“Clinical outcomes” paper – PSP and MSA

This is a very interesting article written by some of Europe’s top PSP researchers (and presumably top MSA researchers too).  The first author is O’Sullivan.  This is also a very important paper because it includes analysis of brains donated to the University College of London brain bank.

110 pathologically-confirmed PSP cases and 83 pathologically-confirmed MSA cases were examined for early clinical features and survival.  PSP cases were divided according to the D. Williams criteria of Richardson’s syndrome (RS) and PSP-parkinsonism.  MSA cases were divided according to the presence of early autonomic failure.

The PSP findings confirms what D. Williams has told us before:

“In PSP an RS phenotype, male gender, older age of onset and a short interval from disease onset to reaching the first clinical milestone were all independent predictors of shorter disease duration to death. Patients with RS also reached clinical milestones after a shorter interval from disease onset, compared to patients with PSP-P.”

The MSA findings are new to me (though maybe not to many of you):

“In MSA early autonomic failure, female gender, older age of onset, a short interval from disease onset to reaching the first clinical milestone and not being admitted to residential care were independent factors predicting shorter disease duration until death. The time to the first clinical milestone is a useful prognostic predictor for survival.”

Interesting (and scary?) that “not being admitted to residential care” predicts *shorter* disease duration in MSA.

I’ve copied below the abstract.

Update:  the full paper is now available at no charge.  See our post here with links.

Robin

—————-

Brain. 2008 Apr 2 [Epub ahead of print]

Clinical outcomes of progressive supranuclear palsy and multiple system atrophy.

O’Sullivan SS, Massey LA, Williams DR, Silveira-Moriyama L, Kempster PA, Holton JL, Revesz T, Lees AJ.

Reta Lila Weston Institute of Neurological Studies, Institute of Neurology, Queen Square Brain Bank for Neurological Disorders and Institute of Neurology, Sara Koe PSP Research Centre, Institute of Neurology, University College London, London, UK, Faculty of Medicine (Neuroscience), Monash University (Alfred Hospital Campus) and Department of Neurosciences, Monash Medical Centre, Melbourne, Australia.

Prognostic predictors have not been defined for progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). Subtypes of both disorders have been proposed on the basis of early clinical features. We performed a retrospective chart review to investigate the natural history of pathologically confirmed cases of PSP and MSA.

Survival data and several clinically relevant milestones, namely: frequent falling, cognitive disability, unintelligible speech, severe dysphagia, dependence on wheelchair for mobility, the use of urinary catheters and placement in residential care were determined.

On the basis of early symptoms, we subdivided cases with PSP into ‘Richardson’s syndrome’ (RS) and ‘PSP-parkinsonism’ (PSP-P).

Cases of MSA were subdivided according to the presence or absence of early autonomic failure.

Sixty-nine (62.7%) of the 110 PSP cases were classified as RS and 29 (26.4%) as PSP-P.

Of the 83 cases of MSA, 42 (53.2%) had autonomic failure within 2 years of disease onset.

Patients with PSP had an older age of onset (P < 0.001), but similar disease duration to those with MSA. Patients with PSP reached their first clinical milestone earlier than patients with MSA (P < 0.001). Regular falls (P < 0.001), unintelligible speech (P = 0.04) and cognitive impairment (P = 0.03) also occurred earlier in PSP than in MSA.

In PSP an RS phenotype, male gender, older age of onset and a short interval from disease onset to reaching the first clinical milestone were all independent predictors of shorter disease duration to death. Patients with RS also reached clinical milestones after a shorter interval from disease onset, compared to patients with PSP-P.

In MSA early autonomic failure, female gender, older age of onset, a short interval from disease onset to reaching the first clinical milestone and not being admitted to residential care were independent factors predicting shorter disease duration until death. The time to the first clinical milestone is a useful prognostic predictor for survival.

We confirm that RS had a less favourable course than PSP-P, and that early autonomic failure in MSA is associated with shorter survival.

PMID: 18385183

“Frontal-subcortical dementias” (PSP, CBD, LBD, and MSA)

This newly-published abstract reviews the clinical presentation of frontal-subcortical dementias, lists them, and suggests how they relate to cortical dementias. The classic “cortical dementia” is Alzheimer’s Disease. Three dementias in our atypical parkinsonism group are mentioned as frontal-subcortical dementias — Parkinson disease dementia (also called Lewy body dementia), progressive supranuclear palsy, and corticobasal degeneration.

Interestingly, multiple system atrophy is listed as a frontal-subcortical dementia though dementia is exclusionary for MSA.

Robin


The Neurologist. 2008 Mar;14(2):100-107.

Frontal-Subcortical Dementias.

Bonelli RM, Cummings JL.
>From the *Department of Psychiatry, Graz Medical University, Graz, Austria; and the †Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Frontal-subcortical dementias are a heterogeneous group of disorders that share primary pathology in subcortical structure and a characteristic pattern of neuropsychologic impairment. Their clinical presentation is characterized by memory disorders, an impaired ability to manipulate acquired knowledge, important changes of personality (apathy, inertia, or depression), and slowed thought processes (or bradyphrenia). It also has marked frontal dysfunction.

Classic frontal-subcortical dementias include Huntington chorea, Parkinson disease dementia, progressive supranuclear palsy, thalamic degeneration, subcortical vascular dementia, multiple sclerosis, the acquired immunodeficiency syndrome dementia complex, depressive pseudodementia, and some other rare dementias like spinocerebellar degenerative syndromes, Hallervorden-Spatz disease, choreoacanthocytosis, idiopathic basal ganglia calcification, Guamanian parkinsonism-dementia complex, corticobasal degeneration, multiple system atrophy, Wilson disease, metachromatic leukodystrophy, adrenoleukodystrophy, hypoparathyroidism, sarcoidosis, and other CNS inflammatory disorders.

Anatomic data suggest that the frontal signs result from a disconnection of the frontal cortex from the basal ganglia. However, most frontal-subcortical dementias show cortical atrophy in later stages, and cortical dementias have subcortical pathology at some point. In fact, the concept might be seen as a continuum, and only the 2 extremes would be represented by pure cortical or subcortical pathology. Anyway, subcortical disorders may still be more similar to one another than they are to AD. Possibly, frontal-subcortical and cortical dementias are the description of the prior main target of the disease process, ending up in both cases in a global dementia. Although the dichotomy cortical versus frontal-subcortical dementia is not strict, the 2 concepts still seem to have advantages.

PubMed ID#: 18332839 (see pubmed.gov for abstract only)

Photophobia, VH, and RBD in PSP+CBD (Mayo Rochester study)

This is a rather weak study because they looked at 10 patients with the clinical diagnosis of PSP and 11 patients with the clinical diagnosis of CBD. No pathological confirmation was available. Their findings included:

* “Photophobia occurred in all 10 (100%) PSP patients vs 2 (18%) patients with clinically suspected CBD (p=0.0002).” And: “The presence of photophobia is significantly more frequent in clinically diagnosed PSP than CBD and can be used as a feature in differentiating between the two diseases in clinical practice.”

Every PSPer I’ve met has photophobia and some (but not all) of the CBDers I’ve met have photophobia.

* “Visual hallucinations and RBD occurred in patients with PSP and CBD but were rare occurrences (5% for each symptom).” And: “Visual hallucinations and RBD occur infrequently in PSP and CBD and are not useful symptoms in clinical differentiation.”

I usually hear “photophobia” called “photo sensitivity.” Whenever I was in the hospital or skilled nursing facility with my dad, I’d always close the blinds/curtains and, if there was an overhead light on, we’d put sunglasses on dad or a washcloth over his eyes to block out the light. “Photophobia” is extreme sensitivity or aversion to sunlight and any other light.

Robin

Parkinsonism & Related Disorders. 2008 Mar 5 [Epub ahead of print]

Photophobia, visual hallucinations, and REM sleep behavior disorder in progressive supranuclear palsy and corticobasal degeneration: A prospective study.

Cooper AD, Josephs KA.
Department of Neurology, Mayo Clinic, Rochester, MN.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) have overlapping clinical features that can make clinical distinction between these two entities difficult. The present study compared the frequency of photophobia, visual hallucinations, and REM sleep behavior disorder (RBD) in patients clinically diagnosed with PSP to those clinically suspected to have CBD. Photophobia occurred in all 10 (100%) PSP patients vs 2 (18%) patients with clinically suspected CBD (p=0.0002). Visual hallucinations and RBD occurred in patients with PSP and CBD but were rare occurrences (5% for each symptom). The presence of photophobia is significantly more frequent in clinically diagnosed PSP than CBD and can be used as a feature in differentiating between the two diseases in clinical practice. Visual hallucinations and RBD occur infrequently in PSP and CBD and are not useful symptoms in clinical differentiation.

PubMed ID#: 18328771 (see pubmed.gov for abstract only)


I received a copy of this full article today. In my earlier post, after reading the abstract only, I concluded that no cases in this Mayo Rochester study had been pathologically-confirmed. This is incorrect. The full article notes that “Ten patients had PSP, two with pathologic confirmation, and 11 patients had CBS, one with pathologic confirmation.”

These patients (and their significant others) were questioned regarding photophobia. “The question regarding photophobia emphasized discomfort as a result of light exposure as opposed to frequent eye closing or lack of eye opening. This distinction is important since both blepharospasm and apraxia of eye opening can be present in these disorders.”

The findings were: “Photophobia occurred in all 10 (100%) PSP patients vs 2 (18%) CBS patients. The mean time between when the patient first reported photophobia and disease onset was 3.1 years.” Based upon this, the authors argue that “the presence of photophobia may help clinicians to better differentiate between PSP and CBS on a clinical basis…”

Interestingly, of the 2 CBS patients with photophobia, one of these was pathologically-confirmed as CBD. And, “both CBS patients with photophobia were two of only three CBS patients with vertical gaze palsy suggesting pathological involvement of brainstem nuclei in these two subjects.”

The authors admit that they need more pathologically-confirmed cases.

This finding was surprising: “Blepharospasm was noted in only one patient in this series. He was one of the two CBS patients with photophobia and was pathologically confirmed to have CBD.” It seems that in our local support group blepharospasm is more common.

One note to the CBD folks: This article says that the term CBS (corticobasal syndrome) is used for the clinical entity while CBD (corticobasal degeneration) is used for the pathologic entity.

See below for some excerpts to this short article.

Robin

Here are some excerpts that may be of interest:

Introduction
“Progressive supranuclear palsy (PSP) and corticobasal de-
generation (CBD) are neurodegenerative disorders that display
some overlapping clinical features. The core clinical features
of PSP include vertical gaze palsy, axial more than appendic-
ular rigidity, and early postural instability. The core clinical
features of CBD include asymmetric appendicular rigidity and
cortical dysfunction including apraxia of limb. The term corti-
cobasal syndrome (CBS) has been applied to the clinical
entity, while CBD refers to the pathologic entity.”

“When the cardinal features of these two diseases are present
at disease onset, diagnosis may be relatively straightforward.
However, clinical features of these two diseases often overlap
and some of the cardinal features may not occur until later in
the disease course. These atypical disease presentations can
present a diagnostic dilemma, which may make it difficult for
clinicians to predict disease progression. Therefore, additional
clinical features that could distinguish PSP from CBD would be
helpful in clinical practice. Photophobia has been described in
PSP but not CBD to our knowledge. Visual hallucinations and
REM sleep behavior disorder (RBD) have not been emphasized
in either PSP or CBD.We conducted a study to determine
the frequency of photophobia, visual hallucinations, and RBD
in these two disease populations.”

Methods
“One movement disorders specialist (KAJ) evaluated all
patients with features suggestive of PSP and CBD from 2003
to 2006 at a single medical institution.”

“We questioned patients and their significant others regarding
the presence of photophobia, visual hallucinations, and RBD.
The question regarding photophobia emphasized discomfort
as a result of light exposure as opposed to frequent eye
closing or lack of eye opening. This distinction is important
since both blepharospasm and apraxia of eye opening can be
present in these disorders. Only well-formed visual hallucina-
tions that were spontaneous and not associated with medica-
tion use were considered. REM sleep behavior disorder was
considered present if the patient’s bed partner reported
abnormal limb movements during sleep that were disruptive or
injurious to either the bed partner or the patient.”

Results
“Ten patients had PSP, two with pathologic confirmation, and
11 patients had CBS, one with pathologic confirmation. The
median ages at disease onset in PSP and CBS were 66
(range 59-77) and 65 (range 49-91)…”

“Based on clinical criteria for PSP, four patients were clas-
sified as possible, four as probable, and two were definite
(i.e. pathologically confirmed).”

“Photophobia occurred in all 10 (100%) PSP patients vs 2
(18%) CBS patients. The mean time between when the
patient first reported photophobia and disease onset was
3.1 years.”

“Blepharospasm was noted in only one patient in this series.
He was one of the two CBS patients with photophobia and
was pathologically confirmed to have CBD.”

“Visual hallucinations occurred in 1 (5%) PSP patient and
RBD occurred in 1 (5%) CBS patient. The visual hallucina-
tions occurred in a PSP patient taking Levodopa/Carbidopa.
… The hallucinations continued despite reduction of the
Levodopa/Carbidoba and, unfortunately, the patient died
before further dose reductions could be made.”

“The CBS patient with RBD had symptoms consisting of
talking and performing exercising movements usually during
the first 1-2 h of sleep.”

Discussion
“The present study demonstrates a significant difference in
the frequency of photophobia in patients with PSP com-
pared to those with CBS. This result suggests that the
presence of photophobia may help clinicians to better dif-
ferentiate between PSP and CBS on a clinical basis, and
may be a helpful feature in predicting underlying pathology.”

“The pathophysiology of photophobia is not entirely under-
stood. Studies have pointed to the trigeminal nerve as one
necessary component for photophobia. … Other studies
have suggested a role of the optic nerve and its connec-
tions with the pretectal nuclei. Indeed, it may be an inter-
action of these two pathways that produce photophobia.
The corresponding subcortical location of the trigeminal
and optic nerve connections and typical subcortical loca-
tion of PSP pathology, such as the superior colliculi, may
explain the high incidence of photophobia found in our PSP
population. The subcortical location of PSP pathology con-
trasts with the more cortical location of pathology found in
CBD and may explain the relatively low frequency of photo-
phobia found in patients with CBS in our study. In fact, both
CBS patients with photophobia were two of only three CBS
patients with vertical gaze palsy suggesting pathological
involvement of brainstem nuclei in these two subjects.”

“Visual hallucinations and RBD were rare occurrences in
each population making them unhelpful in clinical differen-
tiation between PSP and CBS. The low occurrence of RBD
is not surprising since this clinical phenomenon has been
shown to be suggestive of underlying alpha-synuclein path-
ology, and both PSP and CBD are characterized by the
deposition of the microtubule associated protein tau
(MAPT) and not alpha-synuclein pathology.”

“Litvan et al. showed that the presence of gait abnormality,
bilateral bradykinesia, and moderate to severe vertical
supranuclear gaze palsy help to distinguish PSP from
CBS. Their study was based on pathologically confirmed
cases of these two diseases. Since our study is based
on clinical and/or pathologic criteria, we cannot conclude
that the presence of photophobia will definitely predict
pathologic confirmation of PSP. However, 15% of our
cases were pathologically confirmed and prior studies
have shown that more than 75% of clinically diagnosed
PSP patients have PSP pathology.”

“The results of our study suggest that patients suspected
to have PSP or CBD should be questioned regarding the
presence or absence of photophobia as part of routine
questioning. … In this study, we demonstrate for the first
time that the presence of photophobia may be an addi-
tional useful clinical feature to differentiate PSP from
CBD.”

Dr. Paul Donohue on PSP

Quite a few US newspapers carry a health column written by FL-based Dr. Paul Donohue in which he answers letters. One of today’s letters is about PSP. I got this from SouthCoast Today, a MA newspaper (though many papers carry his column). I read about it on a PSP-related Yahoo!Group.
Robin

http://www.southcoasttoday.com/apps/pbc … /ENTERTAIN

Dr. Paul Donohue: Your health
March 09, 2008

DEAR DR. DONOHUE: Eight years ago my husband was said to have Alzheimer’s disease. A few years later, the diagnosis was changed to Parkinson’s disease. Now the diagnosis is progressive supranuclear palsy. What is that? His speech is hard to understand, and his walking is bad. How does it end up? — B.C.

DEAR BC: Quite a few illnesses can look like Parkinson’s disease or Alzheimer’s disease, especially in their early stages. These illnesses share with each other an attack on brain centers that produce similar signs. However, each also affects brain centers not stricken by the others, and that gives each of these illnesses distinctive features.

An unsteady walk with frequent falls is a sign common to both progressive supranuclear palsy and Parkinson’s disease, because the brain area that governs walking is affected in both illnesses.

Some distinctive signs of PSP are a soft, monotone, barely understandable speech; forgetfulness; irritability; and decreased blinking, which leads to dry eyes. Swallowing can become a formidable task. One of PSP’s most distinguishing features is the inability to turn the eyes downward and, later in the illness, to turn them upward. Loss of eye movement makes reading impossible and adds to the patients’ instability. Many patients eventually have to use a wheelchair.

The Society for Progressive Supranuclear Palsy is ready to help patients and their families with reams of information and with support. You can reach the society at (800) 457-4777 (in Canada, (866) 457-4777) or on the Web at www.psp.org

Write to Dr. Paul Donohue at P.O. Box 536475, Orlando, FL 32853-6475.

Overview of Atypical Parkinsonism

This is an overview of Atypical Parkinsonism written by our friend Dr. Golbe. Of course covering five disorders in a two-page document means that lots of information is left out, including subtleties and exceptions. But overall, I think this is a reasonably good overview of these disorders. (The first four disorders are in our local support group. Vascular Parkinsonism is not; I know nothing about it.) I read about this article on an MSA-related Yahoo!Group today. Unfortunately the newsletter isn’t available online yet so there’s nothing to link to; for future reference the APDA’s website is apdaparkinson.org.

“Atypical Parkinsonism”
by Lawrence I. Golbe, MD, Professor of Neurology, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ
The American Parkinson Disease Association Winter 2008 Newsletter

You may have been told by your doctor that you have not Parkinson’s disease but “atypical parkinsonism,” “Parkinson’s-plus” or “Parkinson’s syndrome.” Confused?

What is “Parkinson’s syndrome”?
A “syndrome” is a group of signs and symptoms that often occur together and may be caused by any of a variety of diseases. A “disease” is an abnormal process, usually with a specific cause. For example, the syndrome called the “flu,” which includes fever, muscle aches, cough and headache, can be the result of any of several diseases, only one of which is an infection by the influenza virus.

Similarly, a combination of slowness, muscle rigidity, tremor and impaired balance is a syndrome called “Parkinson’s syndrome” or just “parkinsonism.” The disease that most commonly causes it is “Parkinson’s disease” (PD). PD is strictly defined as parkinsonism associated with gradual loss of certain groups of brain cells that, as they sicken, form within them microscopic balls called Lewy bodies.

Parkinsonism may also be caused by a dozen diseases other than PD. Most of these cause other signs and symptoms in addition to the parkinsonism, which is why they are also called the “Parkinson-plus disorders or the “atypical parkinsonisms.”

Progressive Supranuclear Palsy
The most common atypical parkinsonism is “progressive supranuclear palsy” or PSP. There are only about 20,000 people with PSP in the US, while there may be one million with PD. What’s “atypical” about PSP is its failure to respond to levodopa/carbidopa or other PD medications, difficulties looking up and down, an erect or even backwardly arched neck posture, and the relatively early appearance of falls, slurred speech and swallowing difficulty. Most of these features can occur in PD, but not with the intensity or frequency with which they appear in PSP. Instead of Lewy bodies, the brain cells in PSP have “neurofibrillary tangles.” While Lewy bodies are mostly made up of a protein called alpha-synuclein, neurofibrillary tangles are made of a different protein called “tau.”

Multiple System Atrophy
The next most common atypical parkinsonism is “multiple system atrophy” or MSA. In addition to parkinonism, MSA usually features the type of poor coordination and balance that arises from disorders of the cerebellum, giving some sufferers a “drunken” appearance. Other “atypical” features in most people with MSA are low blood pressure, sensations of being too hot or cold, constipation, urinary difficulties and brief episodes of shortness of breath or sleep apnea. These arise from “dysautonomia” which is a loss of brain cells that control the autonomic nervous system. The dysautonomia of MSA was called “Shy-Drager syndrome” before it was recognized in the early 1990’s as part of a specific disease that can have several forms. Like PSP, MSA causes earlier balance problems than PD and medication for PD usually has little benefit. However, there is medication for most of the dysautonomic features. In MSA, the protein that aggregates is alpha-synuclein, as in PD, but it does so in a different set of brain cells and looks different from Lewy bodies. The protein aggregates in MSA are called “glial cytoplasmic inclusions.”

Corticobasal Degeneration
The third leading atypical parkinsonism is “corticobasal degeneration” (CBD). CBD affects one side of the body first and worst. This is also true, but to a far lesser extent, for PD. For PSP and MSA, the problem is usually symmetric, with left and right sides affected nearly equally. CBD, in addition to parkinsonism, features abnormally heightened reflexes as elicited by tapping with a hammer, and small, sudden, rapid involuntary movements called myoclonus. Its most distinctive feature is apraxia, which is a loss of the ability to perform complex movements with the hands or feet. There is also difficulty with the ability to perceive the spatial features of objects. At present, no medication is effective, unfortunately, and the disorder is treated with physical therapy. In CBD, the protein that aggregates is tau, as in PSP, but it does so mostly on one side of the brain, and disproportionately in the area of the brain responsible for planning complex movement tasks, the frontal lobes.

Dementia with Lewy Bodies
“Dementia with Lewy bodies” is a parkinsonian disorder that often starts with confusion, depression or psychosis (that is, hallucinations or delusions). However, the mental symptoms appear before or together with the movement symptoms and not afterwards, as in PD. The movement difficulty may even be very mild and, as for most of the atypical parkinsonisms, tremor at rest is far less common than in PD. In DLB, the behavioral symptoms can vary greatly over periods of minutes to days and can include periods of unresponsiveness, elaborate delusions and visual hallucinations in addition to the difficulty with memory and thinking. The hallucinations of DLB can occur without levodopa or other dopamine-enhancing medications, while in PD, any hallucinations are a side effect of those medications. The parkinsonism of DLB responds to levodopa/carbidopa. The movement and behavioral symptoms can be severely and dangerously exacerbated by drugs that block dopamine such as Haldol (haloperidol), Compazine (prochlorperazine), and Reglan (metoclopramide).

Vascular Parkinsonism
Another common condition causing atypical parkinsonism is “vascular parkinsonism” or “arteriosclerotic parkinsonism.” This is the eventual result of many tiny strokes, no one of which may be large enough to cause symptoms at the time it occurs. The strokes can be seen on an MRI scaan. Over the years, the cumulative effect causes movement difficulty, especially with walking and other movement of the legs. The condition does not respond to PD medication, but its progression can often be slowed or even stopped by controlling risk factors such as high blood pressure, smoking, or high lipids. Physical therapy is helpful in dealing with the gait problem.

How Do I Tell If I Have Atypical Parkinsonism?
Atypical parkinsonism rather than PD should be suspected when someone with the parkinsonian syndrome has little or no response to a moderate dosage of levodopa/carbidopa or when there is the early appearance of falls, behavioral changes, swallowing problems, abnormal eye movements, bladder problems or lightheadedness on standing. The physician should order an MRI scan, which can show the small strokes of vascular parkinsonism, the asymmetric shrinking of corticobasal degeneration, the unusual pattern of brain shrinkage of progressive supranuclear palsy, or the abnormal pattern of iron and scarring of PSP or multiple system atrophy. Some other radiologic tests such as PET and SPECT can also be helpful in special circumstances.

While the atypical parkinsonism are more difficult to treat than PD, the good news is that they do not run in families nearly as often as PD does. While 20-25% of people with PD have some close relative with PD, fewer than 1% of those with PDP, MSA or CBD have a relative with atypical parkinsonism. For DLB and vascular parkinsonism, the fraction is slightly higher. The causes of the atypical parkinsonism are started to be worked out. As we learn more about the abnormal processes in the brain cells in these conditions, treatments that may slow, stop or even reverse their course will become possible.

On the horizon? – lithium study in PSP

In January ’07, Glenn, a member of the CBD-related Yahoo!Group reported on a trip with his mother (diagnosed with CBD) to Mayo Rochester. Contained in one of the posts (2/3/07) is short mention of lithium:

“Lithium — They had high hopes for lithium because it so effectively
blocked GSK-3B in the lab, but it blocks a number of other things as
well. Mayo had ten patients on lithium and they all elected to cease
treatment because the side effects were so bad.”

Glenn’s father accompanied his mother to Mayo Rochester in Feb ’08. Yesterday Glenn posted a report on his visit. His father raised the topic of lithium with the Mayo Rochester MD:

“The main thing my father wanted to consult with them about was lithium. He has been reading the literature that points to lithium as a potent tau inhibitor. A very recent study released last month showed lithium halting and even reversing some of the tau damage in one of the first human trials. (I have not yet found this study online–I will forward it when I find it.) The Mayo docs said that the study was highly significant (“blockbuster” was the word they used). This backs up what the animal models have been showing in other studies. My father had been talking to a psychiatrist in Pittsburgh who frequently prescribes lithium for bipolar disorder and has gotten very good at monitoring patients who take the drug. In the case of bipolar disorder, the downsides of lithium must not be worse than the downsides of being bipolar. However, the Mayo docs confessed, that neurologists have never much cared for lithium. ‘Psychiatrists put people on lithium and neurologists take them off,’ he said, because of other neurological side-effects lithium can create. The have had a few CBD patients try lithium, but none of them stayed on it very long. However, the Mayo docs were very aware of the increasing evidence in favor of lithium. To be sure, not every study shows it having a dramatic effect, but there is enough evidence there to try it. Not many people have tried it for CBD or even Alzhiemers, and maybe the key to treatment is close monitoring of the drug dosage and effects.

So here is what my parents are planning to do: The doc at Mayo will be working with the ‘lithium-literate’ psych in Pittsburgh and my mother’s local neurologist as well. They will work out a plan for starting her on lithium and tracking her progress. This involves starting with very low doses, then working up until the side-effects are bad and then backing off. I assume they will be running other tests during the treatment as well. We’ll see how it goes!

In other news, I mentioned last year that Mayo was working on another potentially potent tau-blocking drug. They said that the main researcher for the drug is now working with Merck and has access to their resources to bring the drug to market. No idea what kind of timeframe, of course.

They recently began deep brain stimulation on another CBD patient and the jury is still out. It seems to be helping a little, but the location and amount of stimulation are crucial to effective treatment, so it could take some experimentation to get it right.”

I don’t know anything about the tau-blocking drug. This would be useful in AD, PSP, and CBD — all tauopathies. As some of you see MDs at Mayo Rochester, please ask about this during your next appt!

About the exciting lithium study recently published, I did a PubMed search yesterday and couldn’t find anything on lithium and PSP, CBD, or tau published in late ’07 or early ’08. I will try to follow up with a Mayo Rochester MD on this. As some of you see MDs at Mayo Rochester, please ask about this during your next appt!

I’ve been emailing the PSP expert, Dr. Lawrence Golbe, about lithium for many months. (He writes an “Ask the Doctor” column in the CurePSP Magazine.) I finally heard this from him today. Apparently on the horizon is an NIH-funded study of lithium in PSP patients. Here’s his very short email:

“There is no PI yet. There will be 10 sites in the US, Canada and UK and they have not yet been chosen. It will be 28 weeks of treatment with no placebo group.”
(PI = principal investigator)

I’ll update you when I get more info. Could you all please do the same!?

Robin

A call to rename PSP to “Richardson’s Disease”

One of my PSP researcher heroes is Dr. David Williams, formerly with the University College of London and now at an Australian university. He’s the lead author on this article. The second author is Dr. Andrew Lees who is the head of the PSP Europe Association, based in London. The final author is Dr. John Steele, one of the “discoverers” of PSP. At the Society’s PSP research symposium I attended in November ’07, Dr. Steele said that he wanted “PSP” renamed to “Richardson’s Disease,” after Dr. Clifford Richardson, one of the other “discoverers” of PSP. (Dr. Steele is the first speaker in “The Physicians Guide to PSP” at https://www.psp.org/materials/ne_dvd_final.html; he describes the neurological exams conducted by Dr. Richardson in the late 50s with various patients captured on video.)

In this article in the journal Neurology, the authors “propose that the classic clinical presentation of PSP-tau pathology be renamed Richardson’s disease, and that the commonest clinical variant be termed PSP-parkinsonism.”

I’ll copy the abstract below.

Robin


Neurology. 2008 Feb 12;70(7):566-73.

J. Clifford Richardson and 50 years of progressive supranuclear palsy.

Williams DR, Lees AJ, Wherrett JR, Steele JC.
Faculty of Medicine, Monash University, Alfred Hospital Campus, Melbourne, Australia

OBJECTIVE: To trace the historical events leading to Richardson’s clinical description of progressive supranuclear palsy (PSP) in the context of subsequent observations of its clinical heterogeneity and pathologic overlap with other tauopathies.

BACKGROUND: Fifty years ago, Canadian neurologist J. Clifford Richardson identified patients in Toronto with a syndrome of supranuclear vertical gaze palsy, pseudobulbar palsy, axial rigidity-in-extension, and cognitive impairment. In his seminal description, Richardson predicted that further clinicopathologic observations would broaden the clinical syndrome and that this was unlikely to be a disorder restricted to the Toronto region.

METHODS: The recollections of two of Richardson’s contemporaries and archival material from his time were used as primary materials. Publications that follow the evolution of his observations were examined.

RESULTS: Recent factor analysis of pathologically verified PSP cases has confirmed the accuracy and uniformity of the original classic clinical description of PSP and vindicated Richardson’s prediction of clinical variants. Most notably, a presentation with Parkinson syndrome and absent gaze palsy has been identified, with less severe PSP-tau pathology.

CONCLUSIONS: In recognition of his seminal observations, we propose that the classic clinical presentation of PSP-tau pathology be renamed Richardson’s disease, and that the commonest clinical variant be termed PSP-parkinsonism.

PubMed ID#: 18268249 (see pubmed.gov for abstract only)

Short article on Mississippi politician who had PSP

Tuesday, December 25, 2007

Ex-Mississippi Lt. Gov. Evelyn Gandy dies
Associated Press

JACKSON, Miss. — Evelyn Gandy, the first woman in Mississippi ever elected to the offices of state representative, state treasurer, insurance commissioner and lieutenant governor, died yesterday at her home near Hattiesburg. She was 87.

In a time when few Mississippi women earned law degrees or entered politics, Gandy did both successfully.

Former colleagues said she was determined to be fair to those she served, and she displayed a quiet demeanor that belied her political strength.

“She was absolutely a public servant in the classic sense of the words,” said Jackson attorney John Corlew, who served in the Senate from 1976-80 when Gandy, a Democrat, was lieutenant governor. “She had no interest in doing anything but the utmost for the public good.”

Gandy had suffered from Progressive Supranuclear Palsy, a disease similar to Parkinson’s disease, said Carroll Ingram, a law partner of Gandy’s.

Wayne Dowdy, chairman of the Mississippi Democratic Party, said Gandy “left behind a legacy of major achievements.”

In 1943, Gandy was the only woman in her graduating class at the University of Mississippi School of Law. She was elected to the Mississippi House in 1947.

In 1960, she became the first woman elected state treasurer; 12 years later she became the first female state insurance commissioner. In 1976, she became the state’s first female lieutenant governor.

She fell short in two bids for the governorship, in 1979 and 1983.

Gandy is survived by several cousins. Funeral arrangements were incomplete yesterday.

Rare variant of PSP – pallido-nigro-luysial degeneration

Here’s an abstract about a very rare variant of progressive supranuclear palsy (PSP) – pallido-nigro-luysial atrophy (PNLA).  The article is based on brain bank research from Mayo Jacksonville and Mayo Rochester.  Researchers found:

“The clinical course of PSP-PNLA, however, was different, with earlier gait abnormalities and difficulty with handwriting, but later falls, rigidity and dysphagia than PSP.”

According to the full article, dizziness can also be a symptom of PSP-PNLA.

The abstract is copied below.

Robin

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Brain. 2007 Dec 24 [Epub ahead of print]

Clinical and neuropathologic features of progressive supranuclear palsy with severe pallido-nigro-luysial degeneration and axonal dystrophy.

Ahmed Z, Josephs KA, Gonzalez J, Delledonne A, Dickson DW.
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL and Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Pallido-nigro-luysial atrophy (PNLA) is a rare disorder that in many cases has histopathological features similar to progressive supranuclear palsy (PSP). In a pathological series of over 400 cases of PSP, eight cases were noted to have features similar to those described in PNLA, including severe atrophy and neuronal loss in the globus pallidus, substantia nigra and subthalamic nucleus, in addition to many axonal spheroids in the globus pallidus and substantia nigra. These eight cases of PSP-PNLA were compared to 11 typical PSP cases with quantitative neuropathologic indices and assessment of demographics, clinical features and the timing of clinical features. PSP-PNLA cases were younger, had longer disease duration and more often were not initially diagnosed with PSP; in the end, they did not differ from PSP with respect to any major clinical feature. The clinical course of PSP-PNLA, however, was different, with earlier gait abnormalities and difficulty with handwriting, but later falls, rigidity and dysphagia than PSP. Pathologically, the same types of lesions were detected in both PSP and PSP-PNLA, but there were differences in the distribution and density of tau-pathology, with less tau-pathology in motor cortex, striatum, pontine nuclei and cerebellum in PSP-PNLA. These clinical and pathological findings suggest that PSP-PNLA should be considered a variant of PSP.

PubMed ID#: 18158316  (see pubmed.gov for the abstract only – available at no charge)

 

“Doctor is touched by…woman’s devotion” to her husband with locked-in syndrome

Many of us in the PSP and CBD communities feel as though our family members are “locked in.”  This is a sweet article in the LA Times by a physician who was touched by a woman’s devotion in caring for her husband with locked-in syndrome.

Robin

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articles.latimes.com/2007/dec/17/health/he-practice17

IN PRACTICE
In watching a wife tenderly care for her husband, who can blink but can’t move, a doctor is touched by the woman’s devotion.
By Steve Dudley, Special to The Times
December 17, 2007

In a corner of a room he shares with three other residents at the nursing home, a patient with a curious illness stares out the window at an empty bird-feeder.

He holds his arms in a curious, characteristic way — elbows and wrists hyperflexed so that his hands are tucked under his chin, like a child in prayer.

Mr. Fletcher has been bedridden for years. He can’t talk, can only moan. He can’t move other than to blink or shift his gaze. The only sign of responsiveness is that his eyes will sometimes follow stimuli, either of voice or hand movement.

Although he cannot move, his sensations are still intact. This means that Mr. Fletcher can still feel pain like you or I, or have that annoying itch that he cannot scratch. And people like Mr. Fletcher have their reasoning fully intact. They can think, dream, hope and reflect upon their endless prison.

Mr. Fletcher has what is commonly referred to as “locked-in syndrome” — the result, occasionally, of a rare form of stroke, happening viciously and suddenly, often striking down people in the prime of life after head trauma.

In Mr. Fletcher’s case, it happened more slowly. He has supranuclear palsy, a degenerative condition of the central nervous system that usually afflicts the very elderly, although Mr. Fletcher is only in his early 60s. It’s a cousin of Parkinson’s and Alzheimer’s diseases, an insidious condition with symptoms that might start as mild gait abnormalities or difficulty with eye movements and gradually develop over years.

Nobody knows what causes it, and treatments are essentially palliative: You really can’t do a thing for those who suffer from it other than to keep them comfortable.

Mr. Fletcher has been admitted for some rehabilitation as he transitions from the hospital, after a partial bowel obstruction, back to his home. A team of therapists, nurses and aides and, most importantly, his wife, is here to care for him. I suspect that his wife, the one with the least formal training, understands him best.

I’d like to tell you about her.

I am visiting another patient in Mr. Fletcher’s room when Mrs. Fletcher arrives and proceeds to wash him with a moistened towel.

Carefully and tenderly, she alternates between wiping and drying, turning him first one way, then another. Patiently, meticulously and ever so gently, she bathes him.

After she finishes with the bathing, she rubs her husband down with lotion, massaging it into his skin until it is supple. Then the shaving begins. She lathers his face and, with smooth, efficient strokes, manages to remove a three-day growth of stubble. You can see his eyes sparkle as she winds up her ministrations.

I try not to stare. It seems intrusive, to watch them together, intimate, in an interaction almost as private as making love.

She is caring for this man for all she is worth. Being with him, cleaning him, giving of herself to him and receiving at the most a blink or grunt in return.

Now that’s love. That’s commitment. In a time when people get divorced for the most superficial of reasons, it is a tremendous encouragement to see true love in action.

Mr. Fletcher is a handsome black man with beautiful ebony skin. His wife is Vietnamese. I imagine they met during the Vietnam War when he was a dashing GI and she was a scared young woman whose homeland was being split in two.

As I watch her bathe him, I reflect on what their early years together might have been like. Running on the beach, staying out till dawn, picnics, favorite restaurants and lots of dancing — they look like a couple who used to dance a lot.

I read of a young guy over in France, barely in his 40s, who became locked-in after a stroke. He had been a magazine editor. With the patience of Job, he dictated a book by blinking to a scrivener.

He referred to himself as feeling like a captive in a diving bell. One can only imagine the terror and loneliness of being in this state. You’re completely dependent upon others for all your needs, though you cannot voice any of them. Too warm? Too cold? Too bad.

And the people who are there to help often treat you as someone who cannot understand, as if you’re in a coma.

I’ve seen only one other patient who was locked-in, and that was back in medical school. We were on “physical diagnosis” rounds. That’s where a group of sleepy-eyed doctors in training dutifully follow their chief resident all over the hospital looking for interesting cases.

We popped into this guy’s room. I can’t remember his name. For that matter, I don’t know if we were ever told. He was just the interesting case on the eighth floor. As we lined the bed, we were grilled by a supervising resident about the case before us. This drill, known as “pimping,” is endorsed as a useful, hands-on, didactic exercise — and it may serve its purpose, but more commonly it devolves into brash showmanship at best and downright intellectual bullying at worst.

And we were pimped about the poor gentleman who was locked-in. He just lay there, hearing every word we spoke about him.

Not once did anyone address him directly or acknowledge that he was a person of any real worth. He was simply an exercise in learning, a specimen.

As I watch Mrs. Fletcher, I reflect on that experience. I am struck by the contrast between a devoted wife and a group of doctors-in-training making their cursory visit before moving on to the next interesting case.

She is so kind to him, devoted, caring. I suppose that is what the marriage vows mean when they speak of “in sickness and in health.” Here is tangible evidence of someone being faithful to that promise. I’m sure it is way more than she bargained for, but she dispatches her duties willingly, without resentment.

When you’re young, you take your health for granted. Slowly, it is taken away from even the strongest of us. That day, Mrs. Fletcher taught me volumes about the timelessness of love and the gift of health.

Steve Dudley is a family physician in Seattle.