Therapy of autonomic failure
Unfortunately there is no causal therapy of autonomic dysfunction available. 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 to treat symptoms of orthostatic hypotension is based on the increase of intravasal volume and the reduction of volume shift to lower body parts when changing into upright position. The selection and combination of the following options depends on practicability in the single patient as well as symptom severity as revealed by the fall of blood pressure during tilt test. Non-pharmacological options include sufficient fluid intake of minimum 2L per day, high salt diet with up to 1200 mg t.i.d., more frequent but smaller meals per day to spread the total carbohydrate intake to reduce postprandial hypotension and custom made elastic body garments which should provide an ankle counterpressure of 30 mmHg. During night head-up tilt of bed of 30-40° not only reduces hypertensive cerebal perfusion pressure but also increases intravasal volume up to 1 L within a week, which is particular helpful to improve hypotension early in the morning. This is achieved by an increased secretion of renin due to reduced renal perfusion pressure and reduced atrial natriuretic hormone because of lower atrial filling pressure. This approach is successful in particular in combination with fludrocortison 0,1 to 0,2 mg/day, which further supports natrium retention. From the great number of reports on a huge variety of vasoactive or volume expanding substances, in clinical practice and with respect of criteria of evidence based medicine the directly acting a-agonist midodrine is the first line of pharmacological treatment of orthostatic hypotension in MSA, which was shown to be effective in several placebo-controlled trials including severe cases of neurogenic orthostatic hypotension. Characteristic contraindications of sympathomimetics must be observed. Side effects are usually mild and only rarely lead to discontinuation of treatment because of urinary retention or pruritus predominantly on the scalp. The initial dose is 2,5 mg t.i.d. with stepwise increase according to clinical needs up to 40 mg per day in severe cases. Another promising drug appears to be the norepinephrine precursor L-threo-dihydroxy-phenylserine (L-threo-DOPS), which is used in this indication in Japan for years and which efficacy is now shown also in double-blind placebo controlled trials.
In neurogenic bladder dysfunction clean intermittend catheterization 3 to 4 times per day is the accepted approach to prevent secondary consequences from failure to empty urine sufficiently. It can become necessary to provide the patient with a permanent transcutaneous suprapubic catheder if mechanical obstruction in the urethra or motor symptoms of MSA prevent uncomplicated catheterization. Pharmacologic options with anti- or procholinergic or ?adrenergic substances are usually not successfull to adequatly 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. Urological surgery must be avoided in these patients because worsening of bladder control post-operatively is most likely. Sexual dysfunction is common in MSA patients, frequently causes psychological distress and should be openly addressed by the caring physician or neurologist. Therapeutic strategies for erectile disturbance may include oral pharmacotherapy (sildenafil) or intracavernosal injections of vasoactive agents.
Therapy of motor disturbance
There are no established pharmacological treatment strategies for cerebellar ataxia and pyramidal dysfunction, however, latter is rarely associated with clinically significant disability. Although the parkinsonian syndrome of most MSA patients fails to respond to L-dopa, 30% of patients nevertheless experience definite, albeit transient, L-dopa ?derived benefit. Indeed, only 5% of patients still respond to L-dopa after 5-6 years of therapy. Dyskinesias emerge in half of the treated patients in whom they are often dystonic, predominantly affecting orofacial muscles. The response to dopamine agonists such as lisuride, bromocriptine, or pergolide is even more disappointing. In a recent controlled trial of amantadine in a small number of patients with atypical parkinsonian syndromes including MSA-P there was no significant anti-parkinsonian effectalthough uncontrolled reports claim a useful effect in 20-25% of patients. Stereotaxic procedures such as pallidotomy and subthalamic stimulation usually fail to improve the parkinsonian motor disturbance of MSA-P patients. Novel therapeutic strategies such as trophic factor delivery and neurotransplantation are currently being explored experimentally. Amphetamine- and apomorphine-induced rotation asymmetries in a double-lesion rat model of MSA-P appear to be partly reversable by mesencephalic-striatal co-grafts. Further experimental studies are required to optimize the neurotransplantation procedure in the double-lesion rat model. Recently, a multicentre double-blind trial of rilzuole, a blocker of glutamate release, has been launched in MSA and PSP patients across Europe. In the absence of evidence for disturbed glutamatergic neurotransmission in MSA it remains to be seen whether disease modifying effects can be induced by riluzole in this disorder.
The available therapeutic strategies in MSA are summarized in the table below.
Symptomatic Therapy
1. Parkinsonism
1. Choice: Dopamimetics (L-Dopa, Dopamine-Agonists)
2. Choice: Anticholinergics/Amantadine
2. Orthostatic Hypotension
Increased salt intake
Head up tilt (30°)
Elastic stockings
Fludrocortisone
Ephedrine
Octreotide
3. Detrusor Hyperreflexia (Urgency/incontinence)
Oxybutinin
Intermittent Self Catheterization (ISC)
4. Myoclonus
Clonazepam
5. Dystonia (incl. Antecollis)
Botulinum Toxin
6. Depression
Amitriptyline
Serotonin-Reuptake Inhibitors
7. Dysphagia, Dysarthria
Speech therapy
8. Sialorrhoea
Anticholinergics
9. Gait disorders
Physical therapy
Use of walking aids
Wheelchair