Treatment

Because of the small number of randomized controlled trials, the practical management of MSA is largely based on empirical evidence, except for a few controlled studies on midodrine.

A. Autonomic Failure

Unfortunately there is no causal therapy for autonomic dysfunction currently available to clinicians. Therefore, the therapeutic strategy is defined by clinical symptoms and impairment of quality of life in these patients. Due to the progressive course of MSA, a regular review of the treatment is mandatory to adjust measures according to clinical needs. The concept of treating symptoms of orthostatic hypotension is based on the increase of intravasculature volume and the reduction of volume shift to lower body parts when changing into an upright position. The selection and combination of the following options depends on the severity of symptoms and their practicability in the individual patient, but not on the extent of blood pressure drop during tilt test. Non-pharmacological options include sufficient fluid intake, high salt diet, more frequent but smaller meals per day to reduce postprandial hypotension by spreading the total carbohydrate intake, and custom-made elastic body garments. During the night, head-up tilt increases intravasculature volume up to 1L within a week, which is particularly helpful in improving hypotension early in the morning. This approach is particularly successful in combination with fludrocortisone, which further supports sodium retention.

The next group of drugs to use is the sympathomimetics. These include ephedrine (with both direct and indirect effects) which is often valuable in central autonomic disorders such as MSA. With higher doses, side effects include tremulousness, loss of appetite, and urinary retention in men.

Among the large number of vasoactive agents that have been evaluated in MSA, only one, the directly acting a-agonist midodrine, meets the criteria of evidence-based medicine (Jankovic et al., 1993; Low et al., 1997; Wright et al., 1998). Side effects are usually mild and only rarely lead to discontinuation of treatment because of urinary retention or pruritus predominantly on the scalp. Another promising drug appears to be the noradrenaline precursor L-threo-dihy-droxy-phenylserine (L-threo-DOPS), which has been used in this indication in Japan for years and whose efficacy has now been shown by a recent open, dose-finding trial (Mathias et al., 2001). If the preceding drugs do not produce the desired effect, then selective targeting is needed. The somatostatin analogue, octreotide, often is beneficial in postprandial hypotension (Alam et al., 1995), presumably because it inhibits release of vasodilatory gastrointestinal peptides (Raimbach et al., 1989); importantly, it does not enhance nocturnal hypertension (Alam et al., 1995). The vaso-pressin analogue desmopressin, which acts on renal tubular vasopressin-2 receptors, reduces nocturnal polyuria and improves morning postural hypotension (Mathias et al., 1986). The peptide erythropoietin may be beneficial in some patients by raising red cell mass, secondarily improving cerebral oxygenation (Perera et al., 1995; Winkler et al., 2001). A broad range of drugs have been used in the treatment of postural hypotension (Mathias and Kimber, 1999). Unfortunately, the value and side effects of many of these drugs have not been adequately determined in MSA patients using appropriate endpoints.

In neurogenic bladder dysfunction including residual urine clean intermittent catheterization three to four times per day is a widely accepted approach to prevent secondary consequences from failure to micturate. It can become necessary to provide the patient with a permanent transcuta-neous suprapubic catheter if mechanical obstruction in the urethra or motor symptoms of MSA prevent uncomplicated catheterization. Pharmacological options with anti- or pro-cholinergic or -adrenergic substances are usually not successful to adequately reduce post-void residual volume in MSA, but anticholinergic agents like oxybutynin can improve symptoms of detrusor hyperreflexia or sphincter-detrusor dyssynergy in the early course of the disease (Beck et al., 1994). Recently, a-adrenergic receptor antagonists (prazosin and moxisylyte) have been shown to improve voiding with reduction of residual volumes in MSA patients (Sakakibara et al., 2000b). Urological surgery must be avoided in these patients because worsening of bladder control post-operatively is most likely (Beck et al., 1994).

The necessity of a specific treatment of sexual dysfunction must be evaluated individually in each MSA patient. Male impotence can be partially circumvented by the use of intracavernosal papaverine, prostaglandin E1, or penile implants (Colosimo and Pezzella, 2002). Preliminary evidence in PD patients (Zesiewicz et al., 2000) had suggested that sildenafil may also be successful in treating erectile failure in MSA: A recent trial confirmed the efficacy of this compound in MSA, but also suggested caution because of the frequent cardiovascular side-effects (Hussain et al., 2001).

Constipation is relieved by an increase in intraluminal fluid which may be achieved by a macrogol-water solution (Eichhorn and Oertel, 2001). Inspiratory stridor develops in about 30% of patients, occasionally from the disease onset. Continuous positive airway pressure (CPAP) may be helpful in some of these patients (Iranzo et al., 2000). In only about 4% is a tracheostomy needed and performed.

B. Motor Disorder

1. General Approach

Because the results of drug treatment for the motor disorder of MSA are generally poor, other therapies are all the more important. Physiotherapy helps maintain mobility and prevent contractures, and speech therapy can improve speech and swallowing and provide communication aids. Dysphagia may require feeding via a nasogastric tube or even percutaneous endoscopic gastrostomy (PEG). These management decisions should be based on careful clinical judgment, taking into account the expectations of both patient and caregivers. Occupational therapy helps to limit the handicap resulting from the patient's disabilities and should include a home visit. Provision of a wheelchair is usually dictated by the liability to fall because of postural instability and gait ataxia but not by akinesia and rigidity per se. Psychological support for patients and partners should be stressed.

2. Parkinsonism

Parkinsonism is the predominating motor disorder of MSA and therefore represents a major target for therapeutic intervention. Although less effective than in PD and despite the lack of controlled trials, levodopa replacement represents the mainstay of anti-parkinsonian therapy in MSA. Open-label studies suggest that up to 30 to 40% of MSA patients may derive benefit from levodopa at least transiently (Parati et al., 1993; Wenning et al., 1994a). Occasionally, a beneficial effect is evident only when seemingly unresponsive patients deteriorate after levodopa withdrawal (Hughes et al., 1992). Pre-existing orthostatic hypotension is often unmasked or exacerbated in levodopa-treated MSA

TABLE 7 Therapeutic Studies in MSA since 1993

Number

Agent/Reference Target of patients Design Dose Outcome measures Results Side effects

TABLE 7 Therapeutic Studies in MSA since 1993

Agent/Reference Target of patients Design Dose Outcome measures Results Side effects

Amantadine

(Botez et al., 1996)

Ataxia

30 (OPCA)

randomized, controlled, double-blind

200 mg/day

reaction and movement times

improvement on seven out of eight variables

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