Very small trial of Exelon in PSP (for dementia)

This is a small German study of 5 PSP patients with dementia. These patients were given rivastigmine (Exelon is the brand name in the US) for 3-6 months. The researchers “found a slight improvement in specific cognitive function that may justify further controlled studies.”

Exelon is an acetylcholinesterase inhibitor (AChEI). The two other AChEIs are Aricept and Razadyne. Both Aricept and Razadyne are available in generic form. Unlike Aricept and Razadyne, Exelon inhibits two forms of choline — acetylcholine and butyrylcholine. Exelon is the only AChEI that is FDA approved for use in Parkinson’s Disease Dementia. All three AChEIs are approved for use in Alzheimer’s Disease.

When our local support group began, I occasionally heard about PSPers trying Aricept. It didn’t seemed to do any good. In the last year or so, I’ve heard about a couple of PSPers trying Exelon.

Robin

Alzheimer’s & Dementia. 2010 Jan;6(1):70-74.

Rivastigmine for the treatment of dementia in patients with progressive supranuclear palsy: Clinical observations as a basis for power calculations and safety analysis.

Liepelt I, Gaenslen A, Godau J, Di Santo A, Schweitzer KJ, Gasser T, Berg D.
Center of Neurology, Department of Neurodegeneration, and Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany.

Cognitive decline and dementia are present in about 50% of patients with progressive supranuclear palsy (PSP). Based on the known involvement of the cholinergic system in PSP patients, and because rivastigmine, in contrast to other cholinesterase inhibitors, inhibits both acetylcholinesterase and butyrylcholinesterase, we discuss clinical observations of five patients suffering from PSP and dementia who were all treated with rivastigmine over a period of 3 to 6 months.

We found a slight improvement in specific cognitive function that may justify further controlled studies. A calculation of sample size revealed that a study on the effect of rivastigmine in PSP should include about 31 patients to detect a significant effect. In subtests, meaningful results can be obtained with even lower numbers (five patients for a verbal fluency test, and 14 patients for a logical memory task).

PubMed ID#: 20129321 (see pubmed.gov for this abstract only)

Improving diagnostic accuracy of PSP-P

PSP folks –

This article was written by two heroes of the PSP community — David Williams, who is now in Australia, and Andrew Lees, in the UK.

“The aim of this study was to identify particular clinical features (green flags) that may be helpful in differentiating PSP-P from…other disorders.”  PSP-P, the parkinsonism form of PSP (progressive supranuclear palsy), is easily confused with Parkinson’s Disease (PD), multiple system atrophy (MSA), and vascular parkinsonism.  The issue is that the PSP diagnostic criteria include symptoms that are specific to the dementia form of PSP.  But what if someone with PSP-P comes along?

In this study, researchers compared many Queen Square Brain Bank cases:  37 patients with PSP-P, 444 with PD, 46 with dementia with Lewy bodies (DLB), 90 with MSA, and 19 with vascular parkinsonism.

By the way, a total of 127 PSP brains from QSBB were examined.  Of those, 86 had Richardson’s Disease, or the dementia form of PSP, while 37 had PSP-P.  (Four cases must’ve had rare forms of PSP.)  The researchers describe this division as follows:

“PSP cases were further divided according to their clinical features present in the first 2 years of disease. When the clinical notes recorded falls, supranuclear gaze palsy, abnormal vertical saccadic eye movements or cognitive decline within the first 2 years patients they were classified as RD (n = 86). Patients were classified PSP-P when their history included asymmetric bradykinesia, rigidity, a positive L-dopa response or tremor, and the cardinal features of RD were not present (n = 37).”

That breakdown — 29% with PSP-P and 68% with RD — is roughly what we see in our local support group:  most have the dementia form of PSP but about a third have the parkinsonism form.

The authors state:  “The clinical differences between RD and PSP-P are most likely to be due to differences in pathological severity.”  (By the way, an effort is apparently on to rename the dementia form of PSP to “Richardson’s Disease,” or RD, rather than Richardson’s Syndrome.)

Past studies have shown that the diagnostic accuracy for RD is much higher than that for PSP-P: 86% vs. 41%.

After comparing the clinical records, researchers found no clinical features “predictive” of PSP-P.  (No wonder this form of PSP is so hard to diagnose!)

In distinguishing PD, DLB, and PSP-P, three clinical features were found to be most important:  “late drug induced dyskinesias, late autonomic dysfunction, and any visual hallucinations.”  These three symptoms are very uncommon in PSP and “may be helpful exclusion criteria.”  Note that none of these three features is an early symptom.

Researchers also found many features to distinguish MSA and PSP-P:

“Late non-specific eye symptoms and supranuclear gaze palsy were good discriminators of PSP-P. Three other clinical features, when calculated with respect to a diagnosis of MSA, appeared to be reasonable discriminators of MSA, including early autonomic dysfunction, late autonomic dysfunction, and late cerebellar signs, which occurred in more than 50% of MSA patients and less than 10% of PSP-P patients.”

These statements in the Discussion section about differentiating PSP from PD were interesting:

“The nature of bradykinesia has rarely been examined in detail in different diseases, but our impression is that rapid hypokinesia – reduced amplitude of movement, that is, fast and without decay, is more typical in patients with PSP than true bradykinesia typical of PD. Equally, fast micrographia and rapid hypophonia may also be clues to PSP pathology.”

This may be enough for most of you.  The abstract follows.

Robin

———————————–

Movement Disorders. 2010 Jan 27. [Epub ahead of print]

What features improve the accuracy of the clinical diagnosis of progressive supranuclear palsy-parkinsonism (PSP-P)?

Williams DR, Lees AJ.
Van Cleef Roet Centre for Nervous Diseases, Monash University, Melbourne, Victoria, Australia.

Progressive supranuclear palsy-parkinsonism (PSP-P) is a primary tauopathy characterised by neurofibrillary degeneration, which is frequently mistaken for Parkinson’s disease (PD), multiple system atrophy (MSA), and vascular parkinsonism (VP) at presentation. The aim of this study was to identify particular clinical features (green flags) that may be helpful in differentiating PSP-P from these other disorders.

We identified 37 patients with PSP-P from 726 patients archived at the Queen Square Brain Bank. Using a retrospective case notes review the clinical features were compared between the PSP-P group and Lewy body associated parkinsonism (PD, n = 444 and dementia with Lewy bodies (DLB), n = 46), MSA (n = 90), and VP (n = 19), using the chi(2)-test for proportions for a two-by-two contingency table.

The sensitivity, specificity, and positive predictive values (PPV) and negative predictive values (NPV) were calculated for individual clinical features. A specificity of >0.85 or a PPV of >0.85 were considered reliable discriminators.

No clinical features were predictive of PSP-P, but late drug induced dyskinesias (specificity 0.92, PPV 0.99), late autonomic dysfunction (specificity 0.94, PPV 0.99) and any visual hallucinations (specificity 0.94, PPV 0.99) were better in distinguishing PD and PSP-P than predicted using operational diagnostic criteria for PD. PSP-P shares many clinical features with PD and DLB, MSA and VP, but visual hallucinations, drug induced dyskinesias and autonomic dysfunction are very uncommon and may be helpful exclusion criteria.

PubMed ID#: 20108379   (see pubmed.gov for this abstact only – available at no charge)

Case Rpt- “Dramatic improvement” with Ambien CR

I don’t get too excited about a report on a single case but you be the judge!
Robin

Journal of Clinical Neuroscience. 2010 Jan 11. [Epub ahead of print]

The use of zolpidem in the treatment of progressive supranuclear palsy.

Cotter C, Armytage T, Crimmins D.
Department of Neurology, Northern Sydney Central Coast Health, Gosford Hospital, Gosford, New South Wales, Australia.

Progressive supranuclear palsy (PSP) is a debilitating progressive neurodegenerative disorder for which there is no proven pharmacological treatment.

Zolpidem immediate release formulation has been reported to show short-term improvements in motor function and voluntary saccadic eye movements, but the benefits were not sustained.

A 61-year-old man with a 4-year history of PSP was observed over 6 months to have sustained improvement in motor function, pseudobulbar symptoms and ocular motility 2 months after commencing zolpidem controlled release (CR) formulation. He was admitted to hospital and a detailed neurological and functional assessment recorded on video after withdrawal of zolpidem CR, and again following re-introduction of the medication. Within 1 hour of administration of 25mg zolpidem CR the patient had a dramatic improvement in fine motor skills, dexterity, speed and fluidity of movement, facial and vocal expression, oropharyngeal coordination and function and pursuit, and voluntary saccadic eye movements. These improvements were observed for 4 hours to 5 hours post-dose and were reproducible on subsequent withdrawal and re-challenging. We found that zolpidem CR, a gamma aminobutryic acid (GABA)ergic agonist of the benzodiazepine type 1 receptor, caused sustained improvement in motor and ocular symptoms in a patient with PSP over 6 months.

Further studies are needed to determine the potential roles of GABA neurotransmission in PSP.

PubMed ID#: 20071178

[zolpidem = Ambien; zolpidem CR = Ambien CR]

The Eye in PSP/Atypical Parkinson’s – lecture notes

At last week’s atypical parkinsonsim support group meeting at UC Irvine, a neuro-ophthalmologist spoke about eye problems in parkinsonism. The talk wasn’t specific to PSP, CBD, or MSA. Vera James is the facilitator of this PSP/CBD/MSA support group. Here are Vera’s notes, which she posted to one of the MSA-related online support groups last week.

Orange County Atypical PD+ Support Group (PSP, CBD, MSA)
UC Irvine
Meeting date: Wed, Jan 6, 2010
Notes by: Vera James, support group leader [with a few grammatical fixes by Robin]

Guest speaker: Swaraj Bose, MD, a neuro-ophthalmologist at the Gavin Herbert Eye Institute, UCI

His main reason for speaking with us was to give us a fair idea of the eye problems and why do the eyes behave in the way they do in Parkinson’s/PSP/Atypical Parkinson’s and what the caregiver can do.

The eye movement comes from the brain (head computer). We have two eyeballs that are in an orbit/socket. Each eye has 6 muscle that moves the eye left to right or up and down for the visual field. The vision comes from the back of the brain at the cortex, the middle brain, neurons of the pons. These nerve cells and area are what causes the problems.

Dr. Bose gave us a handout called “The Eye in PSP/Atypical Parkinson’s.” The information will all be in this message along with some notes I made when he made remark about some of the common things in Parkinson’s/ PSP/Atypical Parkinson’s. Some information is vision problems in PSP like the down-gaze that is common with PSP patients but some suggestion you may find will help the MSA patients also. I am also putting those in because we know that some patients may be misdiagnosef and may have these same eye issues.

Common eye complaints:

#1 – Related to disturbance of down-gaze PSP.

– Difficulty in coordinating eye movements while reading even if their vision is normal, especially through their bifocal glasses.

– Difficulty in eating because they cannot look down at their food on the plate.

– Difficulty in going downstairs and stepping off curbs.

#2 – Related to lack of convergence/fast and slow tracking- Parkinson/PSP/Atypical PD.
(Note: Convergence means to bring the eyes together)

– Difficulty in focusing, words run into each other.

– Hard to shift down to the beginning of the next line automatically after reaching the end of the first line.

– Inability to quickly move eyes up or down.

– Inability to track moving objects or maintain eye contact.

Dr. Bose said that most patients with any of these illnesses will have problems maintaining eye contact, and in tracking objects. He said this is where the problem comes in with driving and the reason that a patient shouldn’t be driving. He gave an example saying that if you are driving and a child run out in front of you 150 ft away, you will catch them going the one way, but with the slow tracking the eyes are doing, the child could be back in front of you before your tracking would get the eyes to the other side to view where the child would be. By then you could have hit the child.

– Double vision.

One eye sees one thing, the other eye sees another and the brain brings them together. Kind of the way 3D glasses do. When you have double vision, the brain isn’t bringing the eyes together to get the one vision.

#3 – Related to vision disturbances-Parkinson/PSP/Atypical PD.

– Difficulty in focusing/blurry vision/visual hallucinations.

Visual hallucinations can be in all of these illness. Some visual hallucinations can be from to much medication, but it can also be from a lack of dopamine in the cortex where the signal is fallen and gives false images and causes these visual hallucinations also. So not all visual hallucinations are psychotic. Other things that can also cause visual hallucinations are benadryl and OTC cold meds. They can also cause spasm.

– Changes of reading glasses at a quicker intervals.

– Decreased in contrast sensitivity (difficulty in distinguishing shades of gray) and color perception.

#4 – Eyelid abnormality

– Difficulty in voluntarily opening their eyes (apraxia)

– Forceful eyelid closing (blepharospasm). This is treated with botox.

– Decrease in the rate of blinking (3-4/min vs. 20/min)

#5 – Dry eyes

– Burning sensation, redness, watering, itching, excessive tearing, rubbing of eyes, blurry vision.

– Double vision with one eye. Usually results in ‘ghosting’ of images or shadowing of images.

Treatment — A multi-disciplinary approach:

Diagnosis of the movement disorder is important. This will determine the course, manifestations and outcome.

Communication with neurologist, neuro-ophthalmologist, rehabilitation personnel, nurses, therapists, care giver, neuro-psychiatrists amd primary care physicians is VITAL.

Record a thorough history.

Set realistic goals.

A thorough eye examination should include:
– Best correction for distance/near vision
– Color vision
– Visual field examination
– Detailed record of eye movements in all directions
– Prism measurement and correction. Prism lenses or prism overlays take some getting used to.
– Evaluation of eye surface including dry eyes
– Eyelid evaluation
– Convergence estimation.
– Retina and optic nerve evaluation
– Prescribe glasses for distance and near
– Optimize eye movement problems by exercises, prisms and rehabilitation
– Treat dry eyes and other associated eye conditions

Alter/Redesign equipment for reading (lighting, position), position of book and food (at eye level), devices/support for walking and stepping down stairs to prevent falls (safety).

Take medication regularly and watch for side effects.

Living and seeing well:

Safety begins at home:
– Rooms/hallways free of clutter
– Remove cords/rugs from floor
– All rooms well lit, night lights along hallways
– Install grab bars in shower, stairs to prevent falls
– Cane, walker, wheel chair

Proper reading lights (from left and behind)

Reading material (books/newspapers) at eye level. Use a piano reading stand.

Place food at patient’s eye level, raise table, small platform. Suggestion: bed or TV tray placed on the table to raise the plate higher for the PSP patient to view food. This would also be helpful for all patients who are still feeding themselves so they don’t have to work as hard to bring the food up to their mouths.

Get correct glasses prescription filled

Use separate glasses for reading and distance

Use lubricating eye drops like Systane or Refresh during the day and a gel (Genteal gel ointment) at bed time.

Regular eye exercises (when prescribed). Body and breathing exercises.

Take medications regularly

Visual hallucinations can be a side effect of medications or a lack of dopamine in the cortex.

Driving can be tricky. Speak with your eye doctor.

Keep yourself engaged with some creative activities/projects

Regular follow-up with neurologist and neuro-ophthalmologist

Join a support group

Summary:

* Visual disturbances and eye changes including problems with eye movements are commonly seen in patients with Parkinson’s/PSP/Atypical Parkinson’s

* Visual complaints are usually distortion or blurry vision, near vision problems, color vision abnormalities and even visual hallucinations

* Eye movement abnormalities include difficulty in convergence (bringing the eyes together while reading), lack of vertical movement of eyes (upward/downward gaze abnormality) and eye movement asymmetry

* Other problems include a decrease in blinking of eyelids, difficulty in opening the eyelids, dry eyes and lack of facial expression

* These eye conditions, if diagnosed early in the course of the disease, can be treated and managed by an ophthalmologist or a neuro-ophthalmologist

* Simple measures used in visual rehabilitation and medications given by the movement disorders neurologist and supportive care can significantly alter the quality of life of patients with these conditions.

Case report- PSP-P patient recvd DBS

This case report was published last year. It’s about an Italian patient diagnosed clinically with PSP-P (the parkinsonism form of PSP, not the dementia form of PSP) who received deep brain surgery, with an implant placed in an area of the brain called the nucleus tegmenti pedunculopontini (PPTg). This letter reports that the procedure was safe and the patient saw “modest benefits.”

“Gait was improved only in terms of a consistent amelioration of the primary gait ignition failure. On the other hand, the impact on postural stability and direction changes was absent. When evaluated with a specific questionnaire as the Giladi for FOG [freezing of gait] DBS-mediated effect were modest. DBS-related effect could be detected in non-motor domains (such as dysphagia and swallowing impairment). Neuropsychological tests did not reveal major cognitive changes apart from minimal improvement in verbal fluency.

The researchers considered this surgery based upon published data showing “some degree of gait impairment amelioration and cognitive benefits” to PD patients where an implant was placed in a similar part of the brain. In this PSP-P patient, the researchers saw no cognitive benefits and gait improvement only in terms of “consistent amelioration of the primary gait ignition failure.”

The researchers conclude: “Although this single case seems not to support the PPTg implantation as a critical therapeutic option for PSP-P patients, at least in advanced ones, it is possible that larger trials, centred either on PSP-P recruited at the disease onset or on PSP Richardson type, will verify further the potential of DBS-mediated stimulation to activate directly surviving fibres or even delay the disease evolution.”

I’ve copied the citation below.

Robin

Movement Disorders
Volume 24 Issue 13, Pages 2020 – 2022
Published Online: 11 Aug 2009

Letter to the Editor
Implantation of the Nucleus Tegmenti Pedunculopontini in a PSP-P Patient: Safe Procedure, Modest Benefits

Livia Brusa, MD, PhD 1, Cesare Iani, MD 1, Roberto Ceravolo, MD 2, Salvatore Galati, MD 3 4, Vincenzo Moschella, MD 2 4, Francesco Marzetti, MD 3 4, Paolo Stanzione, MD 3 4, Alessandro Stefani, MD 3 4

1 Ospedale S.Eugenio UOC Neurologia, Rome, Italy
2 Dipartimento di Neuroscienze, Clinica Neurologica, Università di Pisa, Pisa, Italy
3 Clinica Neurologica, Universita’ di Roma Tor Vergata, Rome, Italy
4 IRCCS Fondazione S. Lucia, Rome, Italy

Note: no abstract is available on PubMed. The PubMed ID# for this letter is #19672983.