging of the innervated body part); (2) lumbar or brachial plexopathy (the latter being well described but rare); (3) a predominantly sensory polyneuropathy in which paresthesias and loss of superficial sensation in the feet and legs are coupled with loss of ankle jerks; (4) a generalized axonal polyneuropathy (Loggigian et al), mainly sensory and sometimes accompanied by a mild encephalopathy; and (5) acute GBS (we have encountered only 2 such cases in more than 400 patients with Guillain-Barré but the syndrome appears to be more common in Europe following Borrelia infection).


Neurology_Adams

Neurology_Adams. Electrophysiologic testing indicates that the various peripheral nerve syndromes frequently overlap. All of the preceding processes excepting the one that resembles GBS usually occur as subacute or late complications of Lyme disease, several months or, rarely, years after the initial infection (in untreated cases). These late neuropathic syndromes respond less favorably to treatment than do the acute ones, and have a less certain connection to the infection (see further on). As the disease is not fatal, there are few adequate pathologic studies of the peripheral nerves in Lyme disease. The infective agent has not been demonstrated in nerve tissue, but perivascular inflammation and vasculitic changes are found in small vessels within the nerves.


Neurology_Adams

Neurology_Adams. Lyme polyradiculitis and Bannwarth syndrome This is perhaps the best characterized, but not the most common, group of Lyme neuropathies. A painful lumbosacral polyradiculitis has been described in Europe by the term Bannwarth syndrome (in France as Garin-Bujadoux syndrome). The pathogen in Europe is a Borrelia spirochete slightly different from the one that causes Lyme disease in North America. In Bannwarth syndrome there is an intense inflammatory reaction in the cauda equina, giving rise to sciatic and buttock pain and bladder dysfunction. Less frequently, a cervical polyradiculopathy occurs with shoulder and arm pain that cannot be distinguished on clinical grounds from brachial neuritis. Cases of


Neurology_Adams

Neurology_Adams. Bannwarth syndrome from North American Lyme under our care have progressed subacutely over days or weeks and involved the L2-L3-L4 roots, first one leg, then the other, and, subsequently, the midcervical roots on one or both sides. Sparing of a proximal or distal part of a limb while the adjacent part is weakened gives rise to a striking syndrome. One or more thoracic radiculopathies may be added and cause local discomfort.


Neurology_Adams

Neurology_Adams. The nerve conduction tests show preservation of sensory potentials, which marks the process as radicular. Headache and a marked pleocytosis (over 100 mononuclear cells/mm3) in the spinal fluid may accompany the pain and usually precedes the radiculopathies by days. Polymerase chain reaction for the detection of the organism in the CSF gives variable results, especially after several days of neurologic illness. A value above unity of CSF to serum anti-Lyme antibodies is probably a dependable indicator of acute or subacute disease, but there have been few systematic studies of this measurement. Oligoclonal bands in the CSF are common as a reflection of these antibodies. A similar syndrome of lumbar polyradiculitis may also be caused by the herpes and Epstein-Barr viruses or more often by an opportunistic CMV infection in a patient with AIDS.


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Neurology_Adams. A similar syndrome of lumbar polyradiculitis may also be caused by the herpes and Epstein-Barr viruses or more often by an opportunistic CMV infection in a patient with AIDS. Diagnosis This is both aided and at times confused by serologic testing (see Chap. 31). The enzyme-linked immunosorbent assay (ELISA) is not altogether satisfactory because it frequently yields false-positive and, occasionally, false-negative results. Western blot testing of CSF is more specific. Information to the effect that the patient has lived in or visited an endemic area is useful, but far more compelling is evidence of a tick bite followed by the characteristic rash, or a well-defined history of nonneurologic manifestations of Lyme disease (cardiac, arthritic). Bifacial palsy in any of these clinical contexts also favors the diagnosis of Lyme.


Neurology_Adams

Neurology_Adams. Treatment Treatment of the Lyme neuropathic syndromes is with intravenous antibiotics, preferably ceftriaxone 2 g daily for 1 month. More prolonged or intravenous treatment has not been shown to be superior. Corticosteroids have an uncertain role in the painful radicular syndromes, but we have used them in low doses and they relieved pain. In most series, there is recovery or virtually complete resolution of radicular symptoms in approximately 90 percent of patients, although this may take months. Facial palsies also tend to improve, but with a lower rate of complete resolution. It has been stated that many of the peripheral and cranial neuropathies improve even without treatment, but this has not been studied systematically.


Neurology_Adams

Neurology_Adams. This is a chronic, slowly progressive autoimmune disease characterized by lymphocytic infiltration of the exocrine glands, particularly the parotid and lacrimal glands, that results in keratoconjunctivitis sicca and xerostomia (dry eyes and mouth). These core features may be combined with arthritis or with a wide range of other abnormalities, notably lymphoma, vasculitis, IgM paraproteinemia, renal tubular defects (renal tubular acidosis), and, quite often, a predominantly sensory polyneuropathy (see review by Kaplan et al). In the series collected by Grant and colleagues, the neuropathy was the presenting problem in 87 percent of 54 patients with Sjögren disease. The sicca symptoms are often mild and reported only upon specific inquiry. A symmetrical sensory polyneuropathy or a sensory ganglionopathy are the most common patterns. Sensorimotor polyneuropathy, polyradiculoneuropathy, autonomic neuropathy, or mononeuropathy (most often of the trigeminal nerve, as described by Kaltrieder


Neurology_Adams

Neurology_Adams. are the most common patterns. Sensorimotor polyneuropathy, polyradiculoneuropathy, autonomic neuropathy, or mononeuropathy (most often of the trigeminal nerve, as described by Kaltrieder and Talal) are less common. We have observed yet another neuropathic syndrome taking the form of asymmetrical sensory loss, mostly of position sense and involving the upper limbs predominantly, in association with tonic pupils and trigeminal anesthesia that is probably a variant of the ganglionopathy.


Neurology_Adams

Neurology_Adams. The sensory polyneuropathies of the Sjögren syndrome are of particular interest to neurologists, as they will encounter most cases before other physicians (Griffin et al). More than 80 percent of affected patients are older women. The polyneuropathic syndrome often begins with paresthesias of the feet, usually mild in degree. The main clinical features are subacute and widespread sensory loss that may include the trunk and sometimes, profoundly diminished kinesthetic sense, giving rise to sensory ataxia of the limbs and of gait that reflect a ganglionitis. Loss of pain and temperature sensation is variable; tendon reflexes are abolished. A nondescript largeor small-fiber distal sensory neuropathy is also known, for which reason testing for Sjögren-related serum antibodies is included in the general evaluation of polyneuropathies in older patients, and the heterogeneity of sensory neuropathy presentation has been emphasized by several authors. In time, some patients develop autonomic


Neurology_Adams

Neurology_Adams. the general evaluation of polyneuropathies in older patients, and the heterogeneity of sensory neuropathy presentation has been emphasized by several authors. In time, some patients develop autonomic abnormalities such as bowel atony, urinary retention, loss of sweating, and pupillary changes. There is usually little or no pain, but there have been exceptions.


Neurology_Adams

Neurology_Adams. Diagnosis Sjögren disease–associated neuropathy or ganglionopathy should be suspected in an older woman with sensory neuropathy or neuronopathy, particularly if sicca symptoms are present. There may be telangiectasias over the bridge of the nose, on the lips, and fingers. The evaluation is aided by the Schirmer and Rose Bengal tests, which usually demonstrate a reduction of tearing. Even without this confirmatory test, we have found it advisable to perform a biopsy of the lip (at the epithelial–mucosal juncture) to detect inflammatory changes in the small salivary glands. This is a minor office procedure in most instances. The diagnosis of Sjögren syndrome from the biopsy requires at least 2 collections of 50 or more lymphocytes in a 4-mm2 specimen. Some patients have serologic abnormalities such as antinuclear antibodies (anti-Ro, also termed SS-A, and anti-La, or SS-B) or monoclonal immunoglobulins, particularly of the IgM subclass. The frequency of specific Sjögren-specific


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Neurology_Adams. such as antinuclear antibodies (anti-Ro, also termed SS-A, and anti-La, or SS-B) or monoclonal immunoglobulins, particularly of the IgM subclass. The frequency of specific Sjögren-specific antibodies varies between series; they may be useful as screening tests, but the lip biopsy appears to be more sensitive. In our series of 20 cases with minor salivary gland biopsies that demonstrated inflammatory changes diagnostic of the syndrome, only 6 had serologic evidence of the disease and 2 had positive serologic tests but a negative biopsy (Gorson and Ropper, 2003). The sedimentation rate in our patients was often slightly elevated; however, only 5 of our 20 had a value greater than 40 mm/min and many have had normal or only slightly elevated C-reactive protein levels. The main differential diagnostic entity, if the neuropathy appears subacutely, is a paraneoplastic sensory ganglionitis.


Neurology_Adams

Neurology_Adams. Mellgren and also Leger and their colleagues have stressed that a proportion of unexplained polyneuropathies in middle and late life are putatively caused by Sjögren syndrome. The latter authors found typical Sjögren abnormalities in the lip biopsies of 7 of 32 patients with chronic axonal polyneuropathy that could not otherwise be classified. Several other studies have corroborated this finding of inflammatory disruption of the minor salivary glands in obscure neuropathies, particularly in older women and in some men. The diagnosis in our clinics has not been nearly as frequent in this group. Nonetheless, a search for Sjögren disease may be revealing in otherwise obscure sensory neuropathies.


Neurology_Adams

Neurology_Adams. Nerve biopsies have variably revealed necrotizing vasculitis, inflammatory cell infiltrates, and focal nerve fiber destruction. Usually, the CSF protein is normal and there is no cellular reaction. The few times a dorsal root ganglion has been examined in autopsy material; there were infiltrates of mononuclear cells and lymphocytes and destruction of nerve cells. Treatment Corticosteroids in doses of approximately 60 mg daily of prednisone, cyclophosphamide (100 mg per day), and rituximab (1,000 mg per day, 2 weeks apart) have been used when the neuropathy is severe and are indicated when there is vasculitis involving renal and pulmonary structures. We have initially administered prednisone 60 mg daily, sometimes in tandem with intermittent plasma exchange, but with little evidence of response, before adding a second immunosuppressive agent. The review of the neurologic manifestations of Sjögren syndrome by Lafitte and by Berkowitz and colleagues are recommended.


Neurology_Adams

Neurology_Adams. In addition to the subacute pansensory syndrome described previously and paraneoplastic, postinfectious, and toxic processes, there is a yet another more chronic idiopathic syndrome characterized by severe global sensory loss and ataxia. We have encountered several such patients resembling the cases described by Dalakas. The numbness and sensory findings progressed over months and spread to proximal parts of the arms and legs and then to the trunk. The face and top of the scalp were finally involved. Despite ataxia and complete areflexia, muscular power remained normal and pain was not a problem. There are reports of fasciculations in a few patients, but not in the ones we have seen. Within a year, most of these patients became completely disabled from the ataxia, unable to walk or even feed themselves. Autonomic failure was another feature in a few and one of our patients became deaf. Extensive examinations for an occult cancer, paraproteinemia, Sjögren disease, Refsum disease,


Neurology_Adams

Neurology_Adams. feed themselves. Autonomic failure was another feature in a few and one of our patients became deaf. Extensive examinations for an occult cancer, paraproteinemia, Sjögren disease, Refsum disease, autoimmune diseases, and all potential causes of an ataxic neuropathy proved to be frustratingly negative. Of course, it is possible that some patients had an as yet undiscovered tumor. Yet other instances have had all the features of a truncal–limb sensory neuropathy, with little or no ataxia and only muted reflexes; these have had a more benign course but still no cause was found (Romero et al). Illa and colleagues (2001), in a review of 17 patients with idiopathic sensory ataxic neuropathy, found antibodies against the ganglioside GD1 in only 1 case and concluded that the majority was not caused by an immunologic mechanism.


Neurology_Adams

Neurology_Adams. The motor nerve conduction studies have been normal or slightly impaired, while the sensory potentials were eventually lost (but they may at first be normal). A puzzling feature in 2 patients has been an unexpected preservation of many sensory nerve potentials even after a year of illness. In these cases, the process presumably lay in the dorsal roots rather than in the ganglia. In a few instances the MRI has shown a change in the posterior columns of the spinal cord, certainly as a secondary phenomenon from the spinal nerve and root disease. The spinal fluid has generally contained a slightly elevated protein concentration with few or no cells, up to 18/mm3 in our cases. Pathologic examination of the sensory ganglia in a few cases has disclosed an inflammatory process identical to that of Sjögren disease. Our attempts at treatment using plasma exchanges, IVIg, corticosteroids, and immunosuppressive agents have been mostly unsuccessful.


Neurology_Adams

Neurology_Adams. Also mentioned here is a subacute or chronic idiopathic small-fiber ganglionopathy that affects function primarily. These patients complain of pain and burning in proximal body parts, including the face, tongue, and scalp with reduced sensation of pinprick in affected areas. The reflexes may be preserved and vibration sensory perception may be preserved. Our experience with such patients and anecdotal responses to treatment was summarized by Gorson and colleagues (2008). Whether such aberrant proximal sensory complaints as “burning mouth syndrome” (see Chap. 9) are allied with this entity is not clear but they may occur together.


Neurology_Adams

Neurology_Adams. Under this term is collected a group of subacute and chronic dysautonomias that on extensive evaluation cannot be attributed to diabetes, amyloidosis, autoimmune disease, Fabry disease, HIV, toxin exposure, or another systemic disease. A few cases will be found to be due to one of several rare mutations in genes, of which four sites have been described so far (SPTLC1, HSN2, IKBKAP, NTRK1). A number of such cases, almost half in the series of Suarez and colleagues (1994), have been acute in onset and conform most closely to the “pure pandysautonomia” condition described by Young and colleagues, discussed earlier as a variant of Guillain-Barré syndrome. The others follow a subacute or chronic course and about one-fourth of these have a serum antibody that is directed against the acetylcholine receptor of sensory ganglia (Klein et al).


Neurology_Adams

Neurology_Adams. Orthostatic hypotension is the leading feature; in those with the previously mentioned antibody, pupillary changes and difficulty with accommodation, dry mouth and dry eyes, and gastrointestinal paresis were the most common findings according to Sandroni and colleagues. Perhaps a subgroup is in some way related to Sjögren syndrome as sicca symptoms are prominent, but these later features could just as well be a component of the autonomic failure. There is not enough information to determine if all these cases are accounted for by one process or to judge the effects of various immune treatments.


Neurology_Adams

Neurology_Adams. The defining features of this unusual syndrome are searing and pulling sensations involving small cutaneous areas, that are evoked by extending or stretching the limb, as happens when reaching for an object, kneeling, or pointing with the foot (see Wartenberg). The pain is momentary but leaves in its wake a patch of circumscribed numbness. Cutaneous sensory nerves must be involved in some way and are irritated during such mechanical maneuvers. The areas involved are usually proximal to the most terminal sensory distribution of nerves encompassing, for example, a patch on the lateral side of the hand and the proximal fifth finger or a larger region over the patella (these were the sites affected in 3 of our patients). Recovery of the area of numbness takes several weeks, but it may persist if the symptoms are induced repeatedly. Except for these patches of cutaneous analgesia, the clinical examination is normal. Selected sensory nerves may show abnormalities in conduction, but nerve


Neurology_Adams

Neurology_Adams. if the symptoms are induced repeatedly. Except for these patches of cutaneous analgesia, the clinical examination is normal. Selected sensory nerves may show abnormalities in conduction, but nerve conduction studies are for the most part normal. Matthews and Esiri have listed the many areas that may be affected in a single patient and have described an increase in the endoneurial connective tissue in a biopsied sural nerve. The syndrome may come in episodes over many years, without symptoms between attacks. A spurious diagnosis of multiple sclerosis is often made. The pathology is not certain, but some form of fibrosis or inflammation of cutaneous nerves has been suggested, perhaps similar to the condition of perineuritis described below.


Neurology_Adams

Neurology_Adams. Under this title, Asbury and colleagues (1972) described a patchy, burning, painful, partially remitting distal cutaneous sensory neuropathy. The pathologic picture was one of inflammatory scarring restricted to the perineurium, with compression of the contained nerve fibers. As with the Wartenberg syndrome above, reflexes and motor function were unaffected. Digital nerves, as well as the medial and lateral branches of the superficial peroneal nerve, were the ones most often involved. Matthews and Squier have described a trigeminal and occipital distribution of painful sensory symptoms and 1 of the patients of Asbury and coworkers (1972) also had symptoms on the scalp. A Tinel sign is characteristically elicited by tapping the skin overlying the involved cutaneous nerves and is indicative of partial nerve damage and regeneration.


Neurology_Adams

Neurology_Adams. The differential diagnosis includes numerous other forms of painful sensory neuropathy, but the patchy and painful, and often burning, quality of symptoms distinguishes this process. The diagnosis can only be established with certainty by biopsy of a distal cutaneous branch of a sensory nerve. Perhaps some of the large group of patients with “burning” feet may have a small-fiber neuropathy that affects intradermal nerve fibers in a similar way (see further on).


Neurology_Adams

Neurology_Adams. Since the original report, the fibrosing perineurial pathologic changes that characterize perineuritis have been described in a number of polyneuropathies, mainly in diabetic patients but also in those with cryoglobulinemia, nutritional diseases, and malignancies (Sorenson et al). However, these patients displayed diverse clinical patterns of neuropathy, mainly mononeuritis multiplex and demyelinating neuropathy. Nonetheless, the pathologic feature of perineuritis may be less specific than initially thought but a perineuritis clinical syndrome is still a useful concept. A proportion of the idiopathic cases seem to respond to corticosteroids.


Neurology_Adams

Neurology_Adams. Among the multitude of odd neurologic manifestations attributed to this disease, the best known ones are cerebellar ataxia and myoclonus. In addition, Hadjivassiliou and colleagues have reported patients with a range of neuromuscular disorders in whom the neurologic symptoms antedated the diagnosis of the bowel disorder. A nondescript sensorimotor neuropathy was the most frequent, but one patient had mononeuropathy multiplex and Chin and colleagues have reported a multifocal neuropathy pattern. In a small prospective survey of treated celiac disease, Luostarinen and colleagues found 23 percent with evidence of a polyneuropathy by nerve conduction testing, but the clinical findings were scant. Antigliadin antibodies (simple antibodies directed against gluten), as well as more specific anti-transglutaminase antibodies and histologic examination of a duodenal biopsy are confirmatory of the diagnosis. Luostarinen and colleagues suggested that a search be made for these antibodies in


Neurology_Adams

Neurology_Adams. anti-transglutaminase antibodies and histologic examination of a duodenal biopsy are confirmatory of the diagnosis. Luostarinen and colleagues suggested that a search be made for these antibodies in patients with polyneuropathies of obscure origin. It is not clear how many of their cases could be attributed to nutritional deficiency. We have not encountered a definite instance despite attempts to detect the special sprue antibodies in the evaluation of over 200 cases of otherwise obscure polyneuropathy.


Neurology_Adams

Neurology_Adams. Neuropathies Associated With HIV (See Also Chap. 32) Patients infected with HIV are prone to several types of neuropathies, including a predominantly sensory type that may be painful, a lumbosacral polyradiculopathy, cranial (mainly facial nerve) and limb mononeuropathies, CIDP, GBS, and a vasculitic mononeuritis multiplex—none of which differs from the idiopathic or conventional varieties except that there is often a pleocytosis in the spinal fluid. Almost unique and common patterns in this group are the CMV cauda equina neuritis syndrome and an acute or subacute painful infiltrative lymphocytic neuropathy—the diffuse infiltrative lymphocytosis syndrome (DILS; Moulingier et al). Polyneuropathy may also be induced by antiviral agents that are used in the treatment of HIV infection, as discussed in Chap. 32.


Neurology_Adams

Neurology_Adams. These are among the most clinically complex diseases of the peripheral nerves. Involvement of multiple spinal nerve roots produces a distinctive or sometimes confusing constellation of findings, usually quite different from those of polyneuropathy and from multiple mononeuropathies. As described earlier, muscle weakness caused by polyradiculopathy is characteristically asymmetrical and variably distributed in proximal and distal parts of the limbs, reflecting a pattern of muscles that share common root innervations (e.g., the combination of weakness in hamstring and gastrocnemius, or of iliopsoas, quadriceps, and obturator). However, muscles with similar innervation are not necessarily affected to the same degree because of the disproportionate contribution of a given root to each muscle. Sensory loss tends also to be patchy and to involve both the proximal and distal aspects of a dermatome. Pain is common in a radicular pattern, but sometimes only in the distal distribution of the


Neurology_Adams

Neurology_Adams. Sensory loss tends also to be patchy and to involve both the proximal and distal aspects of a dermatome. Pain is common in a radicular pattern, but sometimes only in the distal distribution of the root or in the back. The sensory findings tend to be less prominent than the motor ones. In keeping with nerve root pattern, certain tendon reflexes may be spared; a normal ankle jerk combined with an absent knee jerk, or the opposite, are particularly suggestive of a polyradiculopathy (or a lumbar plexopathy). Pain often takes the form of sharp jabs projected into the innervated zone of the involved root. As with mononeuritis multiplex, the cumulative effect of multiple root lesions can simulate a polyneuropathy in which case the tendency for polyradiculopathy to involve proximal muscles is the most helpful distinguishing feature.


Neurology_Adams

Neurology_Adams. A special pattern of polyradiculopathy occurs wherein all the sensory roots are involved, simulating tabes dorsalis. The clinical state is similar to that of a sensory ganglionopathy described earlier. Largeand small-fiber sensory loss is combined with ataxia while power is normal and there is no atrophy. A prominent feature is shooting and burning pain. We have occasionally found sensory loss over the anterior abdomen and thorax in these cases, a finding more typical of chronic dying-back axonal polyneuropathy.


Neurology_Adams

Neurology_Adams. Some of the diseases that affect nerve roots predominantly already have been discussed. They can be grouped into three broad categories: (1) diseases of the spinal column that compress adjacent roots; (2) infiltrative diseases of the meninges that secondarily involve the roots as they course through the subarachnoid space, mainly neoplastic of granulomatous infiltrations such as sarcoid; and (3) intrinsic neuropathies, inflammatory, infectious, or diabetic, that have a predilection for the radicular portion of the nerves. An elevated CSF protein and a pleocytosis usually accompany neoplastic or inflammatory meningeal diseases; the others show variable formulas in the spinal fluid.


Neurology_Adams

Neurology_Adams. Often what appears to be a polyneuropathy on clinical grounds will be found to have an electrophysiologic pattern of root disease at multiple spinal levels. McGonagle and colleagues estimated that polyradiculopathies accounted for 5 percent of all cases referred to their EMG laboratory and our experience approximates this. Consequently, careful EMG and nerve conductions testing is the most useful ancillary examination in cases of complex neuropathic syndromes because the pattern of muscle denervation can be ascertained with greater certainty than by clinical means and a common root pattern can then be logically derived. Of great confirmatory value is the preservation of sensory potentials in nerves that innervate regions of sensory loss and supply weak and denervated muscles. This proves that the lesion is located proximal to the dorsal root ganglion and spares the peripheral sensory axons. Loss of the F and H late responses is also typical of polyradiculopathies. The proximal


Neurology_Adams

Neurology_Adams. proves that the lesion is located proximal to the dorsal root ganglion and spares the peripheral sensory axons. Loss of the F and H late responses is also typical of polyradiculopathies. The proximal location of the lesion can be further corroborated by early evidence of weakness and denervation in the paraspinal, gluteal, or rhomboid muscles, which are supplied by nerves that arise very proximally from the roots. In axonal cases of neuropathy, these proximal muscles are the last to be involved.


Neurology_Adams

Neurology_Adams. Among the acute and subacute meningeal radiculopathies, neoplastic infiltration (carcinomatous and lymphomatous) is the most common. Others are Lyme disease, sarcoidosis, herpes virus, arachnoiditis, AIDS-related cauda equina neuritis of CMV infection, or independently, EBV meningoradiculitis. In the past, meningeal syphilis, of course, was a common cause (tabes dorsalis). Diseases of the spine, exemplified by lumbar and cervical spondylosis, commonly impinge on nerve roots, as discussed in Chap. 10. Metastatic carcinoma of the vertebral bodies may compress one or several adjacent roots by encroaching on posterolateral recesses of the canal and proximal neural foramina. Among rare causes of polyradiculopathy is a chronic lumbosacral syndrome associated with dural eventrations surrounding nerve roots, which may complicate ankylosing spondylitis.


Neurology_Adams

Neurology_Adams. However, one is often confronted by a pattern of subacute or chronic polyradiculopathy and abnormal CSF formula for which extensive examination fails to identify any of the diseases enumerated above. This idiopathic form of polyradiculopathy comes to our attention several times yearly. Some will turn out to have a lymphomatous infiltration at autopsy for which reason we have on occasion asked a neurosurgeon to remove a midlumbar (L2 or L3) motor rootlet for examination. Also particularly difficult diagnostically is a polyradiculopathy that involves the motor roots exclusively or predominantly and is indistinguishable from motor neuron disease except for the absence of widespread denervation or of progressive upper motor neuron signs and differing from the immune motor neuropathies discussed further on by the absence of conduction block.


Neurology_Adams

Neurology_Adams. In these common syndromes, reduced sensation, weakness, muscular atrophy, and loss of tendon reflexes progress over a period of months or years. Within this large category, two groups are distinguished. In the first and less chronic of the two, the neuropathy appears over months or a year or two. Comprising this group are acquired processes such as certain metabolic and immune-mediated polyneuropathies. Paraneoplastic neuropathies may also fall into this category, although they are more often subacute in onset, being almost fully developed in a matter of weeks. Leprous neuritis is the one infectious member of this group and also the one exception to the rule that all chronic neuropathies are more or less symmetrical in pattern. The polyneuropathies that make up the second group are far more chronic than the first, evolving insidiously over many years or decades; these are mainly the genetically determined diseases of the peripheral nervous system caused by specific genetic mutations.


Neurology_Adams

Neurology_Adams. Acquired Forms of Chronic Polyneuropathy 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.


Neurology_Adams

Neurology_Adams. 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 (1980) 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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, Ropper and Gorson 1998). 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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).


Neurology_Adams

Neurology_Adams. 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).


Neurology_Adams

Neurology_Adams. 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).


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 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.


Neurology_Adams

Neurology_Adams. 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. Treatment 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.


Neurology_Adams

Neurology_Adams. 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, including of anti-MAG neuropathy, but


Neurology_Adams

Neurology_Adams. on the B-cell lymphocyte population, after initial enthusiasm based on small series, has given conflicting and generally negative results in several trials, including of anti-MAG neuropathy, but it may be reasonable to try in intractable cases.


Neurology_Adams

Neurology_Adams. 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 (Gorson et al 2001). 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


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.