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The peripheral neuropathies can be subdivided into two main groups. One of these is dependent upon a degeneration of the distal axon, usually called by some metabolic disorder. These are known as chronic axonal neuropathies. All of these neuropathies share certain common features. They are usually subacute and convert into chronic illness. The clinical findings are symmetrical and primarily distal, usually a mixed sensory and motor disorder, with absent reflexes in the areas affected. Even with reversal of the metabolic disorder, recovery is slow and very incomplete. The most common causes of axonal neuropathy are drugs such as Vincristine and Furadantin, alcoholism, chronic nutritional disorder, diabetes, uremia, and some industrial exposures such as hexane and acrylamide. The heavy metals such as lead and other inorganic toxins, such as arsenic, have virtually disappeared from clinical practice peripheral neuropathy, nuropathy, periferal neuropathy, motor unit.
The other main category of neuropathy is the demyelinating neuropathy. In this group of disorders, the primary disorder does not affect the axon, although the axon may secondarily degenerate. These diseases are typically more widespread, asymmetrical, and may be quite acute in nature. The acute version is known as Guillain-Barre's syndrome, and this is an illness that presents with widespread loss of reflexes, characteristically advancing over several days or, at most, two weeks. The sensory findings are usually slight or absent. As is widely known, the spinal fluid will contain a large amount of albumin, but few cells. This formula develops one or two weeks following the onset of the illness and is often not observed with the first spinal tap. Treatment of Guillain-Barre's syndrome remains supportive, although there have been interesting reports in recent literature of dramatic reversals of severe weakness with plasma exchange. It has now been definitely demonstrated that as a group, patients with Guillain-Barre's syndrome are not made better and may, in fact, do worse with steroid therapy. There have been individual exceptions to this rule, but the routine use of steroid, based on current evidence, cannot be supported. As many as ten percent of patients will have significant residual weakness and a few patients never fully recover.
There is a chronic demyelinating neuropathy which is related to Guillain-Barre, although usually not a direct outcome of it. This is known as chronic inflammatory polyradiculoneuropathy. The condition has a relapsing course and often presents with asymmetrical, painless weakness and sensory loss.
Metabolic disorders are the most common causes of neuropathy in our population.
In Diabetes Mellitus, some 50% of patients have at least electrophysiologic evidence of peripheral nerve damage. Three distinct patterns of involvement are described:
Sensory deficits and especially painful paresthesias in the feel may be presenting complaints in diabetics. Segmental loss of myelin and degeneration of axons both occur. Postulated causes of the neuropathy include a metabolic abnormality and diffuse microvasculopathy.
Autonomic neuropathy is frequent and is manifest primarily by atonic bladder and impotence in male diabetics. Abnormal sweating and blood pressure instability are often seen.
Involvement of femoral nerve and lateral femoral cutaneous nerve may produce proximal symptoms. Quadriceps wasting with pain in the groin radiating to the low back can simulate and L4 radiculopathy. Frequently painless bilateral wasting can be rather marked.
Uremia produces a distal sensorimotor polyneuropathy of the axonal type. This is usually reversed by the renal transplantation and may be improved by dialysis.
Alcoholism and neuropathy are common partners. The neuropathy is predominantly demyelinating although axonal degeneration is seen as well. The combination of nutritional factors, effect of alcohol and toxins due to hepatic failure combine to produce, in some cases, a rather impressive disease. Improvement of the hepatic disorder and nutritional factors usually improve the neuropathy, although some permanent axonal loss may be seen.
Vitamin deficiencies are rarely a result of isolated deficit of one vitamin alone.
B1 - Diet high in calories, but deficient in vegetables. Distal, motor poly neuropathy due to axonal degeneration.
B12 - Pernicious anemia produces a myelopathy and axonal degeneration involving mainly large fibers.
Folate Deficiency of folate is thought to be responsible for the distal polyneuropathy in chronic anti-convulsant therapy.
Heavy metals: most commonly seen is the mononeuropathy multiplex of lead poisoning (wrist drop or foot drop).
Organic solvents: N-hexane, methyl butyl Ketone, Carbon Tetrachloride produce a "dying back" neuropathy with giant axonal swelling in the peripheral nerves. Axonal transport is affected. Acrylamide is an industrial compound used as the prototype model of the "dying back" neuropathy. Organophosphate compounds may produce fasciculations. Drugs, in particular Isoniazide and ethambutol used to treat TB, vincristine used in cancer chemotherapy and some antibiotics, can produce significant neuropathies. Thalidomide, known for its production of phocomelia (Seal Limb) in children of pregnant women using it as a sedative, produces a neuropathy and in some areas is used to treat painful paresthesias in leprosy.
Cancer
Factors producing neuropathies in cancer patients include nutritional deficiency, chemotherapeutic agents and concurrent metabolic disorders.
Myeloma and macroglobulinemia are accompanied by neuropathy. The most common picture is of a distal sensori-motor polyneuropathy sometimes preceding diagnosis of the Ca. A motor neuron-like disorder may be seen as well as the rare defect in neuromuscular transmission (Lambert-Eaton Syndrome) associated with oat cell Ca of lung.
Vasculitides generally produce a mononeuropathy characterized by infarction of fasciculi within nerves. There may be focal weakness and/or sensory loss. Inherited neuropathies are much less common than the toxic and metabolic:
Acute intermittent porphyria, an autosomal dominantly inherited disorder is classically described as (1) psychiatric disturbance, (2) abdominal pain, and (3) peripheral neuropathy precipitated by alcohol or barbiturates. Diagnosis is made by demonstrating porphobilinogen in the urine. Primary amyloidosis, alpha lipoproteinemia (Tangier disease) and A-beta lipoproteinemia (Bassen Kornsweeig) produces a distal neuropathy, although the basis is not clear.
Fabry's disease is X-linked, presenting in males, and is due to ceramide Trihexosidase deficiency. Curiously sensory action potentials are retained in spite of painful paresthesias.
Refsum's disease, accompanied by hypertrophic neuropathy, ataxia, deafness atypical retinitis pigmentosa, ichthyosis results from a failure to break down phytanic acid. Treatment consists of elimination of leafy vegetables and animal fats from the diet.
Peroneal muscular atrophy, previously called Charcot-Marie Tooth disease, is now divided into at least four groups:
In hypertrophic neuropathy conduction velocity is less than 25m/sec.
Dejerine-Sottas recessive disorder produces severe neuropathy. Dominantly inherited hypertrophic peroneal muscular atrophy can produce very mild to moderate deficit.
The pure motor neuropathy with normal conduction velocity is recessive in inheritance and felt by many to be a type of spinal muscular atrophy. There is also a sensorimotor neuropathy with normal conduction velocities and moderate involvement. This is of dominant inheritance.
Many feel that the hypertrophic type are part of a continuum in which there may be posterior column and cerebellar involvement (Roussy Levy).
Guillain-Barre syndrome is an ascending sensorimotor neuropathy typically following a viral illness. Usually conduction velocities show significant slowing as myelin loss occurs. Occasionally only proximal portions of nerves are involved and peripheral nerve conduction is normal. There is frequently cranial nerve involvement. Respiratory difficulty and autonomic dysfunction may be life threatening. Diagnosis is made in part by the presence of elevated CSF protein in the face of acellularity. The course is progressive for 2 weeks or less following which improvement takes place in most patients
In the usual case, neuromuscular transmission takes place when an impulse traveling along an axon causes release of quanta of ACh stored at nerve terminals in synaptic vesicles. The ACh binds with receptor sites on the post-synaptic membrane of a muscle fiber.
It is possible to have a defect in transmission of something affects presynaptically the release of ACh, if there is a receptor abnormality post-synaptically, or if there is an abnormality of ACh.
Botulism, caused by the toxin of clostridium Botulism, interferes with the release of ACh. Dizziness, diplopia and bulbar muscle involvement begin 12-36 hours after ingestion of contaminated food. Stimulating the nerve repetitively at high rates will cause the muscle response to increase gradually while stimulation continues. Guanidine HC1 has been used to enhance release of ACh from nerve terminals.
The Lamber-Eaton syndrome has been likened to Botulism because it is thought to be a defect of ACh release. It is a rare condition described originally in patients with oat cell carcinoma although it has appeared in patients with other malignancies and preceding discovery of a malignancy. It is thought that some sort of globulin produced by the tumor acts presynaptically to prevent ACh release.
Myasthenia Gravis is a disorder of N-M transmission associated with the presence of a circulating globulin that binds to the ACh receptor decreasing the number of receptor sites available for binding by ACh.
There is a definite relationship between MG and autoimmune disorders. Thymic abnormalities have been found in 80% of patients, 10% with onset past age 60 have thymoma, 25% have demonstrable antinuclear antibody. 30% have antimuscle antibody. Thyroid disease, especially thyroiditis, is not uncommon in MG (27%). Diagnosis is made by demonstrating reversal of weakness with edrophonium (one milligram is given slowly IV) and by demonstration of antireceptor antibodies. Abnormalities electrophysiologically include decrement on repetitive stimulation (reversed by cooling) and increased "jitter" on single fiber recording. These patients are supersensitive to curare and certain antibiotics. Treatment for many years consisted of thymectomy and anticholinesterases as needed. Steroid therapy (100 mg Prednisone on alternate days) has been advocated by the NIH group. Plasmapheresis is effective, but because of the time and cost involved has been "saved" for cases unresponsive to other therapy.
The field of myasthenia gravis has changed dramatically in the last decade. In large part, this has come about because of the discovery of a specific antibody, which is directed against the receptor protein of the neuromuscular junction. This antibody is present in large amounts in the serum of the great majority of myasthenic patients. Some patients, for reasons unknown, do not demonstrate large levels of this antibody, and this subgroup of patients is not clinically different from others. The test can be used otherwise to confirm the clinical impression of the disease. In a rough way, antibody titers correlate with the severity of the disease.
The therapy of myasthenia gravis has continued to evolve toward the use of immunosuppressive agents. Seventy-five to eighty percent of patients will make a clinical recovery by the use of large, alternate day steroid doses, usually 100 mg every other day or more. There are serious long-term consequences from this schedule, and about half of these patients become steroid dependent and remain on steroids indefinitely. Plasmapheresis has been used for patients who are steroid and thymectomy resistant and, in some cases, there has been a dramatic response. The cumbersome nature of the plasma exchange therapy limits this treatment.
Many patients with mild and ocular disease can be managed with anticholinesterase medication, usually in the form of Mestinon 6 to 12 mg three or four times per day. Massive doses of anticholinesterase medication are no longer in clinical use.
Muscular Disease
Of the muscle diseases that affect adults, the most common is polymyositis. This is a syndrome or group of related illnesses, and shares certain features with unite them. Some patients with polymyositis are representation of those with larger illness, such as lupus, or occasionally rheumatoid arthritis. The majority of polymyositis patients have restricted illnesses which affects only muscle, and this is demonstrated by the fact that they do not have active serum antibodies against other tissues, may have a normal sedimentation rate, and have as their only laboratory findings an elevation of serum muscle derived enzymes, as well as a positive EMG. Patients with polymyositis frequently respond to steroids, but the does used are very large, usually above 60 mg per day, and they must be given every day. In this setting, there are many complications of steroid use. About two-thirds or more patients will respond in a clinical sense to steroids, and the remainder are often treated with immunosuppressive agents, such as Cytoxan or Imuran. There is an association with cancer, which is primarily seen in older patients. Overall, considering a group of polymyositis patients, approximately eight to ten percent will have a malignant process demonstrable in relationship to that illness. Polymyositis is two to three times more common in females than in males.
The muscular dystrophies typically affect young and adolescent patients. This is particularly true of the common sex-linked type, known as Duchenne dystrophy. The adult forms of dystrophy, particularly that of facioscapulohumeral dystrophy (FSH dystrophy) are more common and have as one of their main features an extremely variable degree of expression. Myotonic dystrophy is an interesting dominant disorder and the affected children of dystrophic fathers are often much less severely affected than those of dystrophic mothers. A few patients are so mildly affected as to remain virtually normal throughout their whole life. Cardiomyopathy is a prominent part of myotonic dystrophy and is a feature of other dystrophies as well.
Interest has continued to develop in the metabolic disorders affecting muscle. There are several disorders related to fatty acid metabolism, particularly to carnitine. A deficiency of carnitine in blood or muscle can be associated with a fluctuating or progressive weakness which is very much like muscular dystrophy. Some of the glycogen storage diseases of adults, particularly that of the adult form of acid maltase deficiency, also closely resemble adult dystrophy and cannot be distinguished without the use of muscle biopsy.
Muscular dystrophies are primary muscle diseases and do not involve peripheral nerve. The progressive muscular dystrophies are divided into categories in terms of inheritance or of patterns of muscle involvement. The most common is Duchennes "pseudohypertorphic" dystrophy which is X-linked recessive and has an incidence of 1 in 3,500 male births. While typical degenerative changes may be seen in fetal muscle, the clinical onset is 2 to 4 years. Classically, the affected child has large pseudohypertrophic gastrocnemii and walks his hands up on his legs to rise to a standing position (Gower's maneuver). Creatinine phosphokinase is extremely high (>1000 units) in patients and is frequently elevated in female carriers, of whom about 5% are mildly symptomatic "manifest careers." Most affected males die by the third decade of respiratory or cardiac muscle involvement.
Becker's dystrophy is also X-linked recessive and resembles Duchennes in terms of pseudohypertrophy of calves and proximal muscle weakness. Onset, however, is later, sometimes in the teens, and progression is less rapid. Cardiac involvement is not usual.
Limb girdle dystrophy is usually autosomal recessive, although out, dominant cases have been reported. Onset is in late childhood and progression is slow. Males and females are equally affected. Pseudohypertrophy is not a feature. This condition is sometimes mimicked by Kugelberg Welander syndrome or polymyositis.
Facioscapulohumeral dystrophy is an autosomal dominant disorder that affects face, shoulder girdle and upper ann, as the name implies. Onset is in adolescence with very slow progression and generally normal life span. There is often congenital absence of some muscles. A variant is accompanied by anterior compartment wasting in the lower extremities and is sometimes mistaken for Charcot-Marie Tooth. Myotonic dystrophy, an autosomal dominant disorder, differs from the other dystrophies in that a clinical dystrophy or wasting is a late feature and there is striking involvement of endocrine system, heart smooth muscle and eye. The characteristic feature is delayed relaxation of percussed muscles and presence of slow relaxation after gripping. The tongue is often involved with resultant slowing of speech. Involvement in infancy is seen in affected children of myotonic mothers. Typically, the child is floppy rather than stiff. Myotonia congenita is usually, but not always, autosomal dominant.Many patients present with back pain.
There are a variety of disorders of lipid and carbohydrate metabolism which are known to produce muscular symptoms. Muscle biopsy generally makes the diagnosis.
Type VII - Muscle phosphofructokinase deficiency is similar but more uncommon.
Type II - Acid maltase deficiency may present in infancy as hypotonia and in adults as a proximal myopathy. EMG sometimes shows myotonia-like discharges.
Lipid Storage:
Carnitine and carnitine palmityl transferase deficiency are extremely rare. Lipid is stored in muscle fibers and, in the latter disorder, myoglobinuria is a complication. Cases have been reported which are diet or steroid responsive. There are perhaps five known cases in the Northeast.
Endocrine Disorders
Thyroid disease, hyperthyroidism often manifests itself as proximal muscle weakness. CPK is often very high before EMG or biopsy changes are seen. Hypothyroidism often produces muscle stiffness, muscle hypertrophy and aching. There is a "myotonic" reaction with slowly relaxing or "hung up" reflex response. CPK is often over 1000U. Steroid induced myopathy, either iatrogenic or associated with Cushing's disease, results in proximal myopathy.
Infection of muscle by Trichina or by viral agents produces a picture of pain and weakness. Polymyositis or dermatomyositis may produce pain along with weakness, but no infectious agent can be demonstrated. Dermatomyositis is sometimes associated with carcinoma in adults.