Management

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General Considerations

At present there are no effective therapies that could slow or completely resolve patients' symptoms, however, state-of-the-art management should include the palliative treatment of patients's symptoms at the different stages of the disease, as well as providing education and support to the patient and their caregivers. In our clinical experience, both contribute to the improvement of the quality of life of patients and caregivers and help delay institutionalization. Informed patients are usually eager to participate in research and should be provided with the latest information.

Neurotransmitter Replacement

Neurotransmitter replacement therapeutic approaches have thus far failed in PSP because of the widespread involvement of dopaminergic and non-dopaminergic neurotransmitter systems

(GABAergic striatal interneurons, cholinoceptive striatal interneurons, cholinergic brainstem, and opioid striatal neurons) (142). Case studies and our clinical experience show no significant improvement with levodopa. Similar findings are observed in double-blind placebo-controlled studies with dopamine agonists (e.g., bromocriptine, pergolide including newer dopaminergic agonists such as ropinirole or pramipexole) (143,144). Although dopaminergic replacement therapies are usually only transiently and/or mildly effective, they should be tried when patients have parkinsonism since lack of sustained and/or marked benefit from levodopa therapy effectively rules out PD, and may also support the diagnosis of PSP (or other atypical parkinsonism). Future studies should evaluate the effects of selective D1 agonists since D1 receptors are relatively preserved in PSP.

Several randomized, double-blind controlled trials using cholinergic agents (physostigmine; RS-86; donepezil) showed similar mild or no efficacy (145-148). However, as PSP patients' mental status and gait may worsen on anticholinergic drugs, these drugs should generally be avoided unless needed to treat particular symptoms (142). Despite reported noradrenergic deficits in PSP (149), these agents failed to benefit patients. Although PSP patients were reported to have some minor improvement in motor performance after the administration of idazoxan (150), they failed to respond to efaroxan, a more potent noradrenergic agent (151).

Palliative Measures

The combination of frontal lobe-type disturbances (impulsivity, unawareness, disinhibition) and postural instability may result in significant difficulty in the management of patients with PSP who, misjudging their disability, are exposed to a higher than necessary risk of falling. Palliative therapeutic approaches used in practice are listed in Table 3 and rehabilitation approaches are detailed in Chapter 29. Future studies should systematically evaluate whether symptomatic palliative therapies (e.g., speech therapy, physical therapy) improve the quality of life or survival of PSP patients (e.g., by preventing aspiration).

A small number of PSP patients have been subjected to pallidotomy, without significant benefit. At present, there is no evidence that pallidotomy or any other surgical procedure helps PSP patients.

Future Therapies

The development of biologic therapies for PSP requires additional pathogenetic studies. Recently developed four-repeat tau-transgenic animal models resembling PSP will likely accelerate efforts to discover more effective therapies (see Chapter 5). Given the recent progress that has been made in understanding the significance of tau in the development of neurodegeneration, it would seem likely that the most promising approaches are those that aim at preventing the abnormal aggregation of microtubule-associated protein tau. Future drug design should explore the use of agents that prevent tau aggregation such as oligonucleotides or peptide nucleic acids that inhibit the splicing of tau E10 or the translation of E10+ mRNA, and thus the generation of four-repeat tau isoforms, (152). Alternatively, microtubule stabilizers such as Taxol derivatives may turn out to be promising therapeutic approaches.

Additional potential biologic therapeutic targets include free radical scavengers, enhancers of cell metabolism, and anti-inflammatory agents (nonsteroidals) that cross the blood brain barrier. Agents that could block microglial activation such as minocyclin may prove to be of therapeutic value.

Similarly, because in PSP the principal neuronal types affected are dopaminergic, cholinergic, and GABAergic, neurotrophic factors that promote the growth, survival, and differentiation of these cells or small molecules having nerve growthlike activity may end up being beneficial. However, potentially useful proteins, such as growth factors, cannot be administered systemically or in the ventricles since they have peripheral and central side effects and do not cross the blood brain barrier. Moreover, high levels of growth factors in the cerebrospinal fluid (CSF) can lead to side effects associated with circulating growth factors. On the other hand direct intraparenchymal administration of proteins into

Table 3

Management Approach: Palliative Treatments

Feature

Gait Instability/Falls Speech disturbances Dysphagia

Blepharospasm, levator inhibition and other dystonias Tearing, light sensitivity Depression

Emotional incontinence Drooling

Patient and family support

Palliative Approach

Physical therapy, weighted walkers Speech therapy, communication devices Thickeners, percutaneus endoscopic grastostomy (PEG) Botulinum toxin (except antecollis)

Natural tears, dark glasses Antidepressants; support therapy Antidepressants

Anticholinergics (use cautiously!) Social services; support therapy; lay associations: (caregiver burden) Society for PSP, Inc. Suite 515, Woodholme Medical Building, 1838 Greene Tree Road, Baltimore, MD 21208, http://www.psp.org/); and the PSP (Europe) Association (The Old Rectory, Wappenhan, Towcester NN12 8SQ, UK,

http://www.ion.ucl.ac.uk/~hmorris/ contact.htm)

the lenticular nuclei by acute and/or chronic infusions may provide a means of delivery. Preliminary results of a double-blind, placebo-controlled pilot study in a single patient using a chronic intraparenchymal administration of GDNF/placebo (one side each) by convection-enhanced delivery recently conducted at the NINDS did not seem as promising as expected (personal communication). Alternative approaches to chronically deliver therapeutic growth factors that might slow down or halt the degeneration process in PSP include the administration of therapeutic genes to the disease-affected regions of the brain. Newly developed transgenic tau animal models will allow us to explore these alternatives as well as whether the administration of viral vectors by convection-enhanced delivery may improve the spread of vector particles in the brain resulting in more uniform transgene expression.

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