Biomedical subjects
Publications and source records attributed to D S Younger.
The therapy of myasthenia gravis and inflammatory myopathy are discussed in detail in this article. The discussion of these two disorders illustrates the extraordinary progress that has been achieved in the therapy of neuromuscular disease.
Forty years ago, a patient with MG probably had a fifty-fifty chance of surviving a myasthenic crisis, defined as the need for mechanical ventilatory support. Approximately 16% of all patients experience a crisis, a figure that has not changed appreciably since then. Progressive weakness, oropharyngeal symptoms, refractoriness to anticholinesterase medication, intercurrent infection, and invasive procedures including needle biopsies of thymic gland masses, and reactions to contrast agents used in the performance of CT of the chest have been implicated in the development of crisis. It is now standard practice to treat severe crisis in an intensive care unit. The ready availability of intensive care in most hospitals belies the fall in the mortality of myasthenic crisis to 6% over the past several decades. Crisis is a temporary exacerbation, regardless of the proximate cause, and the goal is to keep the patient alive until it subsides, usually in 2 weeks. In the past, edrophonium was used to differentiate myasthenic crisis from cholinergic crisis, but that is now moot because withdrawal of cholinesterase medication is necessary for improvement in both situations. The underlying immunologic derangements in myasthenic crisis are not well understood, but there is a rapidly fatal antibody-mediated syndrome that bears resemblance to crisis and is associated with inflammation and necrosis of the end-plate region.
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Quantitative immunocytochemical analysis of complement proteins (CP) was performed on sural nerve biopsies from 15 patients with diabetic neuropathy (DN) and 18 nondiabetic patients with other forms of chronic neuropathy (ON). The mean age of the patients and the pathological severity of the neuropathy were similar in both groups. The percentage of patients that expressed strongly immunoreactive CP in the walls of endoneurial microvessels was significantly greater in DN than in ON for all proteins tested. C3d neoantigen was expressed in 100% of DN cases compared with 17% of ON; and membrane attack complex (MAC), C5b-9 neoantigen, in 93% of DN and 17% of ON. In the cases with DN, 81% of endoneurial microvessels, as identified by the endothelial marker, Ulex europaeus, contained C5b-9 neoantigen deposits, compared with 22% in those of ON, and the staining in DN was significantly more intense. Expression of the neoantigens of C3d and C5b-9 in nerve implies local activation of the complement system. In DN, activation of the complement pathway and formation of the MAC could injure blood vessels and adversely affect the circulation in the endoneurium.
BACKGROUND: The cause of amyotrophic lateral sclerosis (ALS) is not known, and there is no effective treatment. Cell death may be caused by oxidative damage. Selegiline hydrochloride (Eldepryl) is a monoamine oxidase-B inhibitor with antioxidant properties. OBJECTIVE: To determine if selegiline affects the clinical course of patients with ALS. DESIGN: Six-month, double-blind, placebo-controlled study of 133 patients with classical ALS and symptoms for less than 3 years. The primary end point to indicate effectiveness was the rate of change of the Appel ALS total score, an index of disease severity that incorporates strength and function in limbs, respiratory function, and bulbar function. RESULTS: Of the 133 patients, 67 were randomized to receive selegiline and 66 to receive placebo. One hundred four patients (53 in the selegiline group and 51 in the placebo group) completed the 6-month trial. Both groups were comparable for baseline characteristics and mean Appel ALS total score (70.5 points for the selegiline group and 70.6 for the placebo group). There was no difference in the rate of progression as measured by the Appel ALS total score, showing an average increase of 22 points in 6 months. The monthly rate of change was 3.4 for the selegiline group and 3.5 for the placebo group. There was 1 adverse reaction: worsening depression. Seven patients died during the study (4 in the selegiline group and 3 in the placebo group). CONCLUSION: Selegiline treatment had no significant effect on the rate of clinical progression or outcome of ALS.
Diabetes mellitus leads to several recognizable clinicopathologic neuropathic syndromes. Diagnosis and evaluation requires a thorough history and neurologic examination, nerve conductions and needle electromyography (EMG), blood studies, consideration of cerebrospinal fluid analysis, and nerve and muscle biopsy in the most severely affected patients. Microangiopathy is the commonest cause of diabetic neuropathy, associated with potentially reversible metabolic, immunologic, or ischemic injury. Tight glycemic control and symptomatic therapy is beneficial in some patients but does not prevent progression of neuropathy especially in patients with severe motor and gait disability. Intravenous immune globulin is a novel therapy in diabetic patients. It may be considered in selected patients well characterized by clinical, electrophysiologic, histopathologic studies, and one of the following progressive syndromes: mononeuropathy multiplex, primary demyelinating motor or sensorimotor neuropathy, and peripheral nerve perivasculitis or microvasculitis associated with vascular membrane attack complex protein deposits.
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The series on treatable neuromuscular disorders continues with the present article on the peripheral nervous system manifestations of Lyme neuroborreliosis.
Diabetes mellitus leads to several recognizable clinicopathologic neuropathic syndromes. Diagnosis and evaluation requires a thorough history and neurologic examination, electrophysiologic studies, blood studies and, in selected cases, cerebrospinal fluid analysis and nerve and muscle biopsy. Microangiopathy is the leading cause of diabetic neuropathy associated with metabolic, vascular ischemic and immunologic injury. Tight glycemic control and symptomatic therapy is beneficial in a minority of patients but does not prevent the relentless progression of symptoms and signs. Intravenous immune globulin is a novel therapy in patients with mononeuropathy multiplex, primary demyelinating neuropathy and peripheral nerve T-cells microvasculitis associated with C5b-9 membrane attack complex protein deposits.
This article is an introduction to the historical background, clinical and laboratory diagnosis, pathogenesis, and treatment of vasculitis involving the peripheral and central nervous system. It also provides a background for the articles that follow.
Central nervous system (CNS) vasculitis refers to primary and secondary disorders of the CNS vasculature. Most authorities agree that CNS vasculitis is a potentially serious disorder; therefore, prompt diagnosis and initiation of therapy are high priorities in treatment. Remarkable progress has been made in the diagnosis, evaluation, and treatment of this disorder. This article examines many aspects of the radiographic evaluation of CNS vasculitis.
Granulomatous angiitis of the nervous system (GANS) refers to distinctive clinicopathologic disorders with the essential feature of granulomatous inflammation of cerebral and spinal vessels, accompanied by multinucleate giant cells and epithelioid cells. This article reviews and examines the clinical, laboratory, and neuropathologic findings of patients with granulomatous angiitis.
Recent work has shown that inflammatory vasculopathy is commonly seen in biopsies of diabetic patients with neuropathy. Most of these patients have had syndromes consistent with proximal diabetic neuropathy or amyotrophy. This suggests that inflammatory vasculopathy is important in the pathogenesis of these disorders. Immunosuppressive therapy may benefit many of these patients.
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We studied 26 patients with both motor neuron disease and lymphoproliferative disease (LPD). Twenty-three patients had definite or probable upper motor neuron signs; none had electrophysiologic evidence of motor neuropathy. LPD syndromes comprised Waldenström's macroglobulinemia, multiple myeloma, chronic lymphocytic leukemia, follicular cell lymphoma, and Hodgkin's disease. In all but one patient, the cause of disability or death was neurologic. LPD was confined to bone marrow in 14 patients; eight of 14 had monoclonal paraproteinemia. One patient had LPD discovered at autopsy. Treatment of LPD in 20 patients resulted in neurologic improvement in 1 patient and arrest in another; both had progressive spinal muscular atrophy. Eleven patients were worse and 13 died. At least 30 cases have been reported from other centers, bringing the total to 56. Among the unusual reported concomitants were POEMS (polyneuropathy, organomegaly, endocrinopathy, myeloma, and skin changes) syndrome of myeloma and angiotropic lymphoma.
We compared the binding of human antibodies from patients with neuropathy to the myelin-associated glycoprotein (MAG), to its cross-reactive glycolipid sulfoglucuronyl paragloboside (SGPG), and to sections of peripheral nerve. Titers were correlated with the clinical presentation and results of electrophysiological and pathological studies. Most patients had a predominantly sensory or sensorimotor demyelinating neuropathy and highly elevated antibodies to both MAG and SGPG, but 2 had highly elevated antibodies to MAG alone, and 1 to SGPG alone. Two patients had predominantly motor neuropathy and highly elevated antibodies to SGPG which reacted with MAG by Western blot but not by enzyme-linked immunosorbent assay. One patient had amyotrophic lateral sclerosis and antibodies to SGPG but not to MAG. These studies indicate that the neuropathic syndrome associated with anti-MAG or -SGPG antibodies are more heterogeneous than previously suspected, and that although most of the antibodies react with both MAG and SGPG, some may react with MAG or SGPG alone.
We performed quantitative immunohistochemical studies of sural nerve biopsy specimens from 20 patients to determine whether endoneurial and epineurial lymphocytic infiltration occurs in diabetic nerves. The diabetic nerves contained a mean of 129 CD3+ cells per tissue section compared to 19 cells in patients with chronic neuropathy matched for the histologic severity of disease, and 0-5 cells in normal control nerves. The T-cell infiltrates in the diabetic nerves were predominantly of the CD8+ cell type. Activated endoneurial lymphocytes expressed immunoreactive cytokines and major histocompatibility class II antigens. Microvasculitis was found in 12 (60%) patients. Infiltrative T cells may contribute to the pathogenesis of diabetic neuropathy through a variety of effector mechanisms.
Some have suggested that nonfamilial motor neuron disease (MND) may be autoimmune, and the neurological disorder may benefit from immunotherapy. There have been reports of over 30 cases of lymphoproliferative disease (lymphoma, multiple myeloma, Waldenström's macroglobulinemia) with MND, and these patients might he offered immunosuppressive therapy. Bone marrow examination might increase the sensitivity of the diagnostic workup for lymphoma and other lymphoproliferative disorders. We examined the bone marrow in our first evaluation of 161 patients with MND seen at Columbia-Presbyterian Medical Center during 1991-1994. Four of 161 patients (2.5%) had lymphoproliferative disease in the marrow; only 1 of these had a monoclonal paraprotein. Routine bone marrow examination of patients with MND increases the diagnostic yield of lymphoproliferative diseases. The frequency of these bone marrow abnormalities in comparison with a group of age-matched control subjects should be studied further.