Monthly Archives: October 2010

Excerpt from PSP/CBD Guide on Sinemet

Date
Posted by

Several medications, all available only by prescription, can help PSP in some cases.

• Sinemet
This is the brand name for a combination of levodopa and carbidopa. Levodopa is the component that helps the disease symptoms. Carbidopa simply helps prevent the nausea that levodopa alone can cause. When levodopa came along in the late 1960’s, it was a revolutionary advance for Parkinson’s but, unfortunately, it is of only modest benefit in PSP. It can help the slowness, stiffness and balance problems of PSP to a degree, but usually not the mental, speech, visual, or swallowing difficulties. It usually loses its benefit after two or three years, but a few patients with PSP never fully lose their responsiveness to Sinemet.

Some patients with PSP require large dosages, up to 1,500 milligrams (mg.) of levodopa as Sinemet per day to see an improvement, so the dosage should be pushed to at least that level, under the close supervision of a physician, unless a benefit or intolerable side effects occur sooner. The most common side effects of Sinemet in patients with PSP are confusion, hallucinations and dizziness. These generally disappear after the drug is stopped. The most common side effect in patients with Parkinson’s disease, involuntary writhing movements “chorea” or dyskinesias) occur very rarely in PSP, even at high Sinemet dosages.

Patients with PSP should generally receive the standard Sinemet (or generic levodopa/carbidopa) preparation rather than the controlled-release (Sinemet CR or generic levodopa/carbidopa ER) form. The CR form is absorbed from the intestine into the blood slowly and can be useful for people with Parkinson’s disease who respond well to Sinemet but need to prolong the number of hours of benefit from each dose. In PSP, however, such response fluctuations almost never occur. Because Sinemet CR is sometimes absorbed very little or erratically, a poor CR response in a patient with PSP might be incorrectly blamed on the fact that the disease is usually unresponsive to the drug. Such a patient might actually respond to the standard form, which reaches the brain in a more predictable way.

A new formulation of levodopa-carbidopa is Parcopa, which dissolves under the tongue. For people with PSP who cannot swallow medication safely, this could be useful. Another approach for such patients is to crush a regular levodopa-carbidopa tablet into a food or beverage that is easily swallowed. Another new formulation of levodopa-carbidopa (called Stalevo) combines those two drugs with a third drug, entacapone, in the same tablet. The entacapone slows the rate at which dopamine is broken down. It is useful for patients with Parkinson’s whose levodopa-carbidopa works well but only for a few hours per dose. This situation rarely, if ever, occurs in PSP.

Case Report: First Symptoms are Agitation/Anxiety

Date
Posted by

The “Journal of Clinical Neurology” is published in Seoul by the Korean Neurological Association. Last month a case report was published about a 52-year-old woman with behavioral changes. She was thought to have the behavioral variant of frontotemporal dementia (bvFTD). Some of her symptoms were restlessness, insomnia, agitation, inappropriate behavior (meddling in other people’s affairs), and severe anxiety. Later, she developed a gait disturbance. She had no eye movement problems. The working diagnosis changed to FTD with parkinsonism. The clinicians “requested a genetic study for FTD and parkinsonism linked to chromosome 17 (FTDP-17), but this did not reveal a genetic mutation of microtubule associated protein tau.” Eventually vertical gaze problems appeared, and the woman was diagnosed with PSP.

A brain biopsy was done; the diagnosis was PSP. I’ve heard about brain biopsies being done in very rare instances. I was talking years ago to someone about this and they said: “you’re not going to remove any part of my loved one’s brain while he is still alive!”

The authors note that previous investigations of behavioral symptoms in PSP reveal “that apathy was the most frequent behavioral abnormality; …the presence of high apathy and low agitation scale scores correctly identified the patients with PSP. In contrast, in our case, agitation and disinhibition were the earliest and most prominent behavioral symptoms. … To the best of our knowledge, agitation or disinhibition as an initial symptom of PSP is very rare… Based on previous reports and our case, gait instability and gaze abnormality are not absolute requirements as presenting symptoms for a diagnosis of probable PSP, and the initial clinical diagnosis criteria are not mandatory.”

The article is available at no charge online.

Robin

Journal of Clinical Neurology. 2010 Sep;6(3):148-51. Epub 2010 Sep 30.

Behavioral changes as the earliest clinical manifestation of progressive supranuclear palsy.

Han HJ, Kim H, Park JH, Shin HW, Kim GU, Kim DS, Lee EJ, Oh HE, Park SH, Kim YJ.
Department of Neurology, Myongji Hospital, College of Medicine, Kwandong University, Goyang, Korea.

Abstract
BACKGROUND: The clinical and pathological heterogeneity of progressive supranuclear palsy (PSP) is well established. Even with a well-defined clinical phenotype and a thorough laboratory workup, PSP can be misdiagnosed, especially in its early stages.

CASE REPORT: A 52-year-old woman, who we initially diagnosed with a behavioral variant of frontotemporal dementia developed parkinsonian features, which then progressed to gait instability and gaze abnormality.

CONCLUSIONS: We report herein a pathologically confirmed case of PSP presenting with behavioral changes including agitation and irritability, which eventually led to the cardinal symptoms of progressive supranuclear palsy.

PMID: 20944816

The full article is available here:

XML version –>
http://synapse.koreamed.org/search.php? … vmode=FULL

PDF version –>
http://synapse.koreamed.org/Synapse/Dat … -6-148.pdf

“Nigel Dempster – Life with PSP”

Date
Posted by

Every once in awhile I check the PSP Association’s website at pspeur.org as they often post great materials for the PSP community. They are based in the UK. Last week, they posted this announcement:

“The PSP Association have released for the first time film footage featuring the late Nigel Dempster talking about his life with Progressive Supranuclar Palsy (PSP). Nigel made the DVD to raise awareness in the hope that it would help people affected by PSP, their families and carers receive better access to care and support, and also highlight the need for more research in to causes, treatments and ultimately a cure.”

Nigel Dempster died in 2007 at age 65 with PSP. He was a well-known newspaper columnist.

You can find the 8-minute video here:
http://www.pspeur.org/news_and_events/video.html

Over several introductory slides, PSP is described as follows:

“Progressive Supranuclear Palsy is a neuro degenerative disease involving the death of neurons (or nerve endings) mainly in the brain stem and basal ganglia. This is the area, above the nuclei (hence supranuclear), which controls balance, movement, vision (particularly upgaze and downgaze), speech and ability to swallow.”

“Average life expectancy is seven years from onset, for the last two of which the patient is often wheelchair or bedbound, tube fed, on ‘around the clock’ care and unable to communicate with the world around although their intellect remains largely intact.”

“Recent research confirms a prevalence of at least 5 per 100,000 of the population, though leading neurologists estimate there could be up to 10,000 people living with PSP in the UK, many misdiagnosed (often as Parkinson’s Disease, which it can mimic in its early stages) and many, particularly amongst the elderly, left undiagnosed.”

“There is today no effective treatment and no cure for this disease, though there is an increasing amount of ongoing research into its cause, treatment and cure, mainly sponsored by the PSP Association.”

Then the story of Nigel Dempster is told. He is shown at the age of 62, with a PSP diagnosis. He had to quit his job at age 61 due to PSP symptoms (backward falls). Some clips of Dempster as a younger man were shown.

It’s quite a powerful video. Dempster’s story is told openly.

Robin

Dr. Litvan Webinar on CBD – Notes

Date
Posted by

What a shame that this CurePSP webinar with such an expert as Dr. Irene Litvan was held at 6:30am California time with very little advance notice.  I was able to get up in time and noticed one other local support group member on the call.  There was a ten-minute delay in getting started (due to technical problems).  Judging by the few questions that were asked, I don’t think that many people participated in the webinar.

My key takeaway from today’s webinar with Dr. Litvan is that there are three common clinical presentations of CBD:

  • corticobasal syndrome
  • frontotemporal dementia presentation
  • progressive aphasia

Here are the details Dr. Litvan shared on the three presentations:

#1 – corticobasal syndrome:  symptoms are unilateral; parkinsonism (slowness, stiffness); ideomotor apraxia (ie, difficulty using a limb not due to motor of sensory problems); myoclonus (jerky movements); dystonic posture (abnormal posture/contracture); alien limb syndrome (feeling of limb as alien); levitation (uncontrolled elevation of limb); sensory neglect (unaware of sensation only when there is double stimulation).

If presentation #1 includes bilateral parkinsonism, rather than unilateral parkinsonism (which is more common), then the survival time is shorter.

#2 – frontotemporal dementia (FTD) presentation:  the primary symptom is frontal dementia (executive, frontal behavioral and language disturbances).  May or may not have bilateral parkinsonism.

Presentation #2 has a shorter survival time.

#3 – progressive aphasia:  language problems.

Unfortunately, Dr. Litvan did not describe the third presentation at all nor did she give the percentage prevalence of these three common forms.  (Or, if she did, I missed it!)  You’ll have to refer to the notes from Dr. Boeve’s presentation for that.  PPA (primary progressive aphasia) was one of the four disorders Dr. Boeve addressed in his webinar.
One other item mentioned briefly was the use of transcranial ultrasound in Europe (but not in the US) for aiding in the diagnosis of CBD.

In some ways, Dr. Litvan’s presentation was an excerpt of Dr. Boeve’s webinar from several months ago.

If you listened to today’s webinar, please let me know your key takeaways and if your understanding of the three clinical presentations is different from mine (described above).

My notes from Dr. Litvan’s presentation and the very short Q&A follow.  [Editor’s Note:  The webinar recording is no longer on the CurePSP website.]

Robin

————————————————————————-

10/18/20 Webinar
Hosted by CurePSP
Challenges in CBD Management
Irene Litvan, MD, Director, Division of Movement Disorders, University of Louisville, Louisville, KY

Topics addressed in today’s presentation
* Diagnostic Challenges
* Pathogenesis (Cause/s)
* Treatment

CBD Diagnostic Challenges:
* Varied clinical presentations
* No markers for the disease (no blood test)
* Clinical presentations do not always correspond to underlying CBD brain lesions

Early and accurate diagnosis is important for:
* appropriate management
* prognosis
* clinical research

CBD Epidemiologic Aspects
* Underdiagnosed (25-48%).  Fewer than half who have the disease are diagnosed as having it during life.
* Diagnosis:  at half course of the disease
* There are no epidemiologic studies
* Togasaki & Tanner estimated that
(a) 4-6% of patients with parkinsonism have CBD
(b) incidence:  0.6 – 0.9 new patients per 100,000 each year
(c) prevalence:  4.9 – 7.3 per 100,000
* Sources:  Litvan et al, 1996; Wenning et al 1998; Litvan et al 2000; Togasaki and Tanner, 2000

CBD usually has a combination of:
* cognitive features (such as language) and/or
* motor features (such as dystonia or parkinsonism)
* underlying brain lesions of aggregated tau protein.  (This protein is a problem in AD and PSP.)

Classically, CBD presents with the corticobasal syndrome unilaterally:
* parkinsonism (slowness, stiffness)
* ideomotor apraxia (ie, difficulty using a limb not due to motor of sensory problems)
* myoclonus (jerky movements)
* dystonic posture (abnormal posture/contracture)
* alien limb syndrome (feeling of limb as alien)
* levitation (uncontrolled elevation of limb)
* sensory neglect (unaware of sensation only when there is double stimulation)

Underlying brain lesions are heterogeneous in the corticobasal syndrome (CBS):
* 36 people presented with CBS while only 18 had CBD.  6 had PSP; 4 had AD; 3 had CJD; 3 had non-specific changes; 1 had Pick, 1 had Pick/AD.
* Source:  Boeve paper

[Robin’s note:  I will try to find this article.  The one I’ve seen on 36 Mayo cases is on the neuropsychiatric features and all 36 had CBD.]

Alzheimer Disease presenting with CBD:
* visuomotor disturbances
* ideomotor apraxia
* intermanual conflict
* action myoclonus
* left dystonia
* left alien limb syndrome
* aphasia (including difficulty naming objects)
* clock drawing shows hemi-neglect on the right side (of the brain).  So nearly all 12 numbers are on the right side of the clock.  Usually hemi-neglect is on the left side.
* brain autopsy showed:  AD with lesions on one side; this is a rare presentation of AD
* Source:  Chand et al 2006

CBS with underlying TDP-43 proteinopathy with progranulin mutations
* Described by:  Guerreiro et al 2008; Le Ber et al 2008; Lopez de Munain et al 2008; Kelley et al 2007; Spina et al 2007

We need to know the underlying disease in order to find treatments

Clinical diagnoses in 32 consecutive autopsied cases at the Mayo Clinic with brain CBD pathology:
* Initial Clinical Diagnosis:  10 CBD (31%); 6 atypical PD; 2 PSP; 4 Primary progressive aphasia; 6 dementia/AD; 1 DLB; 1 Marchiafava-Bignami disease; 1 Multiple sclerosis; 1 Stroke
* Final Clinical Diagnosis:  18 CBD (50%); 7 PSP (22%); 4 Primary progressive aphasia; 1 AD; 1 DLB; 1 Marchiafava-Bignami disease
* Source:  Boeve et al 2000

[Robin’s note:  I will try to find this article.]

CBD with a frontotemporal dementia (FTD) presentation:
* dementia (executive, frontal behavioral and language disturbances)
* may or may not have bilateral parkinsonism
* Sources:  Bergeron et al 1998; Wenning et al 1998; Litvan et al 1999; Grimes et al 1999

Chart from Murray et al, Neurology 2007;6k:1274-1283 (UPenn study):
Only a few had the final clinical diagnosis of CBD yet the chief complaints were classic CBD (unilateral problems)

CBD presentation matters because survival is different for each presentation.  Shorter survival in CBD when presenting with dementia and/or bilateral parkinsonism.

In summary, diagnostic challenges are:
* No diagnostic biological markers.  Diagnosis still relies on clinical features, confirmed by pathology.
* CBD presents with various clinical presentations including CBS, FTD, and primary progressive aphasia
* The underlying brain lesions of the CBS vary and include CBD, PSP, Alzheimer Disease, FTD, progranulin mutations and Creutzfeld-Jakob Disease

Lab tests that can help some with diagnosis:
* brain MRI in CBD:  might be able to see unilateral atrophy
* transcranial ultrasound:  used in Europe; might help with diagnosis

What goes wrong in the brains of those with CBD?
* Tau aggregates in neurons and glia.
* Astrocytic plaque is indicative of CBD.
* Some key terms:  NFT, tufted astrocyte; threads; coiled body; astrocytic plaque.

Tau is important for the brain cell structure.  In CBD, tau collects in insoluble forms.

What triggers tau to change in CBD?
We don’t really know but question whether the following factors may play a role — genetics; mitochondrial abnormalities (oxidative stress); dietary/environmental toxicants; inflammation; gene/environment combination

What do we know about genetics?
* CBD is very weakly hereditary
* No highly penetrant tau mutations are found
* CBD is associated with H1 haplotypes and H1 hyplotype variants.  Also true in PSP.
* ? Genetic predisposition CBD

From looking at H1/H1, H1/H2, and H2/H2 at PSP, CBD, and in controls, we conclude:
* H1/H1 genotype is (nearly) necessary but far from sufficient for CBD or PSP to develop
H1/H1:  88% of PSP; 84% of CBD; 60% of controls
* Predisposition triggered by other factors of relative rare mutation with low penetrance?
* ? H2/H2 is protective
H2/H2:  0% in PSP; CBD of CBD

Defined tau mutations give rise to tauopathies presenting with PSP/CBD clinical and pathological phenotype.  Example:  PPND (FTDP-17 with N279-K mutation).  Seen in Mr. Wszolek, a Mayo patient.

What do we know about mitochondrial abnormalities and oxidative injury?
* Impaired activity of Complex I of the mitochondrial respiratory chain
* Oxidative stress in CBD.  Cells die.

What do we know about inflammation?
* Activated microglia in the brain in CBD.  Can see this in people who have died and in living people.
* Sources:  Ishizawa and Dickson 2001; Gerhard et al 2004; Henkel et al 2004)

Hypothesized pathways to cell death in CBD and PSP:
* H1 haplotype variants:  do these lead to tau dysfunction?
* Inflammation:  does this lead to tau inclusions, which causes cell death, which leads to more inflammation

CBD Treatment Challenges:
* Difficulties in accurately diagnosing patients during life
* Difficulty in slowing disease progression when the cause is unknown
* Symptomatic treatments have limited efficacy.  We can improve the quality of life.

Symptomatic RX:
Dystonia (limbs) — botox
Dystonia (neck) — botox (avoid when antecollis)
Speech problems — speech therapy; communication aids
Myoclonus — clonazepam, piracetam, valproate
Belpharospasm — botox
Walking — PT; weighted walker
Patient and family support — social services; laymen associations; support RX

In summary:
* CBD has various clinical presentations:  CBS, progressive aphasia (language problem), frontal dementia
* The underlying brain lesions corresponding to these presentations are not always CBD
* Telltale signs (such as focal signs) are present in mid-phase of the disease
* More research is needed to identify:
(a) better ways to diagnose CBD during life;
(b) causes contributing to development;
(c) specific ways to slow the progression of the disease

Questions & Answers:  (all questions were answered by Dr. Litvan)

BRAIN DONATION

In response to someone noting that they’ve made arrangements for brain donation and to someone else to donated her mother’s brain upon death, Dr. Litvan said:  “Thank you for donating your brain!”

RESEARCH

Q:  What are some centers that are studying this disease?

A:  Mayo, UPenn, UCSF

Q:  Are there any known causes?

A:  There is a genetic susceptibility for those with the H1 genotype.  There is a study going on in PSP as to the causes, but not in CBD.  We aren’t studying this in CBD due to the diagnostic challenges.

Q:  Any hope on the horizon for developing biomarkers?

A:  There are multiple groups trying to search for this.  One group is trying to label the protein tau with a PET scan.  This would help with the diagnosis and at least to differentiate from other disorders.  There are a lot of researchers involved.  Of course we want more researchers to be involved and more money.

ABOUT THE THREE PRESENTATIONS AND SYMPTOMS

Q:  Are there typical symptoms to expect as disease progresses?

A:  It depends on the form of the disease.  If the disease presents in a unilateral way, the disease may affect the other side of the body.  If the disease presents with dementia, the disease may affect both sides of the body.

Usually memory is not a major issue in this disease.

Q:  Will dementia appear?

A:  It can happen that dementia never appears.

Q:  Alien limb.

A:  Usually the arms are more effected than the legs.

Q:  My sister has language problems.  What guess can you make about her survival time?

A:  Forms that have speech problems progress slowly.  Those with CBS have a survival time of 5-8 years.

Q:  In PSP, there are two common forms.  Do you guess that the same two forms appear in CBD?

A:  Yes, this is exactly what I said.  There are three forms in CBD.

Q:  Are itching and constipation part of CBD?

A:  Itching is not part of CBD.  Constipation is part of many neurodegenerative diseases.

ABOUT TREATMENTS

Q:  If CBD presents as AD, can AD drugs help?

A:  We don’t have AD drugs that can help with CBD symptoms.

Q:  Would CBD patients benefit from DBS (deep brain stimulation)?

A:  No.  People with PD who get DBS do improve because they respond to dopamine medication.  If you don’t respond to levodopa/carbidopa, then you won’t respond to DBS.

New 6-Page Pamphlet on MSA (Parkinson Society Canada)

Date
Posted by

Pam Bower, one of the moderators of the ShyDrager Yahoo!Group, posted about this pamphlet today.  I think it’s one of the best documents I’ve seen for laypeople.  It’s very similar to the brochure available from the Multiple System Atrophy Trust (UK).

You can find this MSA pamphlet on the Parkinson Society Canada website:

http://www.parkinson.ca/wp-content/uploads/Multiple-System-Atrophy-English.pdf

Pam indicates “This was created with much input from MSA patient Paul Walsh in Toronto. He has lobbied Parkinson Society Canada vehemently to get more resources available for MSA patients and families.”

I’ve copied some of the text below.  I encourage you to check-out the link because the layout is nice and there’s a diagram of the brain.

Robin

————————————————————————-

Excerpts from:

Multiple System Atrophy
Parkinson Society Canada
First Published 2010 (?)

Multiple System Atrophy falls into the category of Atypical Parkinsonism, or Parkinson plus syndrome, a group of diseases linked to a lack of dopamine in the brain. Dopamine controls movement. While Parkinson’s is the most common Parkinsonism, approximately 20 percent of people will be diagnosed with another Parkinson’s-like condition.
What is Multiple System Atrophy?
Multiple System Atrophy (MSA)* is a progressive brain disorder caused by loss of nerve cells in specific areas of the brain. This loss causes problems with movement, balance and autonomic functions of the body. (Autonomic functions are body functions that occur automatically, such as bladder control.)

*Terminology
MSA includes conditions that were previously known individually as Shy-Drager syndrome, striatonigral degeneration and sporadic olivopontocerebellar atrophy. Researchers have learned that there is a common underlying cause in all three disorders, so they are now referred to as MSA.

Who gets MSA?
MSA usually starts between the ages of 50-60 years, although it can affect people younger and older than this. The average age of onset is 54. MSA is a disorder that occurs randomly in the general population and is considered rare (4 – 5 in 100,000). There is a slightly higher incidence in men.

Which parts of the brain are affected in Multiple System Atrophy?
In MSA, cells are damaged in different areas of the brain which control a variety of body functions. The three areas affected are the basal ganglia, cerebellum and brain stem.

In MSA, brain cells in the affected areas shrink (atrophy). This can sometimes be seen on MRI scans. When brain tissue is examined under a microscope, structures called glial inclusion bodies can be seen; they contain a protein called alpha-synuclein. It is the presence of these inclusion bodies in the movement, balance and autonomic control centres of the brain that confirms a diagnosis of MSA.

What are the symptoms of MSA?
Parkinson symptoms – relating to slowness and stiffness of movement
• feeling slow and stiff when moving
• difficulty turning in bed
• difficulty starting to move
• difficulty fastening buttons on a shirt or blouse

Cerebellar symptoms – relating to co-ordinating movement and balance
• feeling clumsy, dropping things
• feeling unsteady in crowds
• inability to balance without support
• difficulty writing
• slurred speech

Autonomic symptoms – relating to automatic body functions
• bladder problems
• erectile dysfunction
• dizziness or fainting (blood pressure problems)
• constipation
• cold hands and feet
• inability to sweat

Other symptoms may include:
• weakness in arms and legs
• heightened emotional response (laughing or crying disproportionate to the situation)
• restless sleep
• nightmares
• noisy breathing during the day, snoring at night
• unintentional sighing
• swallowing problems, difficulty chewing, choking episodes
• weak, quiet voice
• cognitive problems, slowness in thinking, difficulty with multi-tasking

How is Multiple System Atrophy treated?
Currently, there is no treatment to slow the progression of the disease. The complex nature of MSA means you should see a neurologist who specializes in movement disorders. It is important to look at and treat each symptom separately in order to maintain daily activities and quality of life. Often a multidisciplinary team, including a neurologist, social
worker, speech language pathologist, physiotherapist, urologist, clinical nurse and family doctor will be involved.

Suggestions that may be useful for managing symptoms of Multiple System Atrophy

Movement: Drugs to help stiffness and slowness are the same drugs used in Parkinson’s disease. Medications in MSA may be effective for some people and not effective for others.

A drop in blood pressure (orthostatic hypotension): A drop in blood pressure when standing can cause dizziness, lightheadedness, fainting, or blurred vision. It may be treated with drugs that raise blood pressure. Some people find getting up slowly from a chair can reduce fainting spells. Raising the head of the bed can make it easier to get out of bed. Increasing salt in the diet and wearing pressure stockings can also help. It is important to have regular blood pressure checks.

Erectile dysfunction: Medications or penile implants may help with impotence.

Breathing: If you have problems with snoring or sleep apnea (you stop breathing while asleep), you should report this to your doctor. A breathing tube may need to be inserted.

Spasms: Medications may help treat spasms.

Constipation: Increased dietary fiber and plenty of fluids on a daily basis. Taking laxatives may relieve constipation.

Swallowing: To improve swallowing and reduce risk of choking, food may need to be pureed. If swallowing becomes difficult, a tube may be surgically inserted into the stomach.

Muscle coordination: A routine exercise program with stretching, range of movement and strength building is very important. It helps keep muscles strong and allows for safer mobility.

Urinary retention: Medications can reduce urgency and frequency problems, improve tone of bladder muscles or reduce production of urine overnight. You should take care to avoid infection and seek treatment. Consulting a urologist may help.

What do care partners need to know?
If you are a care partner or family member, MSA will affect your life, too. Learn as much as you can. Care partners often believe they will remain healthy and will always able to provide care. However, care partners often burn out and become ill. Take care of yourself. Maintain a healthy lifestyle, including exercise and good nutrition. Consider using community services. Have an emergency plan in case you become ill. Build a network of support.