ADVANCING PARKINSON'S DISEASE DYSAUTONOMIAS CONSTIPATION. Pfeiffer and his colleagues have emphasized the importance of considering two distinct processes responsible for normal stool expulsion.[73-75] First, stool moves through the colon by the sequential contraction of muscles within the intestinal wall. Intrinsic enteric neurons regulate this muscular activity. Second, parasympathetic afferent and efferent fibers mediate the excitatory and inhibitory input to the colon. In patients with PD, Lewy bodies have been found within degenerating colonic neurons (myenteric plexus); the primary clinical correlate is slowed stool transit time related to impaired colonic muscle contraction. In a second syndrome, colonic transit time may or may not be normal, but the primary abnormality is in defecation. Parkinsonian patients are unable to straighten the anorectal angle on straining, accentuating its flap valve action and resulting in an obstruction to the passage of stool. It has been suggested that this paradoxical contraction of the pelvic musculature is dystonic in nature and correlates with the progression of PD. In support of this argument, apomorphine has been shown to alleviate this defecatory problem in some patients with PD.[76] Other disorders associated with constipation in patients with PD include megacolon and sigmoid volvulus. Management (breakout 4). Dietary modification aimed at increasing bulk and softening the stool should be the first strategy for constipation, and ultimately the most efficacious, in patients with PD. They must be encouraged to drink at least eight glasses of water each day. Low-fiber foods, such as many breads and cakes need to be reduced, and bananas must be eliminated from the diet. At least two meals per day should include high-fiber raw vegetables. Carrots, cauliflower, and broccoli are good choices. Oat bran as a hot cereal (Quaker Oats bran) adds significant fiber to the diet, especially when one-fourth to one-third cup is used in the morning. As a morning meal, it reduces the amount of protein, adds bulk, and helps stimulate the gastrocolic reflex. Increasing physical activity is also helpful. Although vigorous exercise is not necessary, just doing a few pushups, situps, or isometric exercises is not enough. Patients must be encouraged to walk as much as several miles a day, if possible, or swim regularly. If stools remain hard despite the measures outlined above, stool softeners such as docusate, given with each meal can be useful. Lactulose, 10 to 20 g per day, may benefit some patients. Patients are warned that the results with any method of softening stool will not be immediate and that persistence with dietary and pharmacologic measures is necessary. Since anticholinergic agents decrease bowel motility, stopping such drugs can be useful for alleviating constipation, but this is often at the price of increased parkinsonism. The next step is a trial of cisapride (a cholinomimetic agent) which increases intestinal motility.[77] Even at the usual dosage of 5 mg bid, it is important to watch for occasional worsening of Parkinson's signs and symptoms. Mild laxatives such as milk of magnesia or enemas should be a last resort and used sparingly-perhaps no more than once a week as part of an overall bowel regimen-but in some patients enemas may be necessary. Apomorphine injection may provide enough benefit to permit successful defecation. URINARY PROBLEMS. The neuro-anatomic substrate for normal voiding is widespread. The detrusor motor area in the frontal lobes connects with a similar functional region in the pontomesencephalic reticular formation. Input from the basal ganglia to this cortico-mesencephalic loop depresses detrusor contraction; hypothalamic input increases detrusor contraction. Peripherally the detrusor is innervated via sacral parasympathetic neurons, a pathway that is facilitated by noradrenergic neurons in the locus ceruleus. Seemingly more important for patients with PD, however, is the loss of dopaminergic output from the substantia nigra, which appears to increase detrusor hyperreflexia. Most patients with PD suffer from detrusor hyperactivity. Relatively few have detrusor hypoactivity or urethral sphincter dysfunction. Common symptoms in PD patients that result from detrusor hyperactivity include urgency, frequency, and nocturia. Nocturia is the most common and usually the earliest complaint, only much later followed by daytime symptoms. In fact, if daytime frequency or urgency occurs as an initial complaint, causes from mechanical outlet obstructions, such as prostatic hypertrophy, must be considered. Management (breakout 5) Many patients can reduce nighttime frequency by the simple expedient of reducing liquid intake in the evening (no liquids after supper). If this nonpharmacologic intervention is ineffective, peripherally acting anticholinergics, such as oxybutynin or propantheline, can be tried. Oxybutynin, 5 to 10 mg, can be administered at bedtime only or on a tid basis. Propantheline, 7.5 to 15 mg, may also work well at bedtime or on a tid schedule. If anticholinergics prove ineffective, hyoscyamine, a parasympatholytic agent, may work on a qid regimen or at night only (0.15 to 0.30 mg). A trial of desmopressin, administered at night in escalating doses (usually 10 to 20 micro g) as an intranasal spray, may work for otherwise refractory cases. Anticholinergic agents, used in the treatment of detrusor hyperactivity, reduce detrusor contractions, an effect that may worsen voiding problems in patients with detrusor hypoactivity or outlet obstruction. Detrusor hyporeflexia, producing incomplete bladder emptying and urinary frequency, may respond to a reduction in the dosage of an anticholinergic antiparkinsonian medication when that is the cause. It is therefore essential that PD patients with urinary dysfunction have urologic evaluations that include recording of bladder and sphincter pressure, sphincter electromyography, and fluoroscopy and that these tests be performed only by a urologist familiar with their interpretation. When cystometric studies reveal a hypoactive detrusor, benefit may be obtained from alpha adrenergic-blocking agents such as phenoxybenzamine or prazosin, which decrease tone in the bladder neck. Unfortunately, these agents can exacerbate or cause orthostatic hypotension and cardiac arrhythmias and should be used with caution in patients with PD. Drugs that relax striated muscle--such as diazepam, baclofen, or dantrolene--can ocasionally be effective when the external sphincter is hyperreflexic. Intermittent catheterization is necessary with myogenic overdystension. Any deterioration in voiding pattern (even in the absence of dysuria) should raise the concern of infection, which should be treated promptly.[78] SEXUAL PROBLEMS. Little attention has been paid to the sexual dysfunction common in patients with PD. Most treatment is aimed at impotence in men, with virtually nothing being known about the sexual function of women with PD. In men, the most common problem is achieving or sustaining an erection. Management (breakout 6). Propranolol or other beta-adrenergic blockers, sometimes used to control postural or action tremor in patients with PD, are common offenders. Other possible problem drugs include antihypertensives (alpha-adrenergic blockers such as clonidine, methyldopa, and guanfacine). Guanethidine, although less frequently used, is a potential offender, as are thiazide diuretics, anxiolytics, digoxin, and cimetidine. Looking for depression is often rewarding; medical evaluation is mandatory but rarely helpful. Although depression is a frequent cause of sexual dysfunction, it is noteworthy that antidepressant drugs (particularly the serotonin uptake inhibitors fluoxetine, paroxetine, sertraline) can cause impotence. Tricyclics also have been implicated as a less frequent cause of impotence. Depressed patients should be treated with either tricyclic antidepressants or serotonin uptake inhibitors, despite the problems described above. Tricyclics (with anticholinergic properties) have the added advantage of alleviating some of the parkinsonian symptoms, but the best approach is to use the most efficacious drug to lift depression in a given patient. Some patients with anxiety- or stress-associated sexual dysfunction benefit from low-dose anxiolytics. Endocrine function can be ascertained with serum levels of prolactin testosterone, and luteinizing hormone and studies of thyroid function. If no medical or psychologic reasons seem to be causing impotence, one can try yohimbine, 5 mg tid for 1 month. Further treatment, under consultation with an expert urologist, can include local injection of phentolamine(an alpha-adrenergic blocker) and papaverine. This combination provides a short-term vasodilator effect by acting on smooth muscle. More invasive approaches, such as implants, are less easily accepted by patients and treating physicians. Previously untreated patients may find that starting treatment with levodopa can help sexual dysfunction, probably by alleviating bradykinesia and increasing desire. In fact, some patients on high doses of antiparkinsonian agents become hypersexual, even in the face of inability to perform. ORTHOSTATIC HYPOTENSION. The anatomic site responsible for orthostatic hypotension (OH) patients with PD are probably heterogeneous, since no consistency in abnormalities has been reported. Sympathetic efferent dysfunction in some patients can be inferred from a failure to increase heart rate with falling blood pressure and the lack of blood pressure overshoot with Valsalva. Abnormalities of renin and inadequate increases in serum norepinephrine on standing may be contributory factors. A central autonomic defect may be involved, as suggested by an increased pressor response to norepinephuine patients with PD. The finding of Lewy bodies in the hypothalamus of these patients support such an etiology in some. More likely in most patients however, is a generalized sympathetic degeneration from Lewy body disease causing cell loss in the sympathetic ganglia.[78] Management (breakout 7). OH, although not uncommon in patients with PD, should be treated only in those who are symptomatic. Levodopa or dopamine receptor agonists exacerbate OH, the latter especially during the first weeks of treatment. Many patients who have been on antihypertensive drugs begin to experience OH with progression of PD. They often can tolerate a reduction in or cessation of their antihypertensive medications. In those patients who are not taking antihypertensives, the first step in treating OH should be the addition of salt and fluids to the diet. Higher salt intake can be achieved by deliberately adding salt to food at the table (as opposed to adding it in the cooking process) so that other family members do not get additional unnecessary salt. Salt tablets, up to 2 g per day, are another alternative. Compressive stockings and behavior modification should be used in conjunction with increased salt and fluid intake. Knee-high stockings are less effective than thigh-high ones, but the former are preferable because of increased compliance. Practitioners can teach patients behavior modification that reduces OH, such as getting up slowly and sleeping with the head tilted. For parkinsonian patients with OH, fludrocortisone (a salt-retaining steroid) can be started in doses of 0.1 rug per day and titrated upwards in 0.1 mg increments up to 0.3 mg tid. Patients taking it should be monitored for possible congestive heart failure and supine hypertension, however Indomethacin, 25 mg tid is not as effective as fludrocortisone but is more easily tolerated. It probably works by inhibiting vasodilating prostaglandins. Midodrine, 5 to 10 mg qid, is an investigational alpha-adrenergic agonist that is particularly effective in some patients. In evaluating patients with "dizziness" OH should be distinguished from complaints caused by postural instability visualmotor dysfunction, or multiple sensory deficits.[79] THERMOREGULATION. The neurochemical and anatomic regulation of temperature is complex and poorly understood. Preoptic and hypothalamic areas appear to have thermoregulatory function. Noradrenergic, serotonergic, and cholinergic systems have an incompletely understood role in thermal homeostatais. Sweating is mediated by efferent sympathetic cholinergic fibers, which may be damaged in PD. Lewy bodies and cell loss in the hypothalamus have been implicated in PD-associated sweating abnormalities. Management (breakout 8). Abnormal sensations of heat or cold, impaired sweating responses, and hypothermia all can occur in the untreated patient. Excessive sweating of the head and neck in response to external heat has been associated with poor heat dissipation. Some of these phenomena disappear with levodopa treatment, which suggests a role for central dopaminergic systems in thermoregulation.[80] Severe drenching sweats occur as an end-of-dose "off" phenomenon in patients with motor fluctuations, further supporting a role for dopamine systems in vasomotor tone and heat regulation. Dopamine agonist therapy may be of benefit to such patients. Although peak-dose chorea can cause sweating, it is rarely if ever as severe as that seen in the "off' state For patients who experience it, however, a reduction in the dopaminergic medications may help but often at the price of more "off" time. These patients are more likely to respond to beta-adrenergic blockers than are patients with "off"-period sweating. Severe hyperpyrexia after levodopa withdrawal resembles the neureleptic malignant syndrome and needs to be treated promptly with reinstitution of dopaminergic agents. Other causes of excessive sweating must not be neglected simply because the patient has PD. Benign sweating can occur with either a visual, olfactory or gustatory stimulus. Ethanol and aspirin in high doses also can cause increased intermittent sweats. Therefore, taking a thorough history usually will clarify these situations Thyrotoxicosis and postmenopausal states need to be considered and appropriate endocrine evaluation initiated. Finally, chronic infections such as tuberculosis must not be forgotten in the differential diagnosis. PAIN. The mechanisms responsible for pain in PD are unclear and probably not the same in all patients. It can be mediated via peripheral somatic or autonomic afferent nerves. Selective autonomic block, however, does not seem to reduce the pain in PD, and signs of autonomic disturbance are not usually present. Since many of these syndromes are associated with dystonia, one possible site for the origin of PD-associated pain is afferent nerve fibers within the dystonic muscles. A spinal cord or cerebral origin for some pains is suggested by the pseudoradicular pattern seen in some patients. Many pain syndromes occur in the "off" state only, suggesting a role for dopamine-containing cells in the diencephalon,[81] which terminate on receptors in the dorsal horn and intermediolateral column.[82,83] Sensory symptoms often appear neuritic in character, including paresthesias, burning dysesthsisa, coldness or numbness, and deep aching.[84] The legs are more often involved than the arms; face and neck are rarely involved.[85] Akathisia sometimes is present. Pain is often, but not always, worse on the side of worse parkinsonism.[86] Management (breakout 9) Pain related to parkinsonism often responds to adjustment of antiparkinsonian medications. Most often, it is linked to levodopa "off" states or insufficient levodopa dosage; thus, optimizing medications (as described later) can be gratifying. Other causes for radicular pain and neuropathy need to be evaluated when appropriate. Pain related to arthritis is not uncommon in elderly patients with PD.[87] DYSPHAGIA. Significant dysphagia in patients with PD is usually; But not always, related to the severity of disease and occurs in up to 40% of patients. direct involvement of oropharangeal muscles is suggested by the observance that many patients suffer severe dysphagia only when "off," a situation that improves dramatically as soon as a dose of levodopa becomes effective Swallowing abnormalities include abnormal lingual control and inability to pass a bolus of food backward into the pharynx. Silent aspiration with repetitive reflux of food from the vallecula and pyriform sinuses into the oral cavity are a significant problem. Retention of food and pills in the vallecula are another contributory cause of erratic levodopa absorption, and therefore, a secondary cause of dysphagia. Esophageal dysmotility occurs in as many as 70% of patients but also is present in a significant number of controls.[88,89] Management (breakout 10). Soft diets help most types of dysphagia by making It easier to move food in the mouth and esophagus. Soft food also decreases aspiration by reducing the need for separate liquid intake, since liquids often cause more aspiration than solids. Since dysphagia is usually decreased dramatically during "on" times, the best strategy is to increase "on" time with additional dopaminergic medications, if possible. Increased "off" time, however; is not a realistic goal for many patients. All patients should eat only during an "on" period. Feeding gastrostomies or jejunostomies are a last resort and are rarely necessary in patients with idiopathic PD; but when needed, these procedures provide the benefit of allowing more normal intake of food and medication. SEBORRHEA. Excessive secretion of oil by sebaceous glands is common in PD. Management (breakout 11) Coal tar shampoos can be used not only for dandruff but also for seborrhea over the eyebrows and forehead. They should not be used more than once or twice weekly Selenium-based shampoos also work in some patients when used in a similar manner. Topical hydrocortisone is most effective on the face but needs to be applied daily. FALLS Falls are a leading cause of morbidity and mortality in the elderly population and frequently contribute to nursing home placement.[90,91] The causes of falls in the elderly are usually multifactorial and can be divided into intrinsic and extrinsic factors. Intrinsic factors are age- and disease-related elements in an individual that predispose him to fails. These factors include gait, balance, and weakness (10 to 25%), dizziness and vertigo (5 to 20%), orthostatic hypotension (2 to 15%), syncope (2 to 10%), drop attacks (1 to 10%), and other causes, such as acute illness, confusion, poor eyesight, and drugs (1 to 10%).[92] Extrinsic factors are environmental elements that may cause an individual to fall. Environmental factors account for 30 to 50% of falls in elderly individuals.[92] Falling is a significant problem in PD (breakout 12).[93-95] Older age, longer duration of disease, advanced stage of disease increased disability, rigidity, bradykinesia, inability to rise from chair, posture and gait impairment, and postural instability are factors that predispose patients with PD to falls.[95] Mental status changes, OH, dyskinesias, and age-related physical changes are other possible factors.[96-100] POSTURAL INSTABILITY. Postural instability often responds poorly to drug therapy especially with advanced disease. Although postural instability improves with the administration of levodopa[94]--or other medications in some patients especially those with more recent onset disease-most patients with more advanced disease fail to improve with a change in levodopa dosage or the addition of dopamine agonists, Gait training and physical therapy may be beneficial, In patients with severe postural instability, wheelchairs can be used to prevent morbidity from falls. SYMPTOMATIC OH. Symptomatic OH can cause falls in patients with PD, It is critical for the physician to distinguish this cause from other conditions that also can cause falling. Treatment of OH is discussed in the "Dysautonomias" section. MOTOR FLUCTUATIONS. Motor fluctuations, including dyskinesias and episodic freezing, may be additive to postural instability and contribute to the tendency to fall. (These problems will also discussed in the "Motor problems" section to follow.) FREEZING AND FESTINATIONS. Freezing refers to a patient's feet getting stuck to the ground while walking, with an inability to initiate lower limb movement for a few seconds to minutes. In PD, the center of gravity is shifted forward and during ambulation the flexed trunk precedes the lower limbs, leading the patient to take increasingly frequent, short steps, often ending with a fall, This phenomenon is known as "festination." Pharmacologic treatment of freezing and festination is sometimes effective but can be very disappointing in more advanced patients.[101] Occasionally, decreasing or. increasing daily levodopa dosage or adding a dopamine agonist may help. When drugs are of no benefit in freezing and festinations, physical therapy may he helpful. Behavioral therapy is often beneficial in freezing. Gait modification by the use of motor and sensory tricks, such as alteration of the distribution of body weight, walking sideways, rocking movements of the body, stamping feet, walking briskly, taking longer steps, consciously lifting one limb higher and sliding one foot backwards then throwing it forwards,[102] may work for some patients. Having someone rhythmically pull or push or passively elevate the patient's knee also can help,[102] Verbal or auditory stimuli that are used include marching like a soldier to commands, walking or dancing to music, sudden clapping of hands and swearing. Visual stimuli include stepping over objects such as the handle of a walking stick, another person's foot, or carpet patterns; watching other people walk; and imagining white lines to step over. DEMENTIA. The proportion of patients with PD who are also demented is approximately 15 to 2O%.[103] At times, PD may be accompanied by Alzheimer's disease, Cognitive impairment is an independent risk factor for falls in the elderly.[90] Hence, parkinsonian patients with dementia have an even higher risk of falls, Patients and their families should be educated about the increased risk of falls, and occasionally these patients may benefit with gait training and physical therapy. OTHER NEUROLOGIC DEFICITS. Patients with PD can have associated neurologic conditions that may increase their risk of falls. These conditions include myopathy, cervical degenerative disease, normal pressure hydrocephalus, lower back problems, multiple sensory deficits (eg, visual, vestibular, proprioceptive), cerebellar deficits, and other deficits caused by strokes.[90] If clinical signs and symptoms suggest any other neurologic condition, a detailed workup should be performed. Aging,[104] arthritis, physical inactivity and cardiac disease[105] in the elderly also should be considered as causes of muscle weakness. It often is overlooked in elderly patients because examiners are often too "generous" to grade their muscle strength.[106] Decreased muscle strength in the lower limbs is associated with falling[107,108] and mortality[109,110] among the elderly. Physical therapy plays an important role in strengthening weakened muscles and improving stability and gait. OTHER MEDICAL CAUSES. Acute illness, such as pneumonia, and the worsening of chronic conditions, such as congestive heart failure, can precipitate falls.111 Stable parkinsonian patients who suddenly begin to have falls or an acute increase in the frequency of falls should undergo complete medical evaluation. Medications can contribute to falls by causing volume depletion, OH, fatigue, impaired mental alertness, or other unknown mechanisms.[90] The total number of medications used appears to be directly related to the risk of falls.[111] RECOMMENDATIONS. Every patient with PD who is experiencing falls should have a home safety evaluation performed by a trained therapist. The ability to avoid falls decreases with age, because of changes in posture, body-orienting reflexes, muscle strength, and decreased height of steppage.[112] Extrinsic factors that contribute to the tendency to fall could include poor lighting, torn carpet, loose rugs, slippery surfaces, small objects on the floor, inappropriate furniture, and unsafe stairs.[90] Adaptive equipment, such as walkers, if inappropriately used, also will increase the risk of falling. As the chances of falling are proportional to the number of risk factors,[90,111] everything possible should be done to correct environmental factors. Not all risk factors are correctable and even after optimal treatment some patients continue to experience falls. Prevention is the best strategy, but an occasional patient may be safest using a wheelchair on a permanent basis. MOTOR PROBLEMS During the early stages of PD, the clinical responses to levodopa therapy are stable and characterized by a "long-duration" pattern.[113] Patients with early disease require several days to plateau following a change in their levodopa dosage. Once plateaued, they experience no clinical variability, even if doses are late or skipped. If levodopa is stopped, it may take up to a week to return to the pre-levodopa baseline. In contrast, with advancement of PD, the levodopa response shifts to a "short-duration" pattern.[113] Patients with advanced disease experience clinical motor fluctuations that reflect ever-changing brain levodopa levels. Knowledge of the individual patient's short-duration levodopa response pattern is often crucial to arriving at the correct treatment advice The short-duration response typically develops, plateaus, and abates over several hours after a single dose of levodopa. The plateau phase of clinical improvement ("on") typically peaks about 45 to 90 minutes after administration of the standard formulation of carbidopa-levodopa and 60 to 150 minutes after the controlled-release CR) formulation. Rare patients with delayed gastric emptying may have a somewhat more delayed response. The clinician should focus on the adequacy of the peak response, the duration of that response, and the time that the dyskinesias are manifest in the response cycle. This often can be determined from the history but may require observation in the office. NO RESPONSE. A few patients with parkinsonism will experience no beneficial response to carbidopa-levodopa in any dose. Such patients with parkinsonian symptoms probably do not have PD but rather striatonigral degeneration or some other similar condition in which the pathology is beyond the substantia nigra, involving other portions of the extrapyramidal motor system. An adequate trial of medication must be employed before concluding that the patient is a nonresponder. Management (breakout 13) Patients who fail to respond to lower dosages of carbidopa-levodopa can have the dosage gradually raised, with the standard rather than the CR preparation for the purposes of this trial. Patients should be instructed to take their doses on an empty stomach. to make certain the poor response is not secondary to the inhibitary effects of dietary protein. Once the dosage has been slowly pushed up to approximately 1,200 mg per day (eg, 300 mg four times daily) with no response, it would then be reasonable to conclude that carbidopa-levodopa therapy is not beneficial. Since the long-duration levodopa response takes several days to become fully manifest, patients should be maintained on the higher doses for approximately 1 week to allow the full effects to occur. Certain patients being seen in the office who report no response to levodopa may be challenged with a somewhat larger dose than they have been taking. If there is still no response, however, this strategy should not preclude going ahead with a trial of chronic administration of higher doses of carbidopa-levodopa, since some patients manifest a long-duration effect that will not be seen after one or two doses. Obviously, the aforementioned strategies pertain to patients who simply fail to respond to carbidopa-levodopa rather than those who cannot tolerate this medication, for whom other strategies may apply. Patients who fail to respond to very high doses of carbidopa-levodopa are unlikely to respond to dopamine agonist medications either, although some clinicians choose to try these nonetheless. Patients who fail to respond to levodopa and whose primary problem is tremor or dystonia can he given a trial of anticholinergic therapy {eg, trihexyphenidyl, benztropine). SUBOPTIMAL PEAK RESPONSE. Patients who experience suboptimal motor control at the time of peak effect of levodopa can have their response potentiated in a variety of ways (breakout 14). The simplest approach is to raise the individual doses of levodopa (with carbidopa) by small and gradual increments until improvement develops. The point of diminishing returns is at approximately 250 mg of levodopa per dose of the standard formulation and 400 mg of the CR formulation. Rare patients may require slightly higher doses for maximum effect. Although no compelling evidence points to levodopa toxicity, some concerns do exist;[114] hence, some clinicians have favored keeping the levodopa dosage lower and instead adding or increasing one of the two available adjunctive dopamine agonist drugs, bromocriptine or pergolide. A minimum total daily dose of 15 mg of bromoctiptine or 1.5 mg of pergolide (divided) is usually necessary to achieve a minimally clinically significant effect. Selegiline also will potentiate the peak effect of levodopa therapy[115] by inhibiting MAO-B, one enzymatic route of dopamine degradation. If tremor is prominent, the addition of an anticholinergic drug, such as trihexyphenidyl or benztropine, may be helpful, if tolerated. Amantadine is also mildly beneficial as an adjunctive drug in this situation. Unfortunately occasional patients experience side effects that limit the dosage of medications that can be administered. These include hallucinations, psychosis, confusion, nightmares, and dyskinesias, which can be induced or exacerbated by levodopa, dopamine agonists, or selegiline. Anticholinergic drugs have their own side-effect spectrum that includes memory impairment, hallucinations, psychosis, constipation, urinary hesitancy, and visual blurring. John Cottingham NEW ADDRESS: [log in to unmask]