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TEACHING TOPICS from the New England Journal of Medicine

Teaching Topics | October 18, 2012 Deep-Brain Stimulation for Parkinson’s Disease: Which patients with Parkinson’s disease are candidates for deep-brain stimulation? Kidney and Respiratory Failure: What are the characteristics of antineutrophil cytoplasmic autoantibodies (ANCA)-associated disease?

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Teaching Topic Deep-Brain Stimulation for Parkinson’s Disease Clinical Therapeutics Deep-Brain Stimulation for Parkinson's Disease M.S. Okun Parkinson’s disease typically develops between the ages of 55 and 65 years and occurs in 1 to 2% of persons over the age of 60 years. Approximately 0.3% of the general population is affected, and the prevalence is higher among men than women, with a ratio of 1.6 to 1.0. Clinical Pearls What are classic manifestations of Parkinson’s disease? Motor manifestations of the disorder commonly include a resting tremor, a soft voice, small handwriting (micrographia), stiffness (rigidity), slowness of movements (bradykinesia), shuffling steps, and difficulties with balance. A classic symptom is resting tremor, although 20% of patients do not have it. Parkinson’s disease also has a multitude of nonmotor manifestations, including disturbances of mood (e.g., depression, anxiety, and apathy), cognition (e.g., frontal-lobe dysfunction, memory difficulties, and dementia), and sleep (e.g., apnea and sleep disorders), as well as autonomic dysfunction (e.g., sexual dysfunction, digestive problems, and orthostasis). What medication-related complications typically develop in patients with Parkinson’s disease? Typically, patients with Parkinson’s disease have a robust response to one or more medications. However, after 5 years of therapy, medication-related complications develop in a majority of patients. Such complications include dyskinesia and “on–off” fluctuations, in which a sudden, sometimes unpredictable loss of benefit from medication occurs, characterized by reduced mobility, tremor, rigidity, and other motor and nonmotor manifestations. Some symptoms (e.g., difficulties with gait, balance, speech, swallowing, or cognition) may become progressively resistant to carbidopa–levodopa and other pharmacologic therapies. Morning Report Questions Q. Which patients are candidates for deep-brain stimulation? A. Deep-brain stimulation was approved by the Food and Drug Administration (FDA) in 2002 “as an adjunctive therapy in reducing some of the symptoms of advanced, levodopa-responsive Parkinson’s disease that are not adequately controlled by medication.” Most centers select patients for deep-brain stimulation on the basis of the nature of the patient’s symptoms and the likelihood of a response to the therapy. Typically, levodopa-responsive symptoms, tremor, on–off fluctuations, and dyskinesia are most likely to improve with deep-brain stimulation, whereas impairments in gait, balance, and speech are less likely to improve and may in some cases worsen. Patients should be considered for deep-brain stimulation only if adequate trials of multiple medications for Parkinson’s disease (e.g., carbidopa–levodopa, dopamine agonists, monoamine oxidase inhibitors, and amantadine) have been unsuccessful. Table 1. Characteristics of Candidates for Deep-Brain Stimulation. Q. What adverse events are associated with the use of deep-brain stimulation? A. Among the most worrisome adverse events associated with placement of leads for deep-brain stimulation are infection and intracranial hemorrhage. In recent large series, rates of infection requiring further surgery have ranged from 1.2 to 15.2%. Infections most often require device removal and a period of antibiotic treatment before consideration of device replacement. In an extensive literature review, the overall rate of intracranial hemorrhage was calculated to be 5.0%; symptomatic hemorrhage occurred in 2.1% of patients, and hemorrhage causing permanent deficit or death occurred in 1.1%. Postprocedural seizures have also been reported, with an estimated incidence of 2.4% in one review of the literature. Neurologic side effects of deep-brain stimulation include cognitive impairment, memory deficits, difficulties with speech, disequilibrium, dysphagia, and motor and sensory disturbances. Emotional or psychological side effects have included mania, depression, apathy, laughter, crying, panic, fear, anxiety, and suicidal ideation.

Teaching Topic Kidney and Respiratory Failure Case Records of the Massachusetts General Hospital Case 32-2012: A 35-Year-Old Man with Respiratory and Renal Failure R.J. Glassock, L. Khorashadi, and Y.B. Kushner The term Goodpasture’s syndrome is applied to the combination of lung purpura and nephritis, regardless of the underlying pathogenesis. We now recognize that diverse mechanisms underlie Goodpasture’s syndrome, so more precise terminology linked to pathogenesis is now preferred for the specific diseases. There are numerous possible causes of Goodpasture’s syndrome. A useful clinical approach to differential diagnosis involves serologic categorization. Table 2. Differential Diagnosis of Diffuse Alveolar Hemorrhage and Nephritis (Goodpasture’s Syndrome). Clinical Pearls What are the characteristics of disease mediated by anti–glomerular basement membrane (GBM) antibodies? Anti-GBM disease is commonly associated with lung hemorrhage, mostly in young men. The severity of the lung hemorrhage varies greatly, but it can be life-threatening. Pulmonary irritants (e.g., cigarette smoke, hydrocarbon fumes, or freebase cocaine) or lung infections can precipitate lung hemorrhage. Systemic manifestations (e.g., fever and hypertension) other than those attributable to uremia or respiratory insufficiency are usually absent. Renal failure is common and usually rapidly progressive. In anti-GBM disease, the renal lesion is most often a necrotizing and crescentic glomerulonephritis, and the pulmonary lesion is most often a bland, noninflammatory alveolar hemorrhage. The diagnostic hallmarks of anti-GBM disease are the presence of autoantibodies (typically IgG and only occasionally IgA) directed to well-defined conformational epitopes expressed on type IV collagen. Approximately 20 to 30% of patients may also be shown to have antineutrophil cytoplasmic autoantibodies. What are the characteristics of ANCA-associated disease? ANCA-associated vasculitis is the single most common cause of the syndrome of lung purpura and nephritis. Approximately 90% of patients with granulomatous polyangiitis (formerly known as Wegener’s granulomatosis) and microscopic polyangiitis have antibodies to neutrophil cytoplasmic constituents (myeloperoxidase or proteinase 3). Systemic features, such as fever, myalgias, arthralgias, and skin lesions (palpable purpura and leukocytoclastic vasculitis), are also common. The pulmonary lesion in ANCA-associated vasculitis is diffuse alveolar damage, hemorrhage, and focal inflammatory vasculitis. In granulomatous polyangiitis, there may also be lesions in the upper airways (e.g., tracheitis, sinusitis, and otitis), necrotic pulmonary lesions, and hilar lymphadenopathy. The serum complement levels are typically normal or elevated and the erythrocyte sedimentation rate and C-reactive protein levels are also elevated. Morning Report Questions Q. How often does systemic lupus erythematosus (SLE) present with renal and pulmonary involvement, and what are the typical manifestations? A. SLE may present with both renal and pulmonary involvement. Pulmonary involvement occurs in only 0.5 to 5% (averaging about 0.2%) of patients with SLE. Diffuse alveolar damage with hemorrhage is among the more common manifestations of pulmonary involvement in SLE, and approximately 50% of patients with pulmonary involvement have overt hemoptysis. Lung hemorrhage in patients with SLE is nearly always associated with lupus nephritis and is commonly associated with antiphospholipid autoantibodies or polyangiitis. The lung lesions can be bland alveolar hemorrhage or a localized inflammatory pulmonary capillaritis, with bland lesions usually predominating over the inflammatory lesions. Other features that may be observed with SLE are hypopigmented and hyperpigmented skin lesions on sun-exposed areas, polyclonal hyperglobulinemia, hypocomplementemia, a positive direct Coomb’s test, biologic false positive tests for syphilis, and positive tests for anticardiolipin antibodies and lupus anticoagulant. Arthritis, arthralgia, serositis, neuropsychiatric involvement, warm-antibody hemolytic anemia, thrombocytopenia, and thrombotic microangiopathy can also be present in SLE. Q. How can complement assays aid in the differential diagnosis of renal disease? A. Measurements of complement (C3 and C4 and sometimes total hemolytic complement) may help refine a differential diagnosis. In hepatitis C–related cryoglobulinemia with nephritis, the C4 level is low and the C3 level may be normal. In hemolytic–uremic syndrome due to complement factor H deficiency, the C3 level is low and the C4 level is normal. In lupus nephritis, both the C3 and C4 levels are low. Although these measurements are useful, other evidence must be weighed as well.

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quote of the week “In this analysis involving 39 patients with XDR pulmonary tuberculosis who had not had a response to any standard treatment regimen for 6 months or more, we found that the immediate addition of linezolid at a dose of 600 mg per day to the ongoing background treatment regimen had a significant beneficial effect on the time to sputum-culture conversion on solid medium, as compared with the delayed addition of linezolid at the same dose.” M. Lee and Others, Original Article, “Linezolid for Treatment of Chronic Extensively Drug-Resistant Tuberculosis”

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