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Neurology_Adams. Treatment of POEMS The neuropathy that complicates a solitary plasmacytoma may improve markedly following irradiation or resection of the bone lesion. Multiple lesions or cases with no apparent bone lesions, including those in the POEMS syndrome, may be treated with chemotherapy (melphalan and prednisone) and may lead to some improvement or stabilization in the neuropathy. Treatment with plasma exchange has yielded uncertain but generally positive short-term results in our patients. The value of plasma exchanged and IVIG have been difficult to affirm in trials. Drugs used to treat multiple myeloma have also been tried, with uncertain results. Autologous stem cell transplantation or bevacizumab (a monoclonal antibody directed against VEGF) have been used, also with mixed results (Kuwabara et al, 2008) and with some positive results in uncontrolled series (Karam et al).


Neurology_Adams

Neurology_Adams. Waldenström macroglobulinemia Macroglobulinemia was the term applied by Waldenström to a systemic condition occurring mainly in older persons and characterized by fatigue, weakness, and a bleeding diathesis. Immunoelectrophoretic examination of the blood disclosed a marked and mostly monoclonal increase in the IgM plasma fraction. About half of patients with Waldenström disease and polyneuropathy will have specific anti-MAG antibodies, similar to the approximately one-third of patients with nonmalignant IgM paraproteins. (An uncertain proportion of patients with a “benign” IgM paraprotein will, over the years, develop Waldenström disease.) A few patients with Waldenström hyperproteinemia have a hyperviscosity state manifest by diffuse slowing of the retinal and cerebral circulations, giving rise to episodic confusion, coma, impairment of vision, and sometimes strokes (Bing-Neel syndrome). Most reports attribute this syndrome to infiltration of neural by malignant plasma cells rather


Neurology_Adams

Neurology_Adams. rise to episodic confusion, coma, impairment of vision, and sometimes strokes (Bing-Neel syndrome). Most reports attribute this syndrome to infiltration of neural by malignant plasma cells rather than to hyperviscosity.


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Neurology_Adams. The polyneuropathy, when present, evolves over months or longer and may be asymmetrical, particularly at the onset, but becomes bilateral, mainly sensory, and distal. The pattern in our patients has been very slowly progressive, and initially limited to the feet and legs with sensory ataxia and loss of knee and ankle jerks. The CSF protein is usually elevated and the globulin fraction increased. In a case recorded by Rowland and colleagues, the polyneuropathy was purely motor and simulated motor neuron disease. Treatment is discussed further on.


Neurology_Adams

Neurology_Adams. Cryoglobulinemia As mentioned in the section on vasculitic neuropathies, cryoglobulin, a serum protein that precipitates on cooling, is usually of the IgG or IgM type and most often polyclonal. While cryoglobulinemia may occur without any apparent associated condition (essential cryoglobulinemia), it also accompanies a wide variety of disorders such as multiple myeloma, lymphoma, connective tissue disease, chronic infection, and particularly, hepatitis C. Peripheral neuropathy occurs in a small proportion both of the essential and symptomatic cases. Occasionally the neuropathy evolves over a period of a few days and remits rapidly. More often it takes the form of a distal symmetrical sensorimotor loss, which develops insidiously (76 percent of the cases in the series reported by Gemignani et al) in association with the Raynaud phenomenon and purpuric eruptions of the skin. Initially, the neuropathic symptoms may consist only of pain and paresthesias that may be precipitated by


Neurology_Adams

Neurology_Adams. et al) in association with the Raynaud phenomenon and purpuric eruptions of the skin. Initially, the neuropathic symptoms may consist only of pain and paresthesias that may be precipitated by exposure to cold (as often, there is no cold sensitivity). Later, weakness and wasting develop, more in the legs than in the arms, and more or less in the same distribution as the vascular changes. In some cases there may be a mononeuropathy multiplex with severe denervation in the territory of the involved nerves (9 percent of the series reported by


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Neurology_Adams. Gemignani et al; see also Garcia-Bragado et al). In a few cases, the two neuropathic syndromes have been combined. As remarked earlier, detection of cryoglobulin requires special handling of the blood sample. The specimen should be carried to the laboratory in a bath of warm water to prevent precipitation of the protein. Any of the paraproteinemic states may be associated with an amyloid polyneuropathy, a subject accorded a separate section later in the chapter.


Neurology_Adams

Neurology_Adams. The pathology of the cryoglobulinemic and macroglobulinemic neuropathies has been incompletely studied and the mechanisms by which these disorders cause neuropathy are uncertain. One presumes that some component of the paraprotein acts as an antineural antibody or that deposition of the protein is in some way toxic to the nerves or to the endoneurial vessels. In our most thoroughly autopsied case, there was widespread distal axonal degeneration of nonspecific type without amyloid deposition or inflammatory cells; yet in other reported cases, amyloid has been found in the nerve and the neuropathy has been attributed directly to it. Immune deposits of IgM had impregnated the inner layers of the perineurium in the case reported by Ongerboer de Visser and colleagues. Dalakas and Engel (1981b) have made similar observations. In yet other instances, the neuropathy of cryoglobulinemia is a result of the intravascular deposition of cryoglobulins, causing a more acute vasculitic mononeuropathy


Neurology_Adams

Neurology_Adams. have made similar observations. In yet other instances, the neuropathy of cryoglobulinemia is a result of the intravascular deposition of cryoglobulins, causing a more acute vasculitic mononeuropathy multiplex, as discussed earlier (Chad et al).


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Neurology_Adams. Treatment In the Waldenstrom-related neuropathies, the use of prednisone, the alkylating agent chlorambucil, cyclophosphamide, and repeated plasma exchange has at times led to improvement both in the systemic and neuropathic symptoms, although recovery has been incomplete. The monoclonal antibody rituximab has been effective in small studies. The optimal treatment of cryoglobulinemic neuropathy has not been settled. We have used plasma exchange and added immunosuppression in the vasculitic variety of this disease. Acquired Primary (Nonfamilial, AL) Amyloid Neuropathy


Neurology_Adams

Neurology_Adams. A heredofamilial type of amyloidosis (familial amyloidosis [FA]) is well known and is described further on. In addition, there are numerous sporadic instances of a peripheral neuropathy caused by amyloid deposition. As in the familial variety, the heart, kidneys, and gastrointestinal tract may be involved. This acquired type of amyloid disease has also been called primary systemic amyloidosis to distinguish it from the variety associated with chronic diseases. The term is misleading in that in most cases the amyloid is derived from a circulating paraprotein, but the proportion of “benign” and malignant plasma cell sources of the protein varies from one report to another. For example, in the large series collected by Kyle and Bayrd, only 26 percent of patients with primary amyloidosis had a malignant plasma cell dyscrasia. This agrees with our own experience, but other series have found rates of myeloma as high as 75 percent. In any case, 90 percent of primary amyloidosis is the result


Neurology_Adams

Neurology_Adams. malignant plasma cell dyscrasia. This agrees with our own experience, but other series have found rates of myeloma as high as 75 percent. In any case, 90 percent of primary amyloidosis is the result of a monoclonal protein in the blood (rarely polyclonal). Macrophage enzymes cleave the larger immunoglobulin molecules and the light chains aggregate to form amyloid deposits in tissue, or the plasma cells may produce light chains directly (“light chain disease”). Lambda light chain predominates in the idiopathic variety of amyloidosis and kappa light chain is more common in myeloma. In a few cases, the light chain is found only in the urine (as Bence Jones protein).


Neurology_Adams

Neurology_Adams. In primary amyloidosis there is no evidence of preceding or coexisting disease (except the association with paraproteinemia or multiple myeloma). Secondary amyloidosis (AA), an infrequent occurrence nowadays, is the result of chronic infection or other chronic disease outside the nervous system and, as a rule, is not associated with neuropathy (e.g., it is not cited in the large recent series by Lachmann and colleagues [2007]). In contrast, familial amyloidosis, a third variety, is almost invariably associated with neuropathy but is associated with a paraprotein in only a small proportion of cases and the amount of immunoglobulin is small (see “Inherited [Familial Amyloidosis] Amyloid Neuropathies” later).


Neurology_Adams

Neurology_Adams. Primary amyloidosis is mainly a disease of older men, the median age at the time of diagnosis being 65 years. In our clinical material, the majority of the patients have had peripheral neuropathy, but this may reflect a referral bias as in other series, less than one-third were so affected (Kyle et al). The neuropathic symptoms and signs are similar to those of hereditary amyloid polyneuropathy discussed further on, but the progress of the disease is considerably more rapid.


Neurology_Adams

Neurology_Adams. The initial syndrome is primarily sensory—numbness, paresthesias, and very often, acral pain—signs that are mainly characteristic of involvement of small-diameter sensory fibers (loss of pain and thermal sensation). It is the painful aspect and the autonomic features discussed later that distinguish this disease from the other paraproteinemic neuropathies and indeed, from most other polyneuropathies. Weakness follows, initially limited to the feet but becoming more extensive as the disease progresses and eventually spreads to the hands and arms. Only later is there loss of mainly large fibers that mediate sensations of touch, pressure, and proprioception. Twenty-five percent of patients have carpal tunnel syndrome from infiltration of the flexor retinaculum. Exceptionally, patterns other than the painful and sensory predominant polyneuropathy have been associated with amyloidosis; preferential involvement of motor nerves, lumbar roots, plexopathy, and amyloidomas involving single


Neurology_Adams

Neurology_Adams. than the painful and sensory predominant polyneuropathy have been associated with amyloidosis; preferential involvement of motor nerves, lumbar roots, plexopathy, and amyloidomas involving single nerves (sciatic, facial, trigeminal) have been reported. Unusual cases of mononeuritis multiplex are difficult to explain.


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Neurology_Adams. Autonomic involvement can be severe in amyloid neuropathy (familial or primary) and may become evident early in the course of the illness; several of our patients presented with disturbances of gastrointestinal motility such as episodic diarrhea and orthostatic dizziness or erectile dysfunction and bladder disturbances. The pupils may show a slow reaction to light, or there may be a reduction in sweating. An infiltrative amyloid myopathy also occurs as a rare complication of the disease; it presents as an enlargement and induration of many muscles, particularly those of the tongue (macroglossia), pharynx, and larynx.


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Neurology_Adams. Progression of the illness is relatively rapid, the mean survival being 12 to 24 months. An indolent neuropathy that evolves over years is unlikely to be a result of amyloidosis, although we have seen such a case. Death is a result of the renal, cardiac, or gastrointestinal effects of amyloid deposits, the manifestations of which are already evident in more than half of the patients who present with neuropathy. A nephrotic syndrome is also characteristic.


Neurology_Adams

Neurology_Adams. Analysis of the serum and urine, searching for an abnormal paraprotein, is the most useful screening test for amyloid neuropathy. Next in value is a microscopic examination of a biopsy of the abdominal fat pad, gingiva, or rectal mucosa for deposition of amyloid in tissue or blood vessels. Biopsy of the sural nerve or of the involved viscera has a high diagnostic yield; muscle tissue gives variable results. The liver biopsy is positive in virtually all cases of primary amyloid and the kidney shows amyloid infiltration in 85 percent. In several of our patients with a clinical syndrome typical of amyloid neuropathy but in whom amyloid was absent in the sural nerve, the diagnosis was established only after sequential biopsy of numerous sites (fat pad, kidney, liver). If the sural nerve is severely depopulated of nerve fibers, the amount of congophilic staining and the characteristic amyloid birefringence may be meager and yield a spuriously negative result. It is also critical to ensure


Neurology_Adams

Neurology_Adams. depopulated of nerve fibers, the amount of congophilic staining and the characteristic amyloid birefringence may be meager and yield a spuriously negative result. It is also critical to ensure the accuracy of congophilic staining by comparison with positive and negative control tissue from the same laboratory. The CSF has a normal or mildly elevated protein concentration, but this does not distinguish the neuropathic process from many others.


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Neurology_Adams. 10 percent of patients who appear by all the usual criteria to have primary amyloidosis will be found to have a genetic type. However, as mentioned, only a small proportion of the latter group has a monoclonal gammopathy and it tends to be of low concentration (it has been estimated to occur in one-quarter of familial cases but we have not encountered it). This difference and the rapid progression of the primary acquired form assist in distinguishing it from the genetic type that is discussed further on. In addition to the more slowly evolving familial types, the differential diagnosis of acquired amyloid neuropathy includes the myelomatous varieties, toxic and nutritional small-fiber neuropathies, diabetic polyneuropathy, paraneoplastic polyneuropathy, Sjögren disease, and an idiopathic small-fiber sensory neuropathy, all of which cause pain and which we have encountered more frequently than amyloidosis.


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Neurology_Adams. Treatment of Amyloid Neuropathy The prognosis of primary-acquired amyloidosis and its associated neuropathy has been poor. Attempts at immunomodulation, immunosuppression (which may help the renal disease), or removal of amyloid by plasma exchange have been marginally effective. Another approach has been bone marrow suppression with high doses of melphalan followed by stem cell replacement (previously harvested from the patient). Several such patients have survived for years with marked improvement in the neuropathy. Recently, several small molecules designed to prevent the aggregation of amyloid fibrils have shown benefit in the familial type of amyloid; see further on.


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Neurology_Adams. Pain is a serious problem in the amyloid neuropathies that may be treated with transcutaneous fentanyl patches or with oral narcotic medications. Orthostatic hypotension responds to the use of leg stockings, midodrine, and mineralocorticoids, as well as sleeping with the bed elevated at the head so that the patient’s entire body is angled down toward the feet.


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Neurology_Adams. This form of polyneuropathy was separated from acute inflammatory polyradiculopathy, or Guillain Barre syndrome, by Austin in 1958 on the basis of a prolonged and relapsing course, enlargement of nerves, and responsiveness to corticosteroids. Excluding the duration of evolution, the acute and chronic forms are similar in many ways. Both are widespread polyradiculoneuropathies, usually with cytoalbuminologic dissociation of the CSF (raised protein concentration with few or no cells); both exhibit nerve conduction abnormalities characteristic of a demyelinating neuropathy (reduced conduction velocity and partial conduction block in motor nerves), and pathologically, both show similar multifocal perivenous inflammatory infiltrates. But there are also important differences, the most evident of which are the modes of evolution, responses to treatment, and prognosis. As a rule, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) begins insidiously and evolves slowly, either in


Neurology_Adams

Neurology_Adams. which are the modes of evolution, responses to treatment, and prognosis. As a rule, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) begins insidiously and evolves slowly, either in a steadily progressive or stepwise manner, attaining its maximum severity after several months. From the beginning it may be asymmetrical or involve the arms predominantly. However, in a small proportion of patients (16 percent in the series of McCombe et al [1987b] and a smaller proportion in our own series) the disease at first emerges from a mild or moderate case of GBS, in which case the illness becomes relapsing or simply worsens slowly and progressively.


Neurology_Adams

Neurology_Adams. An antecedent infection is usually not identified in patients with CIDP as it is in GBS. Furthermore, CIDP may be distinct immunologically from GBS, insofar as certain HLA antigens occur with greater frequency in patients with CIDP than they do in the normal population, whereas there are no clear HLA propensities in patients with GBS. Finally, in contrast to acute GBS, many cases of CIDP respond favorably to the administration of prednisone. An ambiguity is introduced here because, as mentioned in the section on GBS, Hughes et al (1992) has described a group of patients with polyneuritis in whom weakness progressed steadily for 4 to 12 weeks and who responded to corticosteroids (subacute GBS), in such cases, blurring the distinction between GBS and CIDP.


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Neurology_Adams. Chronic symmetric sensorimotor loss and areflexia coupled with nerve conduction findings of demyelination essentially defines the illness. Elevated spinal fluid protein concentration is so frequent that it might be added as a diagnostic criterion. The typical findings in nerve conduction studies are of multifocal conduction block as described in Chap. 2; prolonged distal latencies (“distal block”); nerve conduction slowing to less than 80 percent of normal values in several nerves; loss of late responses; and dispersion of the compound muscle action potentials—all reflecting demyelination in motor nerves. One or several of these changes have been present in 75 percent of our patients (Gorson et al, 1997). In the early stages of the disease, demyelinating features must be carefully sought by testing multiple nerves at several sites along their courses. After several months there is often some degree of axonal change (30 percent of our series), but the fundamental process continues to


Neurology_Adams

Neurology_Adams. by testing multiple nerves at several sites along their courses. After several months there is often some degree of axonal change (30 percent of our series), but the fundamental process continues to be one of multiple foci of demyelination. A fairly dependable finding is the absence of denervation changes early in the illness despite weakness and reduced amplitude of the motor action potential (indicative of a demyelinating block to conduction at a proximal site).


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Neurology_Adams. Several large series of CIDP cases are available for review. Dyck and colleagues (1975) studied 53 patients in whom the neuropathy progressed for more than 6 months. The clinical course was monophasic and slowly progressive in about one-third, stepwise and progressive in another third, and relapsing in the remaining third. The periods of worsening or improvement were measured in weeks or months. Weakness of the limbs, particularly of the proximal leg muscles, or numbness, paresthesias, and dysesthesias of the hands and feet were the initial symptoms. In 45 of the 53 patients, the signs were those of a mixed sensorimotor polyneuropathy with weakness of the shoulder, upper arm, and thigh muscles in addition to motor and sensory loss in the distal parts of the limbs. In 5 patients the neuropathy was purely motor, and in 3, purely sensory. Cranial nerve abnormalities were distinctly unusual. Enlarged, firm nerves were found in 6 patients. Not emphasized in their series is the common


Neurology_Adams

Neurology_Adams. was purely motor, and in 3, purely sensory. Cranial nerve abnormalities were distinctly unusual. Enlarged, firm nerves were found in 6 patients. Not emphasized in their series is the common occurrence of a cerebellar-like tremor in cases of long standing.


Neurology_Adams

Neurology_Adams. In the series reported by McCombe et al (1987a and 1987b) comprising 92 patients, two major subgroups were recognized: relapsing (corresponding to the relapsing and stepwise progressive cases of Dyck et al [1975]) and nonrelapsing ones. In our own series of now over 100 patients, we have been impressed with several variant patterns of clinical presentation. In approximately 10 percent, numbness and weakness of the hands preceded involvement of the feet, which is unusual in other polyneuropathies, and a sensory ataxic form, a purely motor form, and mononeuropathies superimposed on a mild generalized polyneuropathy each accounted for approximately 5 percent.


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Neurology_Adams. As mentioned earlier, a small proportion of cases began as acute GBS but continue to progress or relapse in the following months (Gorson et al, 1997). Another comprehensive account of the disease have been given by Hughes and associates. All of these studies have included cases with clinical progression for longer than 8 or 12 weeks; thus CIDP has come to be defined in part by a progressive polyneuropathy of this duration.


Neurology_Adams

Neurology_Adams. As might be imagined from the experience with GBS, there are variant syndromes that align with CIDP but have special clinical characteristics. The best characterized of these is multifocal conduction block (called multifocal acquired demyelinating sensory and motor neuropathy, or MADSAM). Also described is a polyradicular process that presents as an ataxic illness with large fiber attributable sensory loss and spared sensory nerve action potentials (see Sinnreich et al), and a slowly progressive distal neuropathy (distal acquired demyelinating symmetrical neuropathy; DADS). In the latter, there are distal sensory and sometimes motor, disturbances and greatly prolonged distal latencies in most patients, and two-thirds have an associated IgM monoclonal gammopathy with kappa light chain component; the illness responds poorly to treatment, aligning it clinically in some respects with the anti-MAG neuropathies but in most clinical and electrophysiologic features appearing to be a variant


Neurology_Adams

Neurology_Adams. the illness responds poorly to treatment, aligning it clinically in some respects with the anti-MAG neuropathies but in most clinical and electrophysiologic features appearing to be a variant of CIDP (see Katz et al).


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Neurology_Adams. The status of a predominantly axonal polyneuropathy that clinically simulates CIDP and responds to some extent to the same immunomodulating treatments has been described by Uncini and colleagues and by Gorson and Ropper. The present authors have the impression that it is an immune-mediated neuropathy comparable to CIDP but with preferential destruction of axons rather than of myelin. Its frequency as a cause of acquired polyneuropathy is unknown, but we see several new cases every year.


Neurology_Adams

Neurology_Adams. Also recognized is the frequency (up to 25 percent of the patients in some series, less often in our experience) with which there was a parallel systemic condition such as paraproteinemia, lymphoma, an undifferentiated reactive adenopathy or lupus, in association with an inflammatory demyelinating polyneuropathy (even aside from the rare DADS process mentioned above). These associations create problems in nosology that can be reconciled by labeling a given instance as, for example, “CIDP with paraproteinemia” or “CIDP with lupus,” thus separating such cases from the idiopathic variety but the distinctions are tenuous. These symptomatic inflammatory polyneuropathies respond to corticosteroids, albeit unpredictably, and to treatment of the underlying disease.


Neurology_Adams

Neurology_Adams. Laboratory features The CSF protein is elevated in more than 80 percent of patients with CIDP, typically in the range of 75 to 250 mg/dL. In rare instances there is papilledema and a pseudotumor cerebri syndrome (see Chap. 29) in relation to extremely high levels of CSF protein (usually >1,000 mg/dL). Elevation of the CSF gamma globulin fraction and a mild lymphocytic pleocytosis are found in 10 percent of patients (often in those who are HIV-seropositive), a considerably higher percentage than in our series.


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Neurology_Adams. In sural nerve biopsy material, half are found to have interstitial and perivascular infiltrates of inflammatory cells, although one expects that most nerves would show these changes if a sufficient number could be sampled. Some specimens show only demyelination, or in cases of long standing, severe depletion of all nerve fibers. As in GBS, the demyelination appears to be affected by T cells and macrophages within the endoneurium and perineurium. The loss of myelinated fibers is variable and many of the remaining fibers are seen to be undergoing wallerian degeneration or show changes of segmental demyelination or demyelination-remyelination. Onion-bulb formations are conspicuous in recurrent and relapsing cases. The few adequate autopsy studies have shown only minimal or patchy inflammation and a considerable degree of axonal damage, probably reflecting the long duration of illness before examination. The presence of endoneurial and subperineurial edema has been emphasized by


Neurology_Adams

Prineas and McLeod.

Neurology_Adams. Prineas and McLeod.


Neurology_Adams

Neurology_Adams. Treatment Several trials have shown a short-term benefit from the intravenous infusion of high doses of gamma globulin (IVIg, total 2 g/kg in divided infusions over 2 to 5 days), see Hahn et al 1996b. More than half of our patients have responded to this treatment, albeit for only several weeks or months, after which the infusions must be repeated to maintain clinical improvement. A desire to spare patients the side effects of indefinite prednisone administration (see later) makes this mode of therapy a reasonable alternative, in some cases for almost 10 years without ill effects. Patients who require treatment at such short intervals as to be impractical have benefited from the addition of small doses of prednisone or of an immunosuppressive drug as described in the following text. The main drawbacks of IVIg are its expense and the several hours required for its infusion. Rare instances of nephrotic syndrome, aseptic meningitis, serum sickness, thrombotic venous, or arterial


Neurology_Adams

Neurology_Adams. The main drawbacks of IVIg are its expense and the several hours required for its infusion. Rare instances of nephrotic syndrome, aseptic meningitis, serum sickness, thrombotic venous, or arterial occlusion, including stroke and hypotension, have been reported, particularly if the infusion is too rapid.


Neurology_Adams

Neurology_Adams. Half of patients with CIDP also respond well to plasma exchanges. In a prospective double-blinded trial, Dyck and colleagues (1986a) found that plasma exchange administered twice weekly for 3 weeks had a beneficial effect on both neurologic disability and nerve conduction. The response to plasma exchange in our patients has been comparable to that obtained with IVIg and with steroids, but we have discerned that some patients respond to one type of treatment and not another. The effects of plasma exchanges in most patients subside in 10 to 21 days, or even less; in some, the response lasts longer as found by Dyck and colleagues (1986a) and in the series reported by Hahn and colleagues (1996a). For these reasons we have often tried plasma exchange or immune globulin before committing a patient to long-term treatment with prednisone. The relative ease of administering IVIg favors its use first, followed by a series of plasma exchanges if there is no improvement. When there is a clear


Neurology_Adams

Neurology_Adams. to long-term treatment with prednisone. The relative ease of administering IVIg favors its use first, followed by a series of plasma exchanges if there is no improvement. When there is a clear response, 3 or 4 brief series of plasma exchanges or repeated infusions of immune globulin may suffice to bring the patient to an improved level of function. These treatments can be supplemented by small doses of prednisone when frequent infusions or exchanges become impractical. It has been our experience that in about one-third of cases, IVIg and plasma exchange cease to have benefit after repeated use for 1 or more years. The ideal regimen for either treatment has not been established and is often guided by the clinical examination and reports from the patient about return of symptoms after an interval of weeks or months after each treatment. One of the most difficult problems in this field is the lack of useful clinical measurements to guide treatment with IVIg and plasma exchange and even


Neurology_Adams

Neurology_Adams. of weeks or months after each treatment. One of the most difficult problems in this field is the lack of useful clinical measurements to guide treatment with IVIg and plasma exchange and even the proper adjustment of the dose of corticosteroid. Often, one may be influenced by the patient’s fear of losing any ground and even slight changes in sensory or motor symptoms.


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Neurology_Adams. Glucocorticoids were formerly the mainstay of therapy, but many patients become dependent on the medication and correspondingly suffer side effects. Our approach has been to use corticosteroids as an adjunct to one of the previously mentioned treatments, but other centers use them first. The usual regimen begins with 60 to 80 mg of prednisone daily that is tapered over months to the lowest effective dose, typically 25 to 40 mg. Without substantiation by a controlled trial, we have found that corticosteroids can be withdrawn without relapse in some patients by slow tapering over many months or a year. Attempts to withdraw the steroids more quickly have led to further cycles of relapse.


Neurology_Adams

Neurology_Adams. A number of patients will have no response to glucocorticoids within the first 1 or 2 months but will improve if treatment is continued. Barohn and colleagues (1989) have found that the earliest improvement occurs only after 2 months of treatment and is maximal at approximately 6 months. In addition to all the well-known side effects, the drug may produce tremor or exaggerate the tremor caused by the neuropathy. Long remissions lasting several years have been reported with the use of pulses of orally administered high-dose or daily corticosteroids, for example, by Eftimov and colleagues, who used dexamethasone 40 mg per day for 4 days, repeated for 6 cycles, or daily prednisolone, 60 mg for 6 weeks. Should a sustained trial of prednisone therapy prove unsuccessful, a course of azathioprine (for at least 3 months), 3 mg/kg in a single daily dose, has been recommended (Dalakas and Engel, 1981a), but a controlled trial has failed to show benefit from this combination and we have had


Neurology_Adams

Neurology_Adams. (for at least 3 months), 3 mg/kg in a single daily dose, has been recommended (Dalakas and Engel, 1981a), but a controlled trial has failed to show benefit from this combination and we have had little success with it.


Neurology_Adams

Neurology_Adams. When the preceding measures prove unsatisfactory, cyclophosphamide, mycophenolate, rituximab, or another similar immunosuppressive medication can be added, but we have been unable to draw any firm conclusions as to the effectiveness of these combined regimens.


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Neurology_Adams. High-dose cyclophosphamide has proven helpful in several cases under our care, although it has often failed (see Brannagan et al and the review by Brannagan that lists the applicable clinical trials). The usual regimen is 50 mg/kg IV daily for 4 days followed by granulocyte-stimulating factor beginning on the tenth day until the absolute neutrophil count recovers. Individual reports of successful treatment by autologous stem cell transplantation after high-dose chemotherapy have appeared but 1 patient relapsed after 5 years (Vermuelen and van Oers). This may become an option in severe and treatment-resistant cases. We have no explanation for the remarkable improvement and continued good health of a few of our patients after a severe toxic bacterial infection (Ropper, 1996).


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Neurology_Adams. It has been stated that patients with discrete relapses have a better prognosis than those with a progressive course. In McCombe’s series (1987b), 73 percent were said to have eventually recovered, but the long-term outcome has generally been poor. In fewer than 10 percent of patients has the disease finally remitted; additionally, unexplained remission occurs occasionally. The 5-year followup of 38 patients by Kuwabara and colleagues gives a figure of 49 percent with full or partial remission, far higher than in our series.


Neurology_Adams

Neurology_Adams. Several polyneuropathies that share many of the features of CIDP have been delineated on the basis of unique clinical, immune, or electrophysiologic attributes. These include particularly multifocal motor neuropathy (MMN) and multifocal conduction block (also called MADSAM, as mentioned earlier). The latter has as its main feature a block of mixed nerve conduction at focal sites in a limited number of nerves as described earlier. In multifocal motor neuropathy, only blocks in motor nerve conduction are evident.


Neurology_Adams

Neurology_Adams. There are similarities in clinical features and response to treatment between the two entities, but the purely motor nature of MMN (see Delmont et al), makes it useful to separate them. Multifocal motor neuropathy, but not multifocal conduction block, is associated in half or more of cases with a particular IgM antibody, anti-GM1, directed against a ganglioside component of peripheral myelin (Pestronk et al). For this reason, some view this illness as belonging to the class of paraproteinemic neuropathies (see earlier and Simmons et al) and it is distinctive enough clinically to be categorized separately. Its importance as a clinical entity lies in the similarity of the clinical picture to a purely lower motor neuron type of amyotrophic lateral sclerosis (ALS) and, unlike ALS, its potential responsiveness to treatment. The pathophysiologic role of anti-GM1 antibodies is displayed by a case of transplacental transmission of a motor neuropathy to a neonate (Attarian et al).


Neurology_Adams

Neurology_Adams. Multifocal motor neuropathy and motor conduction block predominate in men. They usually begin with an acute or subacute motor mononeuropathy, manifest, for example, as weakness of the wrist or foot-drop, and are often joined insidiously by another focal motor palsy. The process is painless, unlike vasculitic mononeuritis multiplex, involves the nerve incompletely, and, in its usual form, is unaccompanied by any sensory symptoms such as paresthesias or numbness. Despite the initially demyelinating character of the disorder, there is almost always atrophy of the weakened muscle within months and there may be a few fasciculations, thus simulating ALS. Nevertheless, the weakness tends to be disproportionate to atrophy. Usually, the tendon reflex is lost or muted in an affected region, but for unexplained reasons, some patients have one or more brisk reflexes. Our experience has been that this latter reflex change does not reach the point of appearing “pathologic” and that clonus and


Neurology_Adams

Neurology_Adams. for unexplained reasons, some patients have one or more brisk reflexes. Our experience has been that this latter reflex change does not reach the point of appearing “pathologic” and that clonus and Babinski signs are categorically not part of the illness, as they are in ALS.


Neurology_Adams

Neurology_Adams. When there is an association of the motor features with sensory symptoms or sensory loss and there is slowing of sensory conduction in regions of motor conduction block (multifocal conduction block), the acronym MADSAM (multifocal acquired demyelinating sensory and motor neuropathy) has been used as noted earlier, but the disorder, while similar to multifocal conduction block, more resembles CIDP. This conforms to what had been called Lewis-Sumner syndrome (see Lewis et al 1982) based on the description by these authors and their colleagues of subacute, painless asymmetric, distal multiple mononeuropathies. The ulnar and median nerves were involved in their patients and there was motor conduction block and sensory slowing in affected nerves. Curiously, 2 of their 5 original patients had optic neuritis, a feature not reported subsequently. The disease is not directly connected to antibodies against GM1, but a few patients with the sensorimotor disorder will display them.


Neurology_Adams

Neurology_Adams. Treatment For multifocal motor conduction block and motor neuropathy, with or without anti-GM1 antibodies, IVIg infusions have been effective, albeit temporarily, in more than half of patients. Some authoritative clinicians favor the early addition of rituximab in treatment-resistant cases or when the frequency of infusions is unsustainable and if that fails, cyclophosphamide. Other immune-modulating drugs have been tried in small series with various results. There is no response to corticosteroids. The MADSAM illness responds similarly to corticosteroids, IVIg, or plasma exchange, similar to the effects of these approaches in CIDP.


Neurology_Adams

Neurology_Adams. Polyneuropathy is among the most common complications of chronic renal failure. Robson has estimated that neuropathy complicates end-stage renal failure in two-thirds of patients who are about to begin dialysis therapy. Bolton’s figures are much the same; 70 percent of his patients being dialyzed regularly had polyneuropathy and in 30 percent of all his patients, it was moderate or severe in degree. As described originally by Asbury and associates (1963), the neuropathy takes the form of a painless, progressive, symmetrical sensorimotor paralysis of the legs and then of the arms. In some patients, the syndrome begins with burning dysesthesias of the feet or with sensations of creeping, crawling, and itching of the legs and thighs, which tend to be worse at night and are relieved by movement (comparable to “restless legs” syndrome described in Chap. 18). Renal failure that is accompanied by diabetes gives rise to a particularly severe form of polyneuropathy.


Neurology_Adams

Neurology_Adams. The combination of muscle weakness and atrophy, areflexia, sensory loss, and the graduated, distally predominant distribution of the neurologic deficit in the limbs leaves little doubt about the neuropathic nature of the disorder. Usually the neuropathy evolves slowly over many months. Infrequent instances of a more acute sensorimotor polyneuropathy that have been reported occur mainly in diabetic patients receiving peritoneal dialysis as discussed earlier (Ropper, 1993; Asbury et al, 1963). A rare uremic polymyositis with hypophosphatemia has also been described (Layzer). The neuropathy has been observed with all types of chronic kidney diseases. More important to the development of chronic neuropathy than the nature of the renal lesion are the duration and severity of the renal failure and symptomatic uremia.


Neurology_Adams

Neurology_Adams. With long-term hemodialysis, the neuropathic symptoms and signs stabilize but improve in relatively few patients. In fact, rapid hemodialysis may worsen the polyneuropathy (or perhaps its symptoms) temporarily. Peritoneal dialysis appears to be more successful than hemodialysis in improving the neuropathy, but this observation has not been firmly established. Complete recovery, occurring over a period of 6 to 12 months, usually follows successful renal transplantation for reasons given later.


Neurology_Adams

Neurology_Adams. The pathologic findings are those of a nonspecific and noninflammatory axonal degeneration. In rapidly progressive cases, there is a tendency for the large fibers to be more affected; this is evident particularly on electrophysiologic testing that shows slowing of nerve conduction velocities, but there is no conduction block as occurs in other acquired demyelinating polyneuropathies. In all types of uremic polyneuropathies, pathologic changes are most intense in the distal segments of the nerves with the expected chromatolysis of their cell bodies.


Neurology_Adams

Neurology_Adams. The cause of uremic polyneuropathy is unknown. What has been called the “middle molecule” theory is plausible. The end stage of renal failure is associated with the accumulation of toxic substances in the range of 300 to 2,000 kDa molecular weight. Furthermore, the concentration of these substances, which include methyl guanidine and myoinositol, has been shown to correlate with the degree of neurotoxicity (Funck-Brentano et al). These toxins (and the clinical signs of neuropathy) are not greatly reduced by hemodialysis. In contrast, the transplanted kidney effectively eliminates substances of wide-ranging molecular weights, which would account for the almost invariable improvement of neuropathy after transplantation. As is the case with uremic encephalopathy, urea alone given to experimental animals and in controlled studies of humans, does not seem capable of inducing a metabolic neuropathy.


Neurology_Adams

Neurology_Adams. As described at length in Chap. 41, in virtually all patients with alcoholic–nutritional polyneuropathy who remain untreated with vitamin and protein restoration, the weakness and atrophy of the legs, and to a lesser extent the arms, may reach an extreme degree. Thus this disease, although subacute in its evolution as described earlier in the chapter, becomes a frequent cause of chronic polyneuropathy. There are usually prominent sensory features and considerable acral pain and allodynia. Certain cases of diabetic neuropathy behave similarly. This is the best example of an infectious neuritis, caused by the direct invasion of nerves by the acid-fast Mycobacterium leprae. The disease is still frequent in India and Central Africa and there are many lesser endemic foci, including parts of South America and Florida, Texas, and Louisiana, which border the Gulf of Mexico. Limited outbreaks have been reported during treatment for HIV, with armadillos as the probable intermediate host.


Neurology_Adams

Neurology_Adams. The initial lesion in leprosy is an innocuous-appearing skin macule or papule, which is often hypopigmented and lacking in sensation; it is caused by the invasion of cutaneous nerves by M. leprae. In patients with a degree of immunologic resistance to infection, the disease progresses no further than this stage, which is spoken of as indeterminate leprosy, or it may evolve in several ways, depending mainly upon the resistance of the host. The bacilli may be locally invasive, producing a circumscribed epithelioid granuloma that involves cutaneous and subcutaneous nerves and results in a characteristic hypopigmented patch of superficial numbness and sensory loss (tuberculoid leprosy). The underlying subcutaneous sensory nerves may be palpably enlarged. If a large nerve in the vicinity of the granuloma is invaded (the ulnar, median, peroneal, posterior auricular, and facial nerves are most frequently affected), a sensorimotor deficit in the distribution of that nerve is added to the


Neurology_Adams

Neurology_Adams. the granuloma is invaded (the ulnar, median, peroneal, posterior auricular, and facial nerves are most frequently affected), a sensorimotor deficit in the distribution of that nerve is added to the patch of cutaneous anesthesia.


Neurology_Adams

Neurology_Adams. In contrast to the limited tuberculoid variety of leprosy, lack of resistance to the organism permits the proliferation and hematogenous spread of bacilli and the diffuse infiltration of skin, ciliary bodies, testes, lymph nodes, and nerves (lepromatous leprosy). Widespread invasion of the cutaneous nerves produces a symmetrical pattern of pain and temperature loss involving the pinnae of the ears (earlobes) and nose, as well as the dorsal surfaces of hands, elbows, forearms, and feet and anterolateral aspects of the legs—a distribution that is determined by the relative coolness of these parts of the skin. This temperature-dependent pattern is the most characteristic feature of the disease, as pointed out by our colleague TD Sabin. The sensory maps he has drawn (Fig. 43-4) are typical of established cases. The process evolves over years. Eventually, the anesthesia spreads to involve most of the cutaneous surface. Extensive sensory loss is followed by impaired motor function owing to


Neurology_Adams

Neurology_Adams. established cases. The process evolves over years. Eventually, the anesthesia spreads to involve most of the cutaneous surface. Extensive sensory loss is followed by impaired motor function owing to invasion of muscular nerves where they lie closest to the skin (the ulnar nerve is the most vulnerable). There is loss of sweating in areas of sensory loss but otherwise the autonomic nervous system is unaffected. In distinction to other polyneuropathies, tendon reflexes are usually preserved in leprosy despite widespread sensory loss. Probably this is the result of sparing of most of the muscular and larger sensory nerves. Because of widespread anesthesia, injuries may pass unrecognized, with resultant infections, trophic changes, and loss of tissue. Variations in host immunity result in patterns of disease having both tuberculoid and lepromatous characteristics (dimorphous leprosy). Erythema nodosum occurs in a few cases. The diagnosis can be made from a skin scraping or biopsy, but


Neurology_Adams

Neurology_Adams. patterns of disease having both tuberculoid and lepromatous characteristics (dimorphous leprosy). Erythema nodosum occurs in a few cases. The diagnosis can be made from a skin scraping or biopsy, but multiple samples are often required.


Neurology_Adams

Neurology_Adams. The findings on nerve conduction studies are varied, but they usually include findings that are consistent with a generalized but heterogeneous sensorimotor polyneuropathy that includes features of demyelination such as slowed nerve conduction velocities, temporal dispersion and occasionally, conduction block. Treatment All forms of leprosy require long-term treatment with sulfones (dapsone being the most commonly used), rifampin, and clofazimine. The skin lesions of lepromatous leprosy are responsive to thalidomide, which itself may cause a sensory neuropathy (Barnhill and McDougall). Reactivation of disease, or a conversion from the tuberculoid to the lepromatous pattern, may occur during times of reduced immunity.


Neurology_Adams

Neurology_Adams. The status of this disorder is uncertain and the authors have not encountered a definite case. Although characteristic disturbances of skeletal muscle are known to complicate hypothyroidism, the demonstration of a definite polyneuropathy has been infrequent. However, a number of elderly myxedematous patients complain of weakness and numbness of the feet, legs, and, to a lesser extent, hands, for which no other explanation can be found. Loss of reflexes, diminution in vibratory, joint-position, and touch-pressure sensations, and weakness in the distal parts of the limbs are the usual findings (see Dyck and Lambert). The neuropathic manifestations are seldom severe. Nerve conduction velocities are slowed and the protein content of the CSF is usually increased to more than 100 mg/dL. Possibly the latter finding is a reflection of the increased protein content of the serum in the hypothyroid state. The subjective improvement and complete or near-complete reversibility of neuropathic signs


Neurology_Adams

Neurology_Adams. the latter finding is a reflection of the increased protein content of the serum in the hypothyroid state. The subjective improvement and complete or near-complete reversibility of neuropathic signs following treatment with thyroid hormones provides evidence of a hypothyroid etiology. In biopsies of nerve, an edematous protein infiltration of the endoneurium and perineurium, a kind of metachromatic mucoid material, has been seen. Dyck and Lambert (who should be credited for drawing attention to this neuropathy) noted segmental demyelination in teased fiber preparations. In electron-microscopic sections, a slight increase in glycogen, acid mucopolysaccharides, and aggregates of glycogen and cytoplasmic laminar bodies in Schwann cells have been observed by others.


Neurology_Adams

Neurology_Adams. Polyneuropathy of sensorimotor type has also been observed in association with a syndrome of chronic lymphocytic thyroiditis and alopecia (Hart et al). Idiopathic Small-Fiber Sensory Polyneuropathy (Numb, Burning Feet Syndrome) This, of course, does not have the status of a single entity, but all neurologists encounter numerous cases of a relatively nonprogressive idiopathic sensory polyneuropathy, mainly in older patients. Paresthesias of feet and lower legs, sensory loss, and absent ankle reflexes are the usual findings. The hands may be mildly affected, but leg weakness and imbalance are absent or minor. A painful variety is also known (see later).


Neurology_Adams

Neurology_Adams. The most common situation in our experience has been one that affects elderly women with slowly progressive (over years) burning and numbness of the feet, ascending to the ankles or midcalves. There are few findings on examination. Often, there is only mild loss of pinprick and thermal sensation; ankle reflexes may or may not be reduced. There is little progression over the years. Most of these cases are idiopathic, but there is a broad differential diagnosis, including the diseases mentioned earlier, as outlined by Mendell and Sahenk (Table 43-5 is adapted from their discussion).


Neurology_Adams

Neurology_Adams. Electrophysiologic tests are likewise normal or virtually so; a few show diminished sural nerve potentials and minor changes of motor amplitudes. When the causes listed in the table have been excluded, a substantial group of patients is left and are in need of symptomatic relief. Some have been helped by gabapentin or by antidepressants and analgesic cream applied nightly to the soles and toes. A few of the more severe cases have apparently responded to gamma globulin infusions, but these observations require corroboration (Gorson and Ropper, 1995). In a number of cases of burning feet, the intradermal sensory nerves in skin biopsy specimens are depleted, but the meaning of this finding is not certain (Periquet et al) and the clinical diagnosis of a small-fiber neuropathy in affected older patients can be inferred without this procedure.


Neurology_Adams

Neurology_Adams. Identifiable causes for painful sensory neuropathy in the elderly include mainly diabetes, alcoholic–nutritional deficiency states, connective tissue disease, amyloidosis, and vasculitis. Presumably, in the idiopathic cases, there is a similar small-fiber neuropathy, but the common clinical situation is that an etiology cannot be found. An alternative cause in these neuropathies that are characterized mainly by painful burning is that there is an abnormality of the sodium channel that renders the sensory neurons or fibers hyperexcitable. In the experience of the group from Maastricht, 8 of 28 patients in whom no etiologic diagnosis for small-fiber neuropathy could be found, there were mutations in the gene (SCN9A) encoding voltage-gated sodium channel Nav1.7. The mutation caused a gain of function in this gene and allowed dorsal root ganglion neurons to become hyperexcitable (Faber at al). Yet another rare cause of this syndrome has been the finding of antibodies to peripherin, which


Neurology_Adams

Neurology_Adams. function in this gene and allowed dorsal root ganglion neurons to become hyperexcitable (Faber at al). Yet another rare cause of this syndrome has been the finding of antibodies to peripherin, which is a dominantly inherited trait (Stogbauer et al).


Neurology_Adams

Neurology_Adams. A polyneuropathy that advances slowly over 10 years or more is almost invariably genetic in origin. The neuropathic disease may be remarkably restricted, as in familial analgesia with foot ulcers, or extensive, as in familial peroneal muscular atrophy. The time of onset of these very chronic neuropathies is usually in early life but often cannot be dated with certainty by the patient or family. In infants, the condition may be mistaken for muscular dystrophy or infantile muscular atrophy until sensory testing becomes possible. In the developing child, whose musculature naturally increases in power and volume with age, it may be difficult to decide whether the disease is progressive but typically, there is trouble running or walking making it difficult to keep up with other children, repeated ankle injuries, toe catching, labeled as “clumsiness,” or falls. Strongly indicative of one of these conditions at any age are pes cavus, hammertoes, and, in extreme forms, talipes equinus. One of


Neurology_Adams

Neurology_Adams. ankle injuries, toe catching, labeled as “clumsiness,” or falls. Strongly indicative of one of these conditions at any age are pes cavus, hammertoes, and, in extreme forms, talipes equinus. One of these deformities is commonly detected in most cases of inherited polyneuropathy. In later life, some of the inherited neuropathies are manifest as trophic changes of skin and bone in distal parts of the limbs indicate involvement of small (pain) fibers and the presence of deformed and degenerated joints (Charcot joint). The mutilating effects are the result of repeated injury to analgesic parts and to a lack of autonomic vascular reflexes. Atrophy of muscle and trophic changes in the skin are generally more marked than in the acquired forms of polyneuropathy.


Neurology_Adams

Neurology_Adams. The CSF protein content may be mildly or moderately elevated over a period of years. We retain the nomenclature Charcot-Marie-Tooth (CMT) disease (type 1), which shows slowed nerve conduction as a consequence of a disorder of myelin. A distinctive feature of hereditary neuropathy is the uniformity of the electrophysiologic changes, for example, a similar degree of slowing of nerve conduction velocity in all the nerves, a feature that distinguishes this group from most acquired neuropathies. The distinction between the demyelinating and axonal types of inherited neuropathies is based on the motor nerve (typically ulnar or median nerve) conduction velocities in the arms, with slowing to velocities below 38 m/s defining the demyelinating category.


Neurology_Adams

Neurology_Adams. To the reader not immersed in neuromuscular diseases, the classification, nomenclature, and number of genes that give rise to this group of diseases is dizzying. One approaches the affected patient, however, in a more circumscribed way by noting that the dominantly inherited demyelinating types are designated CMT1 and the dominant axonal types, as Charcot Marie type 2 (CMT2). The group of myelinopathies with onset in infancy (also called Dejerine-Sottas disease or congenital hypomyelinating neuropathy), are subsumed under CMT3, whereas most recessively inherited neuropathies (both axonal and demyelinating) are termed CMT4. There are, in addition, forms with intermediate degrees of conduction slowing that are not easily classified. An older nomenclature uses the term hereditary motor-sensory neuropathies, or HMSNs, for the main CMT types. The hereditary sensory neuropathies (HSNs) and the hereditary sensory autonomic neuropathies (HSANs) are considered separate entities. This category


Neurology_Adams

Neurology_Adams. neuropathies, or HMSNs, for the main CMT types. The hereditary sensory neuropathies (HSNs) and the hereditary sensory autonomic neuropathies (HSANs) are considered separate entities. This category includes a variety of metabolic neuropathies and types that do not fit into the CMT classification.


Neurology_Adams

Neurology_Adams. Recent genetic findings have in some ways simplified the matter of classification and have permitted the creation of a nosology that more or less parallels the clinical one. The systems in Tables 43-2 and 43-6 represent an attempt to conciliate the clinical and genetic data. Of this large and varied group, only the sensorimotor Charcot-Marie-Tooth type is the one likely to be seen with any regularity by neurologists and general physicians. This group has become quite large as more individual mutations are discovered, but a small number accounts for the majority of cases. The commonly encountered varieties are indicated in italics in Table 43-6. The major forms of hereditary neuropathy are designated as subcategories of CMT disease, grouped by patterns of inheritance and described in more detail further on. Inherited Polyneuropathies of Mixed Sensorimotor-Autonomic Types


Neurology_Adams

Neurology_Adams. Clinical features These are the most common forms of inherited peripheral neuropathy and, indeed, among the most common of all inherited neurologic diseases. The early symptoms of childhood clumsiness and athletic imprecision are listed previously, to which are added foot deformities of high arches and hammer toes. There may have been ankle fractures, foot-drop, medical plantar foot calluses and a need for podiatric treatment at an early age, painless or foot ulcers. In adolescence, an “inverted champagne bottle” appearance of the forelegs may become apparent. The typical case of CMT has its onset during late childhood or adolescence, although neurologists are increasingly aware that some cases, particularly type 2, may not attract attention until middle life. CMT1 cases usually make their appearance during the first decade while the peak age of onset of CMT2 is in the second decade or even later. Both motor and sensory signs are said to be more severe in the first type (Harding and


Neurology_Adams

Neurology_Adams. appearance during the first decade while the peak age of onset of CMT2 is in the second decade or even later. Both motor and sensory signs are said to be more severe in the first type (Harding and Thomas, 1980). Adult patients have difficulty dating the onset of symptoms, so much so that with milder forms, they may not even be aware of having a neuropathic illness. In some cases, the widespread nerve conduction changes only come to light when this test is performed for the diagnosis of an unrelated problem or when a parent becomes aware of their own neuropathy after their child proves to have the disease. Some types that present in adulthood may even have a subacute or seemingly acute presentation, particularly the myelin protein zero (MPZ) and the PMP22 deletion (hereditary liability to pressure palsies) types.


Neurology_Adams

Neurology_Adams. Because the clinical description was provided in 1886 almost simultaneously by Tooth in England and by Charcot and Marie in France, all of their names have been attached to it, even though similar cases had been recorded earlier by Eulenberg (1856), Friedreich (1873), Ormerod (1884), and Osler (1880). The two important advances in our understanding of this disease since the original descriptions have been the separation of the main subtypes on the basis of their electrophysiologic (EMG) features and the discovery of genetic mutations that cause most of these diseases.


Neurology_Adams

Neurology_Adams. The frequency of the disease cannot be stated with precision because of its clinical heterogeneity, but the usually quoted prevalence is 1 in 2,500 of the population, the most frequent subtype occurring in 1 in 4,000. This class of neuropathies is characterized clinically, as discussed previously, by the pattern of heredity, the speed of motor nerve conduction, and special clinical characteristics including the age of onset of symptoms such as difficulty walking and certain appended neuropathic syndromic findings such as hearing loss. From a genetic perspective, the classification is based on the gene that is affected and the nature of the mutation; deletions and duplications are the most common, but many single nucleotide polymorphisms have also been identified.


Neurology_Adams

Neurology_Adams. As a guide to the frequency of various types, Saporta and colleagues in a study of over 1,000 patients from neuromuscular clinics found that two-thirds of patients had a mutation detected by conventional means. When combined with the mode of inheritance, the most common type was the typical demyelinating variety of Charcot-Marie-Tooth disease (CMT1A, 17p duplication), and fewer than 10 percent each had X-linked CMTX1, hereditary liability to pressure palsies (HNPP), CMT1B, or the main axonal type, CMT2A; together, these implicated only 4 genes and all other forms, derived from about 30 other mutations, accounted for under 1 percent each. This is informative in guiding genetic testing in clinical circumstances. Still, almost one-third of patients with a clear history of heredofamilial neuropathy had none of the currently detectable mutations.


Neurology_Adams

Neurology_Adams. The chronic degeneration of peripheral nerves and roots results in distal muscle atrophy beginning in the feet and legs and later involving the hands. The extensor hallucis and digitorum longus, the peronei, and the intrinsic muscles of the feet are affected early in life and this muscle imbalance produces the bony changes of pes cavus and pied en griffe (high arches and hammertoes). Later, all muscles of the legs and sometimes the lower third of the thigh become weak and atrophic. The thin legs have been likened to those of a stork or, if the lower thigh muscles are affected, to an inverted champagne bottle. Eventually the nerves to the calf muscles degenerate and the ability to plantar flex the feet is lost. After a period of many years, atrophy of the hand and forearm muscles develops in some cases. The hands later become clawed. The wasting seldom extends above the elbows or above the middle third of the thighs. Paresthesias and cramps are present but only to a slight degree and


Neurology_Adams

Neurology_Adams. in some cases. The hands later become clawed. The wasting seldom extends above the elbows or above the middle third of the thighs. Paresthesias and cramps are present but only to a slight degree and there is always some impairment, usually also mild, of deep and superficial sensation in the feet and hands, shading off proximally. Rarely, the sensory loss is severe and perforating ulcers appear as they do in the pure sensory varieties of inherited neuropathy. The tendon reflexes are absent in the involved limbs. The illness progresses very slowly over decades, giving the impression of stabilization for long periods.


Neurology_Adams

Neurology_Adams. Walking difficulty, which is ultimately the main disability, is caused by a combination of sensory ataxia and weakness. Foot-drop and instability of the ankles are additional handicaps. The feet and legs may ache after use and cramps may be troublesome as mentioned, but otherwise pain is unusual; the feet may become cool, swollen, and blue, secondary to inactivity of the muscles of the feet and legs and their dependent position. There is usually no disturbance of autonomic function. Fixed pupils, optic atrophy, and nystagmus and endocrinopathies, epilepsy, and spina bifida, which have been reported occasionally in association with peroneal muscular atrophy, probably represent coincidental congenital disorders. The only distinguishing clinical feature between types 1 and 2, and this is present in only a minority of cases, is perhaps enlargement of the nerves in type 1, most easily appreciated by palpation of the greater auricular and peroneal nerves. The clinical heterogeneity of CMT


Neurology_Adams

Neurology_Adams. in only a minority of cases, is perhaps enlargement of the nerves in type 1, most easily appreciated by palpation of the greater auricular and peroneal nerves. The clinical heterogeneity of CMT disease has been alluded to in the previous discussion and is evident in the numerous mutations that give rise to similar chronic polyneuropathies. Restricted forms are known to affect only the peroneal and pectoral or scapular muscles (scapuloperoneal form).


Neurology_Adams

Neurology_Adams. The differential diagnosis involves the distal muscular dystrophies, late forms of familial motor system disease, Friedreich ataxia, Roussy-Lévy syndrome (see later) and other familial polyneuropathies, and, in adult onset cases, CIDP and the paraproteinemic neuropathies, discussed earlier.


Neurology_Adams

Neurology_Adams. Electrophysiologic features Dyck and Lambert (1975) and Harding and Thomas (1980) are credited with subdividing CMT into the two broad types based on the speed of motor nerve conduction in the ulnar or median nerves, as mentioned, slow (mean conduction velocity less than 38 m/s but often in the range of 20 m/s) in type 1, and normal or near-normal conduction in CMT2. Electromyographers appropriately refer to these, respectively, as the demyelinating and axonal types. In both, the compound muscle action potentials and sensory potentials are greatly reduced in amplitude, but in type 2 there are findings of denervation in the EMG. In type 1 there is severe and widespread slowing of nerve conduction, but the electrical conduction block that characterizes acquired demyelinating neuropathies is not found and, in distinction to almost most all acquired diseases of peripheral nerves, the electrophysiologic findings, particularly the pronounced slowing of conduction in CMT1, are uniform


Neurology_Adams

Neurology_Adams. is not found and, in distinction to almost most all acquired diseases of peripheral nerves, the electrophysiologic findings, particularly the pronounced slowing of conduction in CMT1, are uniform throughout the peripheral nervous system.


Neurology_Adams

Neurology_Adams. Genetic features and genetic testing Aspects of the genetic causes of these diseases were addressed in the introductory comments and here it is emphasized that a few basic principles apply. First, only a small number of cases of Charcot-Marie-Tooth disease arise as de novo mutations (Hoogendijk et al). Second, different mutations in the same gene can give rise to more than one type of disease. Third, only four genes (PMP22, MPZ, GJB1, and MFN2) account for 92 percent of cases of CMT and this allows efficient testing in practice.


Neurology_Adams

Neurology_Adams. The most prevalent form of the disease is CMT1A, which displays an autosomal dominant pattern of inheritance with almost complete penetrance; it is due to duplication of PMP 22 on chromosome 17p. Less often, CMT1 is autosomal recessive and even less frequently, X-linked dominant or X-linked recessive (see Table 43-6). Two common mutations in chromosomes 1 or 17 cannot be easily distinguished from one another on clinical grounds, but they have distinctive EMG features. The condition of hereditary liability to pressure palsies (HNPP) also displays an aberration on chromosome 17, but in the form of a deletion rather than a duplication of the gene for PMP22. This disease is discussed further on under “Brachial Plexus Neuropathies.” The X-linked variant is the result of a mutation of the gene for connexin-32, another component of myelin. In a large proportion of CMT2 cases, the genetic basis cannot be established with current clinically available genetic testing. Undoubtedly, further


Neurology_Adams

Neurology_Adams. gene for connexin-32, another component of myelin. In a large proportion of CMT2 cases, the genetic basis cannot be established with current clinically available genetic testing. Undoubtedly, further studies of genes and gene products will continue to advance our understanding of the inherited neuropathies. For example, the study by Lupski and colleagues using whole genome sequencing has identified heretofore unknown compound heterozygous alleles that produce CMT phenotypes, most rare, but demonstrating that the frequency of unidentified mutations will be continuously be reduced.


Neurology_Adams

Neurology_Adams. Based on the finding that only a few mutations are implicated in the majority of cases of CMT, various algorithms have been designed, taking into account the degree of slowing of motor nerve conduction velocity and clinical features. For example, PMP22 testing is a reasonable first step if the patient has the typical clinical appearance of CMT1A and motor nerve conductions are slower than 38 m/s. If this shows no mutation and there is male-to-male transmission, screening for CMTX1 is performed, or if autosomal inheritance, for MPZ mutations (CMT1B). If these are unrevealing, a third step may be screening for point mutations in PMP22, SIMPLE, and EGR2. If the nerve conduction velocities are severely slowed, below 15 m/s, PMP22 duplication or MPZ mutations are likely to be present. Those with intermediate conduction velocities, between 35 and 45 m/s are likely to have CMT1X or CMT1B and mutations in the corresponding genes. It is worth again noting that only a third of CMT2 cases will


Neurology_Adams

Neurology_Adams. intermediate conduction velocities, between 35 and 45 m/s are likely to have CMT1X or CMT1B and mutations in the corresponding genes. It is worth again noting that only a third of CMT2 cases will have mutations found by current methods. These prescriptions for testing will change as new sequencing methods are introduced.


Neurology_Adams

Neurology_Adams. Pathologic findings Degenerative changes in the nerves result in depletion of the population of large sensory and motor fibers, leaving only the condensed endoneurial connective tissue. As far as one can tell, axons and myelin sheaths are both affected, the distal parts of the nerve more than the proximal ones. In type I, the nerves may be enlarged, with “onion-bulb” formations of Schwann cells and fibroblasts, as in Dejerine-Sottas disease (CMT3; type III HMSN in the Dyck classification). This change can often be seen in sural nerve biopsies. Anterior horn cells are slightly diminished in number and some are chromatolyzed as a secondary change. Dorsal root ganglion cells suffer a similar fate. The disease involves sensory posterior root fibers with degeneration of the posterior columns of Goll more than of Burdach. The autonomic nervous system remains relatively intact. The muscles contain large fields of atrophic fibers (group atrophy). Some of the larger fibers have a target


Neurology_Adams

Neurology_Adams. of Goll more than of Burdach. The autonomic nervous system remains relatively intact. The muscles contain large fields of atrophic fibers (group atrophy). Some of the larger fibers have a target appearance and may show degenerative changes. All these muscle changes are typical of neurogenic denervation. Former claims of a coincidental myelopathy and degeneration of spinocerebellar and corticospinal tracts probably indicate that the associated disease was really Friedreich ataxia or some other combination of chronic myelopathy and neuropathy.


Neurology_Adams

Neurology_Adams. Treatment No specific treatment is known. Stabilizing the ankles by arthrodeses is indicated if foot-drop is severe and the disease has reached the point where it is not progressing. Pediatric orthopedic specialists have experience with several techniques to stabilize the joints of weakened limbs. Regular exercise, but avoiding excessive weight training, is usually prescribed. In mild and early cases, fitting the legs with light braces and the shoes with springs to overcome foot-drop can be helpful. (HNPP, PMP22 Deletion)


Neurology_Adams

Neurology_Adams. This unusual but distinctive process of multiple recurrent local neuropathies, first reported by Earl and colleagues, is caused by a deletion of the PMP22 gene, the one that is duplicated in the previously described CMT1A. In both CMT1A and hereditary neuropathy with pressure palsies (HNPP), the PMP22 gene is functionally normal and these disorders arise because the total amount of the protein is abnormal. In CMT1A the gene is duplicated on one chromosome, thereby increasing the total PMP22 protein; by contrast, in HNPP, the gene is deleted so that the PMP22 protein is at approximately half-normal levels. HNPP is transmitted as a dominant trait. In these individuals, the focal neuropathies and plexopathies are generally not painful (in contrast with related conditions of hereditary neuralgic amyotrophy discussed further on). Focal nerve lesions are often provoked by slight or even brief compression. In addition to recurrent focal nerve palsies, most individuals with HNPP have an


Neurology_Adams

Neurology_Adams. amyotrophy discussed further on). Focal nerve lesions are often provoked by slight or even brief compression. In addition to recurrent focal nerve palsies, most individuals with HNPP have an underlying chronic but slowly progressive demyelinating sensorimotor neuropathy that is mild on clinical examination (e.g., not all cases show areflexia). Electrophysiologic studies are abnormal, but may be only subtly so, with some slowing of conduction and distal motor and sensory nerve abnormalities, particularly across sites of compression. Nerve biopsies from these patients are most remarkable for the presence of localized nerve sheath thickening with duplication of the myelin lamellae (so-called tomaculae, meaning sausage shaped).


Neurology_Adams

Neurology_Adams. Hypertrophic Neuropathy of Infancy (Dejerine-Sottas Disease, Congenital Hypomyelination, CMT3)


Neurology_Adams

Neurology_Adams. This relatively rare but striking neuropathy is inherited as an autosomal recessive trait. It begins in childhood or infancy, earlier than the typical form of peroneal muscular atrophy. Walking is delayed in onset and then progressively impaired. Pain and paresthesias in the feet are early symptoms, followed by the development of symmetrical weakness and wasting of the distal portions of the limbs. Talipes equinovarus postures with clawfeet and later clawhands are common. All modalities of sensation are impaired in a distal distribution, and the tendon reflexes are absent. Miotic, unreactive pupils, nystagmus, and kyphoscoliosis have been observed in some cases. The trunk and other cranial nerves are spared. The ulnar, median, radial, posterior tibial and peroneal nerves stand out like tendons and are easily followed with the gently roving finger. The enlarged nerves are not tender. Unlike other forms of hereditary neuropathy, the CSF protein is persistently elevated in


Neurology_Adams

Neurology_Adams. out like tendons and are easily followed with the gently roving finger. The enlarged nerves are not tender. Unlike other forms of hereditary neuropathy, the CSF protein is persistently elevated in Dejerine-Sottas disease, in all likelihood because the spinal roots are enlarged. Nerve conduction velocities are markedly reduced, even when there is little or no functional impairment. Patients are usually more disabled than those with peroneal muscular atrophy and are confined to wheelchairs at an early age. Treatment is purely symptomatic.


Neurology_Adams

Neurology_Adams. It is important to emphasize that the occurrence of hypertrophic neuropathy is not confined to this particular inherited disease. If one groups all patients in whom the nerves are diffusely enlarged (incorrectly called “hypertrophic” as it is mainly a nonspecific reaction of the epineural and perineural connective tissue that contributes to the bulk of the nerves), several diseases, both genetic and acquired, are included. The identifying histologic lesion in these cases is the “onion bulb,” which consists of a whorl of overlapping, intertwined, attenuated Schwann cell processes that encircle naked or finely myelinated axons and of endoneurial fibrofilaments. Enlarged nerves have been described in cases of recurrent demyelinating polyneuritis (CIDP), familial amyloidosis, Refsum disease, CMT type I, and other diseases. As was first pointed out by Thomas, any pathologic process that causes recurrent segmental demyelination and subsequent repair and remyelination may have this effect.


Neurology_Adams

Neurology_Adams. CMT type I, and other diseases. As was first pointed out by Thomas, any pathologic process that causes recurrent segmental demyelination and subsequent repair and remyelination may have this effect. In some patients with a history of early childhood hereditary polyneuropathy, the nerves are not yet palpably enlarged, but the characteristic Schwann cell abnormalities are revealed in biopsy material from a cutaneous nerve.


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Neurology_Adams. Phenotype-Genotype Correlations in the Inherited Sensorimotor Polyneuropathies


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Neurology_Adams. As the molecular basis of the inherited polyneuropathies has been elucidated, it has become clear that diverse mutations and molecular defects can give rise to the same clinical phenotype. From a neurobiologic perspective, it is intriguing that both Dejerine-Sottas and Roussy-Lévy syndromes are linked to a recessively inherited loss of the myelin protein P0, and that the salient clinical features of this disorder are manifestations of defective nerve myelination. However, it has also become apparent that nearly identical clinical syndromes are associated with mutations in the genes for PMP22 and for the Schwann cell DNA-binding protein EGR2. Moreover, while some mutations in the P0 gene cause infantile onset neuropathies with the Dejerine-Sottas and Roussy-Lévy phenotypes, other mutations in the same gene cause adult onset neuropathies. Although the early-onset cases show marked slowing of nerve conduction, the adult ones have conduction velocities that are typically above 35 m/s. The


Neurology_Adams

Neurology_Adams. in the same gene cause adult onset neuropathies. Although the early-onset cases show marked slowing of nerve conduction, the adult ones have conduction velocities that are typically above 35 m/s. The infancy-onset cases reveal major disruptions of folding of compact myelin, whereas in the adult-onset cases subtle alterations in the myelin protein PO lead to a slow, predominantly axonal degeneration in adult life. Many other insights into the genetic and structural alterations of this vast category of disease have been revealed and can be appreciated from reading subspecialty texts on the subject, including the chapters by Amato and Russell and the monograph by Klein, Duan, and Shy, and the study by Saporta and coworkers, which are recommended.


Neurology_Adams

Neurology_Adams. Inherited Polyneuropathies of Predominantly Sensory Type Common to the diseases comprising this group are insensitivity to pain, lancinating pains, and ulcers of the feet and hands, leading to osteomyelitis, osteolysis, stress fractures, and recurrent episodes of cellulitis. Because similar symptoms and signs occur in syringomyelia, leprosy, and tabes dorsalis, there is considerable uncertainty in older writings on this subject as to whether the reported cases were examples of one of these diseases or of hereditary neuropathy. According to Dyck and Lambert (1975), it was Leplat in 1846, who first described plantar ulcers (mal perforant du pied).


Neurology_Adams

Neurology_Adams. The characteristic features of this group of polyneuropathies are an autosomal dominant mode of inheritance and onset of symptoms in the second decade or later. Characteristically this begins with subtle loss of sensation for painful stimuli in the feet (e.g., inability to feel the hot sand or hot water in a tub). As the disease evolves, there is involvement of the feet with calluses of the soles and, later, episodes of blistering, ulceration, and lymphangitis followed by osteomyelitis and osteolysis, shooting pains, distal sensory loss with greater affection of pain and thermal sensation than of touch and pressure, loss of sweating, diminution or absence of tendon reflexes, and only slight loss of muscle power. Over time, loss of pain sensation in the fingers leads to fingertip ulcerations, osteomyelitis, and amputations.


Neurology_Adams

Neurology_Adams. The plantar ulcer overlying the head of a metatarsal bone is the most dreaded complication, because it often leads to osteomyelitis. Infection of the pulp of the fingers and paronychias are uncommon. Some patients have a mild pes cavus and weakness of the peroneal and pretibial muscles, with foot-drop and steppage gait. Lancinating pains may occur in the legs, thighs, and shoulders, and, exceptionally, the pain may last for days or longer and be as disabling as that of tabes dorsalis; however, in the majority of patients there is no pain whatsoever. Neural deafness was present in one of Denny-Brown’s patients. In that case, which was studied postmortem, there was a loss of small nerve cells in the lumbosacral dorsal root ganglia; the dorsal roots were thin, and the fibers in the posterior columns of the spinal cord and those in the peripheral nerves were diminished in number. Myelinated and unmyelinated fibers were both affected. Both axonal degeneration and segmental demyelination


Neurology_Adams

Neurology_Adams. columns of the spinal cord and those in the peripheral nerves were diminished in number. Myelinated and unmyelinated fibers were both affected. Both axonal degeneration and segmental demyelination have been demonstrated in teased nerve preparations. Sensory nerve conduction may be absent or is uniformly slowed in every nerve tested.


Neurology_Adams

Neurology_Adams. It must be emphasized that despite its categorization as a “sensory and autonomic neuropathy,” the most common, dominantly inherited form, termed HSAN1, also entails progressive, disabling, distal motor weakness, a consequence of ongoing axonopathy and denervation. HSAN1 is a consequence of a loss of function of the enzyme serine palmitoyltransferase, which is the rate-limiting step in the biosynthesis of sphingolipids. Recessive Mutilating Sensory Polyneuropathy of Childhood


Neurology_Adams

Neurology_Adams. Recessive Mutilating Sensory Polyneuropathy of Childhood Here the pattern of inheritance is autosomal recessive. Onset is in infancy and early childhood and walking is delayed; there is pes cavus deformity and the first movements are ataxic. Ulcerations of the tips of toes and fingers and repeated infections of these parts result in the formation of paronychias and whitlows. The tendon reflexes are absent, but power is well preserved. All sensory modalities are impaired (touch-pressure somewhat more than pain-temperature), mainly in the distal parts of the limbs but also over the trunk. In addition, there are reports of several sibships in which multiple members had a sensory neuropathy manifest by a generalized insensitivity to pain of the type described later. The lesions and electrophysiologic findings are similar to those in the dominantly inherited sensory neuropathy described previously.


Neurology_Adams

Neurology_Adams. In all types of hereditary sensory neuropathies, measures must be taken to prevent stress fractures, acral mutilation, and infection. This is more difficult in the small child who does not understand the problem. It is also now evident that some of the infantile hereditary sensory neuropathies are a result of a disruption of molecular signaling pathways for neurotropic substances, such as nerve growth factor, that are critical to neural development. Congenital Insensitivity to Pain


Neurology_Adams

Neurology_Adams. In congenital insensitivity or indifference to pain, a syndrome in which the patient throughout life is unreactive to the pain of injury, there is no loss of the ability to distinguish pinprick and other noxious stimuli from nonnoxious ones. Furthermore, the nervous system of such individuals seems to be normal. There is another variety characterized by universal analgesia (Swanson et al). This latter type is inherited as an autosomal recessive trait and at least one form involves the gene for a nerve growth factor receptor located on chromosome 1q immediately adjacent to the site of the mutation for Charcot-Marie-Tooth disease type 1B (see Table 43-6). During childhood, one of the patients of Swanson and colleagues had high fever when the environmental temperature was raised and the other had orthostatic hypotension. One of the patients died in his twelfth year and was found to have an absence of small neurons in the dorsal root ganglia, an absence of Lissauer tracts, and a decrease


Neurology_Adams

Neurology_Adams. had orthostatic hypotension. One of the patients died in his twelfth year and was found to have an absence of small neurons in the dorsal root ganglia, an absence of Lissauer tracts, and a decrease in size of the descending spinal tracts of the trigeminal nerves. Sweat glands were present in the skin but were not innervated.


Neurology_Adams

Neurology_Adams. Whereas the usual cutaneous lipomas have no neurologic accompaniments, this clinical curiosity, known as Launois-Bensaude disease, consists of symmetrical lipomas of the neck and shoulders that are associated with polyneuropathy and sometimes, deafness. A mitochondrial disorder of similar genetic origin as the MERRF syndrome (see Chap. 36) has been identified (see Neumann’s review for clinical details).


Neurology_Adams

Neurology_Adams. This interesting process was mentioned in Chap. 38 in relation to dementia in which it is pointed out that there is a multisystem neurologic disease characterized by the widespread deposition in nervous tissue of corpora amylacea, in this disease termed polyglucosan bodies. The main presentation of this disorder is of slowly progressive motor and pronounced sensory loss in the legs due to an axonal polyneuropathy, neurogenic bladder, and a degree of upper motor neuron signs that may also be evident. It is the early appearance of the urinary difficulties or the upper motor neuron features that mark the illness as unusual in relation to other polyneuropathies. Biopsy of the sural nerve demonstrates profuse deposition of the polyglucosan bodies in the endoneurium. When dementia occurs, either with the neuropathy or in isolation, the corpora amylacea are found throughout the cerebrum. The process is detailed by Robitaille and colleagues and an upper motor neuron presentation that


Neurology_Adams

Neurology_Adams. either with the neuropathy or in isolation, the corpora amylacea are found throughout the cerebrum. The process is detailed by Robitaille and colleagues and an upper motor neuron presentation that simulates amyotrophic lateral sclerosis, by McDonald and coworkers.


Neurology_Adams

Neurology_Adams. The bodies are made up largely of glucose polymers that are well known to occur in the aging brain and, when present in small numbers, have been assigned an innocuous meaning. In the usual type of polyglucosan disease, which is found in individuals of Ashkenazic Jewish origin, there is a deficiency in glycogen branching enzyme (GBE) that is shared with glycogenosis type IV, and infantile recessive process, Anderson disease. As such, it could be considered with the other neuropathies that have an identifiable metabolic cause, discussed as a group further on. However, a proportion of cases do not have the inherited GBE enzyme abnormality. Riley-Day Familial Dysautonomia (See Also Chap. 25)


Neurology_Adams

Neurology_Adams. This disorder, inherited as an autosomal recessive trait, affects predominantly children of Ashkenazic Jewish heritage. Familial dysautonomia is usually manifested soon after birth (poor sucking, failure to thrive, unexplained fever, episodes of pneumonia). Hyporeflexia and impairment or loss of pain and temperature sensation, with relative preservation of pressure and tactile sense, are the main manifestations. Motor fibers are probably involved as well, but only to a slight degree; this is shown more effectively by reduced motor conduction velocity in peripheral nerves than it is by weakness. At a later age, the neuropathy becomes overshadowed by other manifestations of the disease, notably repeated infections and abnormalities of the autonomic nervous system—lack of tears, corneal ulceration, fixed pupils, blotchiness of the skin, defective temperature control, cold hands and feet, excessive sweating, lability of blood pressure, postural hypotension, difficulty in swallowing,


Neurology_Adams

Neurology_Adams. ulceration, fixed pupils, blotchiness of the skin, defective temperature control, cold hands and feet, excessive sweating, lability of blood pressure, postural hypotension, difficulty in swallowing, esophageal and intestinal dilation, emotional instability, recurrent vomiting, and stunted growth. The tongue lacks fungiform papillae.


Neurology_Adams

Neurology_Adams. Nerve biopsy reveals a diminution of small myelinated and unmyelinated fibers, which explains the impairment of pain and temperature sensation. In autopsy material, sympathetic and parasympathetic ganglion cells and, to a lesser extent, nerve cells in the sensory ganglia are diminished in number. Patients excrete increased amounts of homovanillic acid and decreased amounts of vanillylmandelic acid and methoxyhydroxyphenylglycol. Weinshilboum and Axelrod demonstrated a decrease in serum dopamine β-hydroxylase, the enzyme that converts dopamine to norepinephrine. The disease is caused by a mutation in a gene that expresses a kinase-associated protein (see HSAN3 in Table 43-6). There is no treatment for the disease except to provide symptomatic relief of gastrointestinal symptoms and orthostatic fainting.


Neurology_Adams

Neurology_Adams. Other examples of congenital polyneuropathy with absence of autonomic function, probably differing from the Riley-Day dysautonomia, have been reported. Some of these develop transient episodes of reflex sympathetic dystrophy. A congenital failure of development of neural elements derived from the neural crest has been postulated. Ataxia-telangiectasia and Chédiak-Higashi disease are other genetic diseases with a recognized metabolic abnormality that may cause a polyneuropathy. They are described in Chap. 36, with the hereditary metabolic disorders. Other Forms of Inherited Sensory Neuropathy


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Neurology_Adams. Included here are numerous disorders similar to the ones described in the preceding pages but caused by different mutations; neuropathy with cerebellar degeneration; and the neuropathies in which there are recognized metabolic abnormalities, including familial amyloidosis. Some years ago a young man and woman with universal anesthesia affecting head, neck, trunk, and limbs came to attention (Adams et al); all forms of sensation were absent. The patients were areflexic but retained nearly full motor power; their movements were ataxic. Autonomic functions were impaired but not abolished. In a sural nerve biopsy, nearly all fibers—large and small, myelinated and unmyelinated—had disappeared. Surprisingly, there were no trophic changes of any kind. Donaghy and coworkers and others have described a variant of the recessively inherited form of sensory neuropathy in which there was an associated neurotrophic keratitis and a selective loss of small myelinated fibers in sural nerve biopsies.


Neurology_Adams

Neurology_Adams. a variant of the recessively inherited form of sensory neuropathy in which there was an associated neurotrophic keratitis and a selective loss of small myelinated fibers in sural nerve biopsies. We continue to observe variant and unclassifiable cases of purely motor, sensory, or mixed types in which genetic testing does not reveal a mutation such as these every year.


Neurology_Adams

Neurology_Adams. In 1926, Roussy and Lévy reported 7 cases of a dominantly inherited ataxic and neuropathic malady that had not previously been described. Its close relation to Friedreich ataxia and the amyotrophy of Charcot-Marie-Tooth disease was recognized. On the basis of molecular genetic testing, these relationships been clarified. Most classifications group it with CMT1 on the basis of the causative mutations and nerve conduction studies.


Neurology_Adams

Neurology_Adams. The condition is a sensory ataxia with pes cavus and areflexia, affecting mainly the lower legs and progressing later to involve the hands. Some degree of sensory loss, mainly of vibratory and position sense, is described in all cases. Atrophy of the muscles of the legs and postural tremor eventually become prominent, but the patients do not have signs of cerebellar disease (dysarthria, tremor, nystagmus). Kyphoscoliosis, a feature typical of Friedreich disease, has been described in several cases. Although the feet may be cold or slightly discolored, no autonomic defects are documented and the nerves are not palpably enlarged. Electrocardiographic abnormalities similar to those of Friedreich ataxia have been noted in one family but are not usual. The onset in many patients is during infancy, possibly dating from birth, and the course is relatively benign; all descendants of the original Roussy-Lévy family were still able to walk during their seventh decade of life.


Neurology_Adams

Neurology_Adams. On clinical and pathologic grounds, Dyck and Lambert (1975) placed the Roussy-Lévy kinships within the category of the demyelinating type of Charcot-Marie-Tooth disease (CMT1). The mode of inheritance of the 2 syndromes, their benign course, pattern of neurologic signs, slow nerve conduction, and biopsy features (demyelination of nerve fibers with onion-bulb formation) are much the same. This view has been reinforced by the genetic findings reported by Planté-Bordeneuve and colleagues. In affected members of the original Roussy-Lévy family, these investigators identified a point mutation in the domain of the myelin protein gene PO, the same gene that is implicated in Dejerine-Sottas disease. Most currently studied cases (there are few) have point mutations in PMP22 or MPZ. Based on limited pathologic study, there is no cerebellar degeneration; nevertheless, the shared clinical features with Friedreich ataxia are unmistakable and create diagnostic confusion before genetic testing.


Neurology_Adams

Neurology_Adams. Polyneuropathy With Cerebellar Degeneration (See “Predominantly Cerebellar Forms of Hereditary and Sporadic Ataxia” in Chap. 38)


Neurology_Adams

Neurology_Adams. Several such cases of adult onset have come to our attention over the years. Unlike Friedreich disease, the ataxia is mild and there is no kyphoscoliosis, but pes cavus or hammer-toe deformities are found, attesting to the early onset of the neuropathy. The lower legs become atrophic and findings characteristic of CMT such as absent ankle reflexes and mild to moderate loss of distal deep sensibility are present. There is no Romberg sign and no Babinski signs. The outstanding feature is a profound atrophy of the cerebellar hemispheres, and to some extent of the vermis, on MRI. Although the illness is slowly progressive, our patients, like those with Roussy-Lévy disease, have remained highly functional into late age, having difficulty mostly with maintaining balance when dancing or wearing high-heeled shoes. The EMG is consistent with CMT2. The electrocardiogram has been normal. Several, but not all, such patients have had a family history of a similar process, but the available genetic


Neurology_Adams

Neurology_Adams. shoes. The EMG is consistent with CMT2. The electrocardiogram has been normal. Several, but not all, such patients have had a family history of a similar process, but the available genetic testing has failed to reveal the site of a mutation. As mentioned, the process can simulate Friedreich ataxia in some respects. The genetic basis is uncertain and various genotypes have been reported in single families.


Neurology_Adams

Neurology_Adams. From time to time we have observed children and young adults with unmistakable progressive spastic paraplegia superimposed on a sensorimotor polyneuropathy of extremely chronic evolution. Sural nerve biopsy in 2 of our cases disclosed a typical “hypertrophic” polyneuropathy. In another case, only loss of nerve fibers was found. Cavanaugh and colleagues and Harding and Thomas (1984) reported similar patients. Our patients were severely disabled, being barely able to stand on their atrophic legs. An even more ambiguous form of disease was described by Vucic and colleagues in which there is typical CMT but with brisk reflexes. There were Babinski signs in half the patients and spastic dysphonia in a few others. The mutation is not known.


Neurology_Adams

Neurology_Adams. Although few in number, some cases of chronic polyneuropathy are combined with optic atrophy, with or without deafness or retinitis pigmentosa, and Dyck and Lambert (1975) classed these in a separate group. Jaradeh and Dyck have also described a hereditary motor-sensory polyneuropathy with the later development of a parkinsonian or a choreic-dystonic syndrome that responded to l-dopa. Most cases of this type have had an autosomal recessive inheritance. This entity, mentioned earlier in relation to hereditary neuropathy with pressure palsies because of the implication of a similar genetic locus, is discussed in the later section under “Brachial Neuritis, Brachial Plexitis (Neuralgic Amyotrophy, Parsonage-Turner Syndrome).” Refsum Disease (HMSN IV, PHYH, and PEX7 Mutations)