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My Treatment Approach to Multiple System Atrophy

      Abstract

      Multiple system atrophy (MSA) is a neurodegenerative disorder primarily characterized by autonomic failure plus parkinsonism or cerebellar ataxia. The diagnosis may be challenging and is usually made at a tertiary care center. The long-term management issues are equally challenging and frequently require collaboration with the patient’s local care providers. Whereas there is currently no cure for MSA, treatment focuses on the most problematic symptoms experienced by the patient. Autonomic symptoms may include severe orthostatic hypotension with syncope, urinary symptoms culminating in incontinence, constipation, anhidrosis, and erectile dysfunction. Motor symptoms include parkinsonism, cerebellar ataxia, and falls. Although certain motor symptoms may respond partially to medications, some of these medications may exacerbate autonomic problems. In this manuscript, we seek to bridge the gap between tertiary care providers and the patient’s local care providers to provide multidisciplinary care to the MSA patient. Patients are often best served by management of their chronic and evolving complex problems with a team approach involving their primary care providers and subspecialists. Treatment guidelines typically list myriad therapeutic options without clarifying the most efficacious and simplest treatment strategies. Herein, we provide a guideline based on what has worked in our MSA clinic, a clinic designed to provide care throughout the disease course with subspecialty integration with the goal of empowering a partnership with the patient’s home primary care providers.

      Abbreviations and Acronyms:

      BP (blood pressure), MSA (multiple system atrophy), MSA-P (multiple system atrophy—parkinsonism), OH (orthostatic hypotension)
      Multiple system atrophy (MSA) is a sporadic and progressive neurodegenerative disorder with onset between 40 and 80 years of age.
      • Bower J.H.
      • Maraganore D.M.
      • McDonnell S.K.
      • Rocca W.A.
      Incidence of progressive supranuclear palsy and multiple system atrophy in Olmsted County, Minnesota, 1976 to 1990.
      • Coon E.A.
      • Sletten D.M.
      • Suarez M.D.
      • et al.
      Clinical features and autonomic testing predict survival in multiple system atrophy.
      • Wenning G.K.
      • Ben Shlomo Y.
      • Magalhaes M.
      • Daniel S.E.
      • Quinn N.P.
      Clinical features and natural history of multiple system atrophy. An analysis of 100 cases.
      • Wenning G.K.
      • Tison F.
      • Ben Shlomo Y.
      • Daniel S.E.
      • Quinn N.P.
      Multiple system atrophy: a review of 203 pathologically proven cases.
      Early in the disease, the diagnosis is often elusive and mistaken for Parkinson disease or a spinocerebellar syndrome. MSA is typically suspected once the associated autonomic symptoms, including orthostatic hypotension (OH) and urinary incontinence, become prominent. The current consensus criteria have levels of diagnostic certainty; possible MSA requires at least one feature of autonomic dysfunction in addition to the motor syndrome, whereas probable MSA requires urinary incontinence/urinary retention or OH (Table 1).
      • Gilman S.
      • Wenning G.K.
      • Low P.A.
      • et al.
      Second consensus statement on the diagnosis of multiple system atrophy.
      Table 1Diagnostic Criteria for MSA
      MSA = multiple system atrophy.
      The criteria state that MSA is a sporadic, progressive, adult-onset disease with increasing degrees of clinical suspicion from possible to probable MSA.
      Adapted and modified from Neurology,
      • Gilman S.
      • Wenning G.K.
      • Low P.A.
      • et al.
      Second consensus statement on the diagnosis of multiple system atrophy.
      with permission.
      Possible MSAParkinsonism or cerebellar syndrome and at least one feature of autonomic dysfunction
      Probable MSAParkinsonism poorly responsive to levodopa or cerebellar syndrome and autonomic failure involving urinary incontinence/retention with erectile dysfunction (in men) or orthostatic hypotension
      Orthostatic hypotension is defined as a decrease of blood pressure within 3 minutes of standing by at least 30 mm Hg systolic or 15 mm Hg diastolic.
      Additional clinical featuresBabinski sign with hyperreflexia, stridor
      Supporting featuresOrofacial dystonia, disproportionate anterocollis, camptocormia, hand or foot contractures, inspiratory signs, severe dysphonia, severe dysarthria, new or increased snoring, cold hands and feet, pseudobulbar affect, myoclonus
      Additional magnetic resonance imaging featuresAtrophy on magnetic resonance imaging of putamen, pons; atrophy of the middle cerebellar peduncle, pons; “hot cross bun” sign
      a MSA = multiple system atrophy.
      b The criteria state that MSA is a sporadic, progressive, adult-onset disease with increasing degrees of clinical suspicion from possible to probable MSA.
      c Orthostatic hypotension is defined as a decrease of blood pressure within 3 minutes of standing by at least 30 mm Hg systolic or 15 mm Hg diastolic.
      Presentations of MSA are diverse, and different names have been applied to the component phenotypes in past decades. Thus, when the primary focus was cerebellar, it was termed olivopontocerebellar atrophy
      • Dejerine J.
      • Thomas A.A.L.
      'atrophie olivo-ponto-cerebelleuse.
      ; the parkinsonian phenotype was categorized as striatonigral degeneration
      • Adams R.D.
      • Van Bogaert L.
      • Vander Eecken H.
      Striato-nigral degeneration.
      ; whereas Shy-Drager syndrome
      • Shy M.G.
      • Drager G.A.
      A neurological syndrome associated with orthostatic hypotension. A clinical-pathologic study.
      became synonymous with prominent neurodegenerative autonomic failure. These were ultimately recognized to represent the same disorder,
      • Graham J.G.
      • Oppenheimer D.R.
      Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy.
      with oligodendroglial inclusions containing α-synuclein immunohistochemistry common to all phenotypes.
      • Tu P.H.
      • Galvin J.E.
      • Baba M.
      • et al.
      Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein.
      In the current era, MSA is recognized as a well-circumscribed disorder that is diagnosed when parkinsonism or cerebellar ataxia is manifested with prominent autonomic failure (especially OH). It is often accompanied if not preceded by REM sleep behavior disorder.
      • Giannini G.
      • Mastrangelo V.
      • Provini F.
      • et al.
      Progression and prognosis in multiple system atrophy presenting with REM behavior disorder.
      Clues to MSA include incomplete levodopa responses among those with parkinsonism; comorbid ataxia and parkinsonism; frequent falls; and clinical evidence of brainstem dysfunction, such as nocturnal stridor, severe dysarthria, and dysphonia (Table 1).
      • Kollensperger M.
      • Geser F.
      • Seppi K.
      • et al.
      Red flags for multiple system atrophy.
      Unlike in other neurodegenerative syndromes, dementia is uncommon. Although mild cognitive impairment may occur, especially later in disease,
      • Stankovic I.
      • Krismer F.
      • Jesic A.
      • et al.
      Cognitive impairment in multiple system atrophy: a position statement by the Neuropsychology Task Force of the MDS Multiple System Atrophy (MODIMSA) study group.
      moderate to severe intellectual deterioration has been noted in only 2.5% of a large series.
      • Wenning G.K.
      • Tison F.
      • Ben Shlomo Y.
      • Daniel S.E.
      • Quinn N.P.
      Multiple system atrophy: a review of 203 pathologically proven cases.
      When the diagnosis is suggested by the history and neurologic examination findings, it typically is confirmed by autonomic testing and certain magnetic resonance imaging brain scan features. Diagnosis tends to occur approximately 3 years after symptom onset in MSA.
      • Coon E.A.
      • Sletten D.M.
      • Suarez M.D.
      • et al.
      Clinical features and autonomic testing predict survival in multiple system atrophy.
      From the time of diagnosis, motor and autonomic symptoms tend to worsen, causing significant stress for the patient, caregivers, and family. With an expected survival of 7.5 to 9.8 years from symptom onset,
      • Bower J.H.
      • Maraganore D.M.
      • McDonnell S.K.
      • Rocca W.A.
      Incidence of progressive supranuclear palsy and multiple system atrophy in Olmsted County, Minnesota, 1976 to 1990.
      • Coon E.A.
      • Sletten D.M.
      • Suarez M.D.
      • et al.
      Clinical features and autonomic testing predict survival in multiple system atrophy.
      • Wenning G.K.
      • Ben Shlomo Y.
      • Magalhaes M.
      • Daniel S.E.
      • Quinn N.P.
      Clinical features and natural history of multiple system atrophy. An analysis of 100 cases.
      ,
      • Low P.A.
      • Reich S.G.
      • Jankovic J.
      • et al.
      Natural history of multiple system atrophy in the USA: a prospective cohort study.
      patients often struggle to deal with the myriad autonomic problems as well as with parkinsonism and ataxia.
      These patients are not rare in our movement and autonomic disorder clinics and often come from distant places. We seek to send them home with enough knowledge to complement the treatment efforts of their community clinicians, recognizing that many practitioners have not previously encountered MSA patients. For many, it is the primary care clinicians that are on the front lines of their MSA treatment.
      Managing constantly evolving OH, parkinsonism, neurogenic bladder, and sleep disorders requires certain expertise. We designed our MSA clinic as a multidisciplinary model, incorporating the neurology, palliative care, physical medicine and rehabilitation, speech pathology, sleep medicine, and urology services. Managing patients with MSA beyond the initial visit and in conjunction with local providers has taught us that empowering the local physician and therapy teams can be helpful.
      With that as background, we have constructed this manuscript to be a practical guide for optimizing ongoing MSA treatment with currently available options. We especially focus on MSA symptoms that have treatment options, including OH, parkinsonism, sleep disorders, neurogenic bladder, and constipation, as well as strategies to avoid catastrophes, such as falls. We end with a discussion of vigorous exercise to counter neurodegeneration.

      Autonomic Symptoms

      This section addresses autonomic symptoms of OH, which often has accompanying supine hypertension as well as genitourinary failure and constipation.

      Orthostatic Hypotension

      Orthostatic hypotension with presyncope or syncope can be the most disabling problem of MSA and, if inadequately treated, often precludes ambulation. The autonomic nervous system normally counters the influence of gravity on the upright blood volume by reflexive constriction of the vasculature (especially lower body and splanchnic vasculature) plus, as necessary, elevation of the heart rate. This maintains a fairly constant blood pressure (BP) irrespective of posture. Failure of these baroreflex mechanisms translates into OH, in which the standing systolic BP is at least 20 mm Hg below the sitting or supine value.
      • Gibbons C.H.
      • Schmidt P.
      • Biaggioni I.
      • et al.
      The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension.
      Neurogenic OH is characterized by minimal or absent compensatory heart rate increase associated with the drop in BP.
      • Norcliffe-Kaufmann L.
      • Kaufmann H.
      • Palma J.A.
      • et al.
      Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies.
      Recording of standing BP is necessary in patients with MSA. The patient and caregivers should have a reliable BP device and record values for the clinician in the supine, sitting, and standing positions. Orthostatic hypotension symptoms typically are manifested when the standing systolic values drop below 90 mm Hg. The magnitude of the BP decline can be sizable without hypotensive symptoms if the standing BP is above this minimum value. Thus, the goal should be to keep the standing systolic BP above 90 mm Hg. OH symptoms may be manifested as lightheadedness, “dizziness,” sense of unease, or fatigue. Patients with long-standing OH may tolerate systolic values below 90 mm Hg or have vague symptoms, such as feeling unwell or “coat-hanger” distribution pain (neck and upper back region).
      • Lanier J.B.
      • Mote M.B.
      • Clay E.C.
      Evaluation and management of orthostatic hypotension.
      The lowest BP of the day will typically be after breakfast, reflecting the influences of a night’s sleep (following nocturnal diuresis that is accentuated by supine hypertension) and dilation of the splanchnic circulation (postprandial hypotension). Hence, after breakfast is a good time to record the standing BP.
      Evening BP readings in bed can address the opposite problem, supine hypertension. Supine hypertension (ie, BP>140/90 mm Hg) should be minimized to reduce the risk of stroke and chronic microvascular damage to the brain.
      • Fanciulli A.
      • Jordan J.
      • Biaggioni I.
      • et al.
      Consensus statement on the definition of neurogenic supine hypertension in cardiovascular autonomic failure by the American Autonomic Society (AAS) and the European Federation of Autonomic Societies (EFAS): endorsed by the European Academy of Neurology (EAN) and the European Society of Hypertension (ESH).
      Strategies for treating OH and supine hypertension are as follows.

      Review of Offending Medications

      Review of the medication list is imperative when OH is suspected. Offending drugs include antihypertensives, diuretics, α-blockers for male urinary symptoms, and nonselective β-blockers for tremor; these should be eliminated in the setting of OH unless there is some highly compelling indication. In the setting of supine hypertension, antihypertensives may be transitioned to bedtime dosing.
      • Fanciulli A.
      • Jordan J.
      • Biaggioni I.
      • et al.
      Consensus statement on the definition of neurogenic supine hypertension in cardiovascular autonomic failure by the American Autonomic Society (AAS) and the European Federation of Autonomic Societies (EFAS): endorsed by the European Academy of Neurology (EAN) and the European Society of Hypertension (ESH).

      Volume Expansion (Salt, Fluids, Fludrocortisone)

      Orthostatic hypotension is often initially treated with blood volume expansion, including increased dietary salt and fluids.
      • Cheshire W.P.
      Chemical pharmacotherapy for the treatment of orthostatic hypotension.
      Sufficient oral fluid intake is on the order of 1.5 to 2.5 L daily. Increased intake of sodium chloride is typically tried, such as 5 to 10 g daily or use of salt tablets (eg, ½ to 1 Thermotab twice daily). This is often supplemented with the mineralocorticoid fludrocortisone, which increases sodium retention (0.1 mg daily to 0.2 mg twice daily). Fludrocortisone often causes hypokalemia, and potassium levels should be monitored. Fludrocortisone is contraindicated in the setting of renal failure or heart failure.
      The outcome of salt, fluid, and fludrocortisone treatment of OH is modestly beneficial and will be insufficient in the setting of marked OH and may increase supine BP. Hence, in typical MSA with autonomic failure, other strategies are often necessary and sometimes preferable.

      External Compression of the Vasculature

      Lower body compression is another common strategy to treat OH. The intent is to externally constrict the lower body vasculature to substitute for the failed reflexive vasoconstriction. Theoretically, this makes excellent sense. However, practically, there are problems. For this to work, the external constriction should ideally be waist high (ie, not knee high). Compressive hose can be efficacious, but in the real world these are not tolerated (hot; difficult to put on; need to be fitted to the leg size; expensive; washed in gentle detergents and warm water to spare the elastic). Although we still discuss this with MSA patients, this does not turn out to be a longer term solution in most individuals.
      A related and more tolerable strategy for patients with postprandial hypotension is to put on an abdominal binder before each meal. This is relatively available and inexpensive, functioning similar to a girdle. It compresses the splanchnic circulation that dilates during mealtimes and can pool approximately 30% of blood volume.

      Vasoconstrictor Medications

      In our experience, the most consistently efficacious single strategy for OH is the use of midodrine or droxidopa with or without pyridostigmine. The drug with the most experience and tolerable expense is midodrine, which is our first choice.

      Midodrine

      Midodrine was approved by the Food and Drug Administration about a quarter-century ago. It is a prodrug, generating desglymidodrine through enzymatic cleavage. Desglymidodrine is a potent α1-receptor agonist that exclusively mediates the BP-elevating effect from midodrine. Neither moiety crosses the blood-brain barrier; hence, there are no central effects. It elevates BP by arteriolar and venous vasoconstriction, with dose-related responses.
      • McClellan K.J.
      • Wiseman L.R.
      • Wilde M.I.
      Midodrine. A review of its therapeutic use in the management of orthostatic hypotension.
      ,
      • Cruz D.N.
      Midodrine: a selective alpha-adrenergic agonist for orthostatic hypotension and dialysis hypotension.
      It does not elevate the heart rate and in fact tends to lower it.
      • Zachariah P.K.
      • Bloedow D.C.
      • Moyer T.P.
      • Sheps S.G.
      • Schirger A.
      • Fealey R.D.
      Pharmacodynamics of midodrine, an antihypotensive agent.
      ,
      • Grobecker H.F.
      • Kees F.
      Pharmacokinetic parameters and haemodynamic actions of midodrine in young volunteers.
      Adverse effects primarily include piloerection, scalp paresthesias, pruritus, and urinary retention.
      • McClellan K.J.
      • Wiseman L.R.
      • Wilde M.I.
      Midodrine. A review of its therapeutic use in the management of orthostatic hypotension.
      Blood pressure elevation after each midodrine dose lasts about 4 hours.
      • McClellan K.J.
      • Wiseman L.R.
      • Wilde M.I.
      Midodrine. A review of its therapeutic use in the management of orthostatic hypotension.
      ,
      • Low P.A.
      • Gilden J.L.
      • Freeman R.
      • Sheng K.N.
      • McElligott M.A.
      Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study Group.
      ,
      • Wright R.A.
      • Kaufmann H.C.
      • Perera R.
      • et al.
      A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension.
      The duration of this effect is advantageous in 2 ways. First, this allows termination of the BP elevation before bedtime to avoid supine hypertension. Second, this 4-hour effect tends to offset the BP-lowering effect of carbidopa/levodopa, which lasts about 3 to 4 hours.
      Although the starting midodrine dose is often stated to be 2.5 mg, that is typically subtherapeutic in MSA patients with prominent OH; we typically start with a 5-mg dose. BP recordings 1 to 2 hours after midodrine administration can determine whether the dose is sufficient. Increments of half of a 5-mg tablet (2.5 mg) can subsequently be made up to as high as 15-mg single doses (rarely 20-mg doses). The BP target for midodrine (and in general) is to keep the standing systolic BP above 90 mm Hg. Ideally, it should be a little bit higher to allow the usual BP fluctuations.
      The timing of the doses depends on whether carbidopa/levodopa is also being taken. If no carbidopa/levodopa is being taken, each midodrine dose can be administered every 4 hours, stopping 4 hours before bedtime.
      • McClellan K.J.
      • Wiseman L.R.
      • Wilde M.I.
      Midodrine. A review of its therapeutic use in the management of orthostatic hypotension.
      ,
      • Low P.A.
      • Gilden J.L.
      • Freeman R.
      • Sheng K.N.
      • McElligott M.A.
      Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study Group.
      ,
      • Wright R.A.
      • Kaufmann H.C.
      • Perera R.
      • et al.
      A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension.
      If carbidopa/levodopa is being taken, the BP-lowering effect of each carbidopa/levodopa dose lasts about 3 to 4 hours. Thus, midodrine (4-hour effect) can be taken at the same time as each of these carbidopa/levodopa doses. If the last dose of carbidopa/levodopa is taken near bedtime, midodrine should not be administered at that time.
      Untreated OH is typically more prominent in the morning through noontime or early afternoon. Sometimes, midodrine is necessary only during the morning or the first half of the day. In other cases, a reduced midodrine dose is appropriate later in the day.

      Droxidopa

      Droxidopa (l-threo-dihydroxyphenylserine; l-threo-DOPS) is a synthetic prodrug. It is converted by dopa decarboxylase to the vasoconstrictor norepinephrine. It shares a similar mechanism as that of midodrine (vasoconstriction), and these should not be used together.
      Blood pressure elevation through droxidopa-generated norepinephrine may be by several mechanisms.
      • Cheshire W.P.
      Chemical pharmacotherapy for the treatment of orthostatic hypotension.
      Droxidopa crosses the blood-brain barrier and potentially elevates norepinephrine in relevant regions as the noradrenergic rostral ventrolateral medulla or intermediolateral cell column in the spinal cord. It also can restore or elevate norepinephrine in peripheral postganglionic sympathetic neurons. Finally, it may generate norepinephrine in nonneuronal tissues, many of which contain dopa decarboxylase.
      MSA patients taking the antiparkinsonian medication carbidopa/levodopa may experience an attenuated BP response to droxidopa.
      • Kaufmann H.
      Droxidopa for symptomatic neurogenic orthostatic hypotension: what can we learn?.
      Carbidopa blocks dopa decarboxylase outside the brain; this will reduce norepinephrine production from droxidopa in the periphery (ie, outside the brain).
      Droxidopa is conventionally initiated with a dose of 100 mg 3 times daily. Because the pressor benefit is estimated to last about 6 hours,
      • Kaufmann H.
      • Norcliffe-Kaufmann L.
      • Palma J.A.
      Droxidopa in neurogenic orthostatic hypotension.
      that would be an appropriate dosing interval. Increments of 100 mg for all 3 doses can be made, guided by the BP responses, up to 600 mg in each dose.
      Once the optimum individual dose of droxidopa has been determined, further adjustments of the dosing interval can be addressed as necessary. An appropriate dosing interval avoids recurrence of low BP values at the end of each cycle. Serial standing BP measurements after a single droxidopa dose can document the full BP cycle. If the dosing interval is optimally adjusted, one dose should be kicking in as the preceding dose is wearing off.
      For MSA patients with the parkinsonian form of MSA (MSA-P) who take carbidopa/levodopa, droxidopa can be taken with each carbidopa/levodopa dose. However, if the levodopa response is brief, with dosing intervals of 2 to 3 hours, the droxidopa dosing interval needs to be adjusted accordingly, such as taking it with every other dose of carbidopa/levodopa.
      The potential for supine hypertension should be assessed when droxidopa is being taken. At a minimum, droxidopa should not be taken within about 6 hours of bedtime to avoid supine hypertension. The BP-elevating effect of droxidopa is mediated by norepinephrine, and the half-life of norepinephrine after a dose of droxidopa is approximately 9 hours.
      • Kaufmann H.
      • Norcliffe-Kaufmann L.
      • Palma J.A.
      Droxidopa in neurogenic orthostatic hypotension.
      ,
      • Goldstein D.S.
      • Holmes C.
      • Kaufmann H.
      • Freeman R.
      Clinical pharmacokinetics of the norepinephrine precursor L-threo-DOPS in primary chronic autonomic failure.
      Contrast this to midodrine, for which the active pressor metabolite, desglymidodrine, has a 2- to 3-hour half-life.
      • McClellan K.J.
      • Wiseman L.R.
      • Wilde M.I.
      Midodrine. A review of its therapeutic use in the management of orthostatic hypotension.

      Pyridostigmine

      This medication has been used for decades to treat myasthenia gravis. It inhibits acetylcholinesterase, the enzyme that degrades acetylcholine. Acetylcholine is the neurotransmitter that activates the penultimate neuron in the baroreflex effector pathway. Thus, pyridostigmine indirectly increases sympathetic tone (ie, vasoconstriction). Because it specifically facilitates the baroreflex that is activated when upright, it does not provoke supine hypertension.
      • Singer W.
      • Opfer-Gehrking T.L.
      • Nickander K.K.
      • Hines S.M.
      • Low P.A.
      Acetylcholinesterase inhibition in patients with orthostatic intolerance.
      Pyridostigmine has a modest effect when it is used separately from midodrine or droxidopa; however, it has as additive effect when it is used concurrently with either of those vasoconstrictor drugs. Much of this effect is on increasing diastolic BP.
      • Singer W.
      • Opfer-Gehrking T.L.
      • Nickander K.K.
      • Hines S.M.
      • Low P.A.
      Acetylcholinesterase inhibition in patients with orthostatic intolerance.
      ,
      • Singer W.
      • Sandroni P.
      • Opfer-Gehrking T.L.
      • et al.
      Pyridostigmine treatment trial in neurogenic orthostatic hypotension.
      Pyridostigmine is typically started with a 30-mg or 60-mg dose. It has about a 4-hour effect, and if it is used alone, it can be taken every 4 hours throughout the day. Among MSA patients taking concurrent carbidopa/levodopa and midodrine, pyridostigmine may be combined with them.
      Pyridostigmine is a quaternary ammonium compound and therefore should not cross the blood-brain barrier. Hence, its procholinergic adverse effects are peripheral and primarily gastrointestinal, although it occasionally may cause urinary frequency. Because many MSA patients often struggle with severe constipation, the prokinetic effect of pyridostigmine may be a useful gastrointestinal effect.

      Lifestyle Measures to Counter OH

      Nonpharmacologic measures are of utmost importance in combating OH and are summarized in Table 2.
      Table 2Lifestyle Measures to Counter Orthostatic Hypotension
      Lifestyle measureReasoning
      Cold-water bolusDrinking about 16 ounces of water quickly (cold temperature) will elevate blood pressure for about an hour through an osmopressor response.
      • May M.
      • Jordan J.
      The osmopressor response to water drinking.
      Postural countermaneuversPostural countermaneuvers reduce orthostatic hypotension symptoms during prolonged standing (ie, contraction of lower limb muscles, such as leg crossing, buttock clenching, standing on tiptoes).
      Elevate head of bedPlace the legs of the head of bed on risers 4 to 6 inches to reduce nocturnal diuresis and to counter supine hypertension.
      Avoid large meals, especially carbohydrate-rich foodsLarge meals and high-carbohydrate meals increase postprandial hypotension.
      Exercise and physical therapy to address lower body conditioningMaintaining and increasing lower body and core muscle tone reduces venous pooling.
      Avoid alcoholThe vasodilatory effects of alcohol worsen hypotension.
      Avoid hot temperaturesExposure to high temperatures leads to vasodilation, which exacerbates orthostatic hypotension.

      Supine Hypertension

      Nonpharmacologic measures to combat supine hypertension involve elevation of the head of the bed. Pharmacologic measures may be necessary when BPs are persistently elevated to reduce the risk of end-organ damage.
      • Fanciulli A.
      • Jordan J.
      • Biaggioni I.
      • et al.
      Consensus statement on the definition of neurogenic supine hypertension in cardiovascular autonomic failure by the American Autonomic Society (AAS) and the European Federation of Autonomic Societies (EFAS): endorsed by the European Academy of Neurology (EAN) and the European Society of Hypertension (ESH).
      However, patients should be instructed to exercise extreme caution after taking these medications to reduce the risk of nocturnal syncope if they are getting up during the night. We favor the use of short-acting antihypertensives (such as losartan) to mitigate the risks of worsening morning OH.
      • Jordan J.
      • Biaggioni I.
      Diagnosis and treatment of supine hypertension in autonomic failure patients with orthostatic hypotension.
      Clonidine effectively lowers BP and also reduces nocturnal diuresis but may still worsen morning OH.
      • Shibao C.
      • Gamboa A.
      • Abraham R.
      • et al.
      Clonidine for the treatment of supine hypertension and pressure natriuresis in autonomic failure.
      The transdermal formulation can be used when the patient is supine and taken off on awakening as the oral formulation has a relatively long half-life.

      Neurogenic Bladder

      Neurogenic bladder in MSA tends to represent a hypoactive bladder; incontinence typically reflects overflow of a poorly contracting bladder.
      • Shin J.H.
      • Park K.W.
      • Heo K.O.
      • Chung S.J.
      • Choo M.S.
      Urodynamic study for distinguishing multiple system atrophy from Parkinson disease.
      The medications for urinary urgency (anticholinergics, mirabegron) are for hyperactive bladders and may worsen hypoactive bladder symptoms. Hence, before a medication is prescribed for a neurogenic bladder in MSA, postvoid residual urine should be checked. Retention of more than 100 mL of urine suggests a hypoactive bladder.
      Hypoactive bladders cannot be managed with medications, and these problems frequently fall into the domain of the urology service. Approaches to improve bladder symptoms include timed voiding to reduce overflow incontinence. When retention becomes severe or with frequent incontinence, clean intermittent catheterization, indwelling catheterization, or suprapubic catheterization may be recommended by the urology team.

      Sexual Dysfunction

      Sexual dysfunction is often an early sign in MSA and is manifested with erectile dysfunction, ejaculation problems, and anorgasmia in men. Women often report vaginal dryness, decreased libido, and anorgasmia, although it is less frequently addressed.
      • Coon E.A.
      • Nelson R.M.
      • Sletten D.M.
      • et al.
      Sex and gender influence symptom manifestation and survival in multiple system atrophy.
      Treatment often includes phosphodiesterase type 5 inhibitors in men; however, these must be used cautiously as they can drastically reduce BP.

      Constipation

      The usual advice for initial treatment of constipation in the general population is increased intake of fiber, fluids, fruit, and vegetables as well as exercise plus stool softeners. In MSA, constipation tends to be refractory to simple measures, and regular use of a potent laxative is often necessary, perhaps daily. For frequent laxative use, an osmotic laxative is the simplest and least expensive option, such as polyethylene glycol.
      Patients going many days without a bowel movement may become impacted. Impaction is sometimes manifested as watery stool incontinence, which typically requires a high-volume cleansing enema. The typical over-the-counter 4.5-ounce enema kits contain far too little volume to reach impacted stool higher in the colon.

      Motor Symptoms

      Motor manifestations of MSA primarily include parkinsonism and cerebellar ataxia, and later in disease, both may often be present. This section addresses the most common motor symptoms in MSA: parkinsonism, cerebellar ataxia, and falls.

      Parkinsonism

      Parkinsonism is a syndrome characterized by bradykinesia, rigidity, tremor, and postural instability. Parkinsonism in patients with MSA tends to be partially levodopa responsive but not as prominently as with Parkinson disease. If the parkinsonism is minimal, it does not need to be treated. Parkinson medications other than carbidopa/levodopa are not recommended; keep things as simple as possible. The other parkinsonism drugs are not nearly as efficacious as carbidopa/levodopa and tend to have more adverse effects, including affecting autonomic function.
      The primary adverse effect of concern in using carbidopa/levodopa is exacerbation of OH, which is a common problem in MSA. Thus, the standing BP should be recorded at baseline before this drug is started and subsequently recorded after it is initiated and increased. As previously stated, a reasonable BP target is to maintain standing systolic BP above 90 mm Hg. If lower BP values are frequently recorded, measures need to be taken to offset that, as described before.
      Carbidopa/levodopa is best started with the 25/100 regular (not sustained-release) formulation. It must be taken at least 1 hour before and at least 2 hours after the end of meals because dietary protein products (amino acids) can prevent levodopa from being transported across the blood-brain barrier.
      • Nutt J.G.
      • Woodward W.R.
      • Hammerstad J.P.
      • Carter J.H.
      • Anderson J.L.
      The "on-off" phenomenon in Parkinson's disease: relation to levodopa absorption and transport.
      • Pincus J.H.
      • Barry K.M.
      Plasma levels of amino acids correlate wilth motor fluctuations in parkinsonism.
      • Ahlskog J.E.
      The New Parkinson's Disease Treatment Book.
      • Leenders K.L.
      • Poewe W.H.
      • Palmer A.J.
      • Brenton D.P.
      • Frackowiak R.S.
      Inhibition of L-[18F]fluorodopa uptake into human brain by amino acids demonstrated by positron emission tomography.
      The starting dose is typically 1 tablet 3 times per day, which can be increased by a half-tablet each dose at 1- to 2-week intervals, up to 2.5 tablets 3 times daily. Ultimately, the best of these carbidopa/levodopa doses can be chosen for ongoing treatment. If several doses are equally efficacious, the lowest of those equipotent doses is appropriately chosen.
      The motor symptoms (bradykinesia, shuffling gait, rigidity, tremor, dysarthria/dysphonia) are not the only symptoms that may benefit from carbidopa/levodopa. Levodopa-responsive nonmotor symptoms include anxiety, insomnia, and inner restlessness (akathisia).
      With longer standing MSA-P, the dynamics of the levodopa response may change, resulting in “short-duration” levodopa responses. Thus, the benefit follows each dose, lasting a few hours, and then dissipates, leading to a fluctuating response. The appropriate strategy is to use the same carbidopa/levodopa dose found to be optimal but at intervals that match the response duration. This approach generally works satisfactorily unless the required dosing interval drops to less than 4 hours, making it impossible to consistently avoid the blocking effect of meals.
      If a patient has no response to an adequate dose of levodopa, the medication should be discontinued. If the patient benefits from levodopa but OH is accentuated, initiation and titration of medications to combat low BPs is recommended (see earlier). Individual levodopa doses should also be reduced or discontinued if dyskinesias surface. Facial dystonia is a unique levodopa side effect among patients with MSA.

      Ataxia and Falls

      Cerebellar ataxia does not benefit from medications, and neither does imbalance and fall risk. However, elimination of daytime use of sedating drugs or muscle relaxants may improve balance.
      A physical therapist is an important member of the care team. Physical therapy can improve motor symptoms through personalized care programs and assess fall risk. Physical therapists also provide important recommendations regarding gait aids and how to properly use the correct aid for each patient.
      • Swan L.
      • Dupont J.
      Multiple system atrophy.
      Fall risk should trigger strategies to avoid fractures. This includes a nuclear medicine bone density study (DEXA scan). Bisphosphonates or related drugs should be considered, even in the osteopenia range, if falls are frequent. Vitamin D supplementation or at least measurement of serum vitamin D level would generally be appropriate.

      Sleep Disorders

      Sleep disorders are highly prevalent in MSA. Approaches to address stridor, central and obstructive sleep apnea, REM sleep behavior disorder, and insomnia are highlighted here.

      Stridor, Central Neurogenic Hypoventilation, and Central Sleep Apnea

      Neuropathologic changes of MSA affect brainstem respiratory neurons.
      • Benarroch E.E.
      • Schmeichel A.M.
      • Low P.A.
      • Parisi J.E.
      Depletion of putative chemosensitive respiratory neurons in the ventral medullary surface in multiple system atrophy.
      Patients with MSA may die unexpectedly during sleep, and this has been attributed to respiratory malfunction or failure. Stridor may be a marker of that potential.
      • Silber M.H.
      • Levine S.
      Stridor and death in multiple system atrophy.
      There has been ongoing debate about the substrate for nocturnal demise in MSA, and it remains unclear whether this is due to stridor, central neurogenic hypoventilation, or central sleep apnea.
      • Giannini G.
      • Calandra-Buonaura G.
      • Mastrolilli F.
      • et al.
      Early stridor onset and stridor treatment predict survival in 136 patients with MSA.
      Stridor seems to be a marker of brainstem respiratory center involvement by MSA. If stridor has been witnessed by a sleep partner, we recommend sleep medicine consultation; this typically involves overnight polysomnography. Even if stridor has not been witnessed, a sleep clinic appointment or overnight oximetry is appropriate. MSA patients without stridor or abnormal overnight oximetry who are unable to return to our practice are advised to have their primary care clinician follow up. A yearly “stridor” inquiry and oximetry should be considered.
      Involvement of brainstem respiratory centers may represent an early MSA problem, not necessarily something that occurs late in the course. It sometimes occurs as the presenting symptom.
      • Glass G.A.
      • Josephs K.A.
      • Ahlskog J.E.
      Respiratory insufficiency as the primary presenting symptom of multiple-system atrophy.
      In taking the history, the sleep partner is important but may not recognize the word stridor. It can be described as a screeching sound made during inhalation. Imitation of that sound is often helpful.
      It will ultimately be up to a sleep specialist to determine how to address this important sleep issue, and the appropriate treatment approach has not been established.
      • Giannini G.
      • Calandra-Buonaura G.
      • Mastrolilli F.
      • et al.
      Early stridor onset and stridor treatment predict survival in 136 patients with MSA.
      Compared with no such treatment, continuous positive airway pressure is beneficial to survival; however, tracheostomy may be beneficial in selected patients.
      • Giannini G.
      • Calandra-Buonaura G.
      • Mastrolilli F.
      • et al.
      Early stridor onset and stridor treatment predict survival in 136 patients with MSA.
      A variant of continuous positive airway pressure, adaptive servoventilation, has been proposed for patients with MSA; it adjusts pressure to support ventilation in addition to countering airway obstructing events.
      • Hamada S.
      • Takahashi R.
      • Mishima M.
      • Chin K.
      Use of a new generation of adaptive servo ventilation for sleep-disordered breathing in patients with multiple system atrophy.
      As yet, there have been no comparative trials of this strategy to determine efficacy in MSA.

      REM Sleep Behavior Disorder

      Acting out dreams represents a neurologic disorder that may occur in any of the α-synucleinopathies and is common in MSA. This REM sleep behavior disorder may precede MSA by years.
      • Claassen D.O.
      • Josephs K.A.
      • Ahlskog J.E.
      • Silber M.H.
      • Tippmann-Peikert M.
      • Boeve B.F.
      REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century.
      If dream enactment is not a problem for the sleeper or sleep partner, it does not need to be treated. However, if there is concern for injury to the MSA patient (eg, falling out of bed) or to the sleep partner (eg, being struck by the MSA patient in a dream state), treatment is necessary. The current first choice is over-the-counter melatonin with a starting dose of 3 to 5 mg at bedtime, with increments as necessary up to 12 to 15 mg at bedtime.
      Clonazepam is also beneficial in treating REM sleep behavior, but this benzodiazepine is a second choice because of potential for exacerbating imbalance or nocturnal sedation. The starting clonazepam dose is 0.5 mg at bedtime. Clonazepam and melatonin can be used in conjunction.
      For those at risk for falling out of bed, the furniture beside the bed should be addressed to avoid sharp corners of nightstands. Consideration should be given to padding the floor beside the bed or use of bed rails.

      Insomnia

      Among those with parkinsonism (ie, MSA-P), untreated brain dopamine deficiency may result in stiffness, akathisia, or impaired ability to turn over in bed; these symptoms may translate into insomnia. As with patients with Parkinson disease, this problem may be adequately treated with carbidopa/levodopa. For those recently starting carbidopa/levodopa, the “long-duration” effect of the daytime carbidopa/levodopa dosage often carries over to nighttime. However, if MSA-P patients experience short-duration carbidopa/levodopa responses, a dose an hour before bedtime may allow sleep. Another dose during the night is sometimes necessary to maintain sleep. The individual carbidopa/levodopa doses must be adequate (ie, above the daytime “on” threshold) to counter these sleep-inhibiting symptoms.
      Carbidopa/levodopa at bedtime or during the night may provoke OH if the patient is walking to the bathroom at night. To avoid risk of nocturnal OH, use of a bedside urinal or commode is advisable.

      Additional Features

      Dystonia

      Dystonia is a muscle contraction state that is frequently encountered in patients with MSA, particularly those with MSA-P.
      • Boesch S.M.
      • Wenning G.K.
      • Ransmayr G.
      • Poewe W.
      Dystonia in multiple system atrophy.
      MSA-P patients may also experience significant dystonia or dyskinesias related to levodopa that should trigger adjustments in the levodopa dose. Dystonia may involve cervical regions, manifested as anterocollis, or involve limbs. Anticholinergic medications for dystonia are usually of limited benefit and can worsen autonomic dysfunction; they are not recommended. On occasion, levodopa effectively treats limb dystonia among those with MSA-P, although this is much less likely to be beneficial compared with Parkinson disease.
      Targeted botulinum toxin injections may be useful for symptomatic therapy for focal dystonia. Unfortunately, muscle groups contributing to anterocollis are typically not amenable to injection.
      • Papapetropoulos S.
      • Tuchman A.
      • Sengun C.
      • Russell A.
      • Mitsi G.
      • Singer C.
      Anterocollis: clinical features and treatment options.
      Patients with MSA-P may also experience dystonia (or choreiform dyskinesia) triggered by levodopa, which can be eliminated by reductions in the individual levodopa doses (or discontinuation if severe and necessary). As noted before, perioral facial dystonia triggered by levodopa is unique to MSA.

      Dysarthria

      The speech findings in MSA typically include a mixed pattern of dysarthria with combinations of hypokinetic, ataxic, and spastic components.
      • Kluin K.J.
      • Gilman S.
      • Lohman M.
      • Junck L.
      Characteristics of the dysarthria of multiple system atrophy.
      Speech examination and therapy are essential tools for diagnosis and to improve communication throughout the disease course. Severe dysarthria or hypophonia early in the condition is a clue to MSA.

      Depression and Anxiety

      Patients with MSA commonly have depressive and anxiety symptoms that have a negative impact on their quality of life.
      • Benrud-Larson L.M.
      • Sandroni P.
      • Schrag A.
      • Low P.A.
      Depressive symptoms and life satisfaction in patients with multiple system atrophy.
      • Zhang L.Y.
      • Cao B.
      • Zou Y.T.
      • et al.
      Depression and anxiety in multiple system atrophy.
      • Schrag A.
      • Geser F.
      • Stampfer-Kountchev M.
      • et al.
      Health-related quality of life in multiple system atrophy.
      Selective serotoninergic reuptake inhibitors are frequently prescribed and have an adverse effect profile that tends to be more favorable than that of other medications.

      Pseudobulbar Affect

      Pseudobulbar affect, defined as uncontrollable laughing or crying disproportionate to or incongruent with the social context, is often unrecognized in patients with MSA.
      • Parvizi J.
      • Joseph J.
      • Press D.Z.
      • Schmahmann J.D.
      Pathological laughter and crying in patients with multiple system atrophy-cerebellar type.
      Describing this phenomenon to the patient and caregiver is useful and may be all that is necessary in terms of treatment. In the few patients in whom pseudobulbar affect is disruptive, dextromethorphan/quinidine combination is approved for use.
      • Pioro E.P.
      • Brooks B.R.
      • Cummings J.
      • et al.
      Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect.

      Pain

      Pain is reported in approximately half of the patients with MSA.
      • You H.Y.
      • Wu L.
      • Yang H.T.
      • Yang C.
      • Ding X.L.
      A comparison of pain between Parkinson's disease and multiple system atrophy: a clinical cross-sectional survey.
      ,
      • Tison F.
      • Wenning G.K.
      • Volonte M.A.
      • Poewe W.R.
      • Henry P.
      • Quinn N.P.
      Pain in multiple system atrophy.
      The type of pain reported by patients with MSA is variable; some patients report improvement in pain with levodopa, similar to other parkinsonian disorders. If there appears to be a neuropathic component, gabapentin or pregabalin may be beneficial. In patients with muscle contraction pain associated with dystonia, such as in the cervical region or limbs, targeted botulinum toxin injections may be beneficial. Involvement of palliative care specialists or pain medicine specialists may be helpful in patients in whom pain is significantly influencing quality of life.

      Palliative Care, Physical Medicine and Rehabilitation, and Multidisciplinary Teams

      Palliative care seeks to improve the quality of life of patients and caregivers of patients with life-threatening illnesses through prevention and relief of suffering. Growing evidence favors the incorporation of palliative care early in the course of MSA.
      • Wiblin L.
      • Lee M.
      • Burn D.
      Palliative care and its emerging role in multiple system atrophy and progressive supranuclear palsy.
      In MSA, symptomatic treatment can be challenging throughout the disease course, and numerous factors may contribute to distress in patients and caregivers. In our MSA clinic, we have found that a team approach with palliative care providers is useful both early in MSA and later in disease for management of symptoms and dealing with issues such as advance care planning.
      Physical medicine and rehabilitation subspecialists may play important roles in treatment of patients with MSA. In addition to evaluation and therapy protocols for motor problems such as ataxia, physiatrist involvement along with physical therapists and occupational therapists can improve motor function in patients with MSA.
      • Swan L.
      • Dupont J.
      Multiple system atrophy.
      ,
      • Raccagni C.
      • Goebel G.
      • Gassner H.
      • et al.
      Physiotherapy improves motor function in patients with the Parkinson variant of multiple system atrophy: a prospective trial.
      Physical medicine and rehabilitation and occupational therapists can play invaluable roles in evaluating for assistive devices to reduce the risk of falls and adapting devices for the individual patient’s needs.
      Multidisciplinary care of patients with MSA may be done in a centralized location, such as a Center of Excellence model. However, this is likely to be available only to patients near a tertiary care center. Local providers may also seek out teams that have experience in caring for patients with complex neurologic disorders and partner with movement or autonomic specialists regarding care of patients with MSA. Clear communication between teams, such as accessibility of electronic medical records, is important to maintain communication between care providers.

      Slowing Progression of MSA

      There is now literature arguing that regular aerobic-type exercise has a directly beneficial effect on the brain. Vigorous exercise influences myriad mechanisms that can counter neurodegenerative diseases as well as potentially slow brain aging. This occurs through generating brain neurotrophic factors (eg, brain-derived neurotrophic factor), facilitating cerebral synaptogenesis, and enhancing neuroplasticity.
      • Ahlskog J.E.
      Aerobic exercise: evidence for a direct brain effect to slow Parkinson disease progression.
      ,
      • Ahlskog J.E.
      • Geda Y.E.
      • Graff-Radford N.R.
      • Petersen R.C.
      Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging.
      Exercise in MSA may be compromised by both the motor (eg, fall risk) and autonomic (OH) symptoms. However, a wide range of exercise equipment can be used while sitting (eg, exercise bicycles, rowing machines); physical therapists are often essential to teach patients safe and effective ways for aerobic exercise.
      • Swan L.
      • Dupont J.
      Multiple system atrophy.
      A treatment summary of autonomic, motor, and sleep disorders with tips to slow progression of MSA is shown in Table 3.
      Table 3Treatment Summary for MSA
      SymptomApproach
      Orthostatic hypotension• Eliminate blood pressure-lowering drugs, when possible.

      • Record standing blood pressure (typically after breakfast, when symptomatic, and when lying in bed at night).

      • Liberalize salt and fluid intake.

      • Low standing systolic blood pressure values (ie, frequently <90 mm Hg) are treated by us with midodrine, starting with 5-mg doses. This can be escalated by half-tablet (2.5-mg) increments. In the absence of carbidopa/levodopa, it can be taken every 4 hours during the waking day but not within 4 hours of bedtime.
      Supine hypertension• Elevate the head of the bed.

      • Consider short-acting antihypertensive agents at bedtime.
      Parkinsonism• Exclusively use carbidopa/levodopa.

      • Be mindful that each dose of carbidopa/levodopa will exacerbate orthostatic hypotension for 3 to 4 hours after each dose.

      • For carbidopa/levodopa dosing intervals of 4 hours or more, a midodrine dose may be added to each daytime carbidopa/levodopa dose to counter orthostatic hypotension (starting with a 5-mg midodrine dose).
      Constipation• Fluid, fiber, fruit, vegetables, and exercise are always advisable.

      • The constipation of MSA may be refractory to simple strategies such as the above or stool softeners. In that case, use an osmotic laxative, daily if necessary (eg, polyethylene glycol).
      Neurogenic bladder• Record postvoid residual urine. If retention is substantial, avoid drugs for overactive bladder (eg, anticholinergics).

      • Refer to a urologist who is informed of the diagnosis (MSA with neurogenic bladder).

      • A handheld urinal can be useful for nocturia (available for both sexes).
      Stridor• Inquire from the sleep partner whether this has been heard.

      • If unknown, overnight oximetry may be used.

      • Referral to a sleep specialist is appropriate but especially if stridor has been heard or if overnight oximetry documents episodic oxygen desaturation during sleep.
      REM sleep behavior disorder• Make the environment around the bed safe if falling out of bed might occur during episodes of REM sleep behavior disorder.

      • Melatonin, in doses between 3 mg and 15 mg, may suppress behaviors.

      • The second-line medication is clonazepam with a starting dose of 0.5 mg; note that it may cause sedation or imbalance.
      Insomnia• Adequate carbidopa/levodopa dosage often facilitates natural sleep among those with the parkinsonian form of MSA (but may provoke nocturnal presyncope/syncope during trips to the bathroom).
      For slowing MSA progression• Encourage vigorous exercise, with proper selection of exercise outlets to avoid syncope or fall risks.
      MSA = multiple system atrophy.

      Recommendations

      The complexity of MSA symptoms challenges both the MSA patient and caregivers. It is preferable to keep the treatment as simple as possible but not at the expense of disability. With that in mind, this advice matches the strategies we typically use in our neurology clinics and MSA clinic.

      Supplemental Online Material

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