CurePSP had a webinar today on MSA. The organization’s terrific director of research, the neurologist Lawrence Golbe, MD, was the presenter. I was working on an urgent brain donation case when the webinar began, so I had to rely on Dr. Golbe’s slides for my notes there. For the final 20 minutes of the webinar, I really appreciated that he was rapid-fire with answering questions as this meant he got through a lot of questions but it was incredibly hard to take notes! So my apologies if I got something wrong.
Below, I’ve provided the following:
* link to the recorded webinar on the CurePSP website (Note: this recording is no longer available!)
* link to Dr. Golbe’s slides
* my notes from Dr. Golbe’s presentation and the Q&A
Link to Dr. Golbe’s slides:
Robin’s Notes from Webinar:
MSA: Symptoms, Causes and Treatment
April 5, 2013
Speaker: Lawrence Golbe, MD
Neurologist at Robert Wood Johnson Medical School, New Brunswick, NJ
Director of Research and Clinical Affairs, CurePSP
Note: Because of the size of the audience, he’ll skip some technical slides so as to leave more time for Q&A.
Johnny Cash – celebrity with ShyDrager variant of MSA. 1932-2003.
MSA is a complicated disease. You can think of it as a triangle. There are three main components — parkinsonian, cerebellar, autonomic. Each component is highly variable from one person to the next. There are lots of smaller components as well.
The parkinsonian variant looks like Parkinson’s Disease. This variant is called striatonigral degeneration. There is a variant with mostly autonomic problems. This used to be called Shy-Drager Syndrome. These terms — striatonigral degeneration, Shy-Drager Syndrome, and sporadic olivo-ponto-cerebellar ataxia — are now outdated as they’ve been discovered as all MSA. And there’s a variant that is mostly cerebellar: the person looks and talks like they are drunk. The problem is with the cerebellum – the main balance and coordinating organ in the brain. The people who have that form used to be called sporadic OPCA (olivo-ponto-cerebellar ataxia).
Each person with MSA is a point in the triangle, with a varying combination of the three components. There are people all over this triangle. And there can be people in the extremes of the corners of the triangle; they can be real diagnostic dilemmas.
PARTS OF THE BRAIN INVOLVED IN MSA
The “multiple” in “multiple system atrophy” means that multiple areas of the brain are affected. The principal areas of the brain affected by MSA:
* basal ganglia (ganglia = collection of brain cells in one place, connected together)
* mid-brain, which is where the substantia nigra is. This is responsible for the parkinsonian parts of MSA (slowness, stiffness). But not everyone with MSA has this symptom. This area is affected in Parkinson’s Disease.
The cerebral cortex, the thinking part of the brain, is pretty much spared in MSA. Not completely. “Very little dementia in MSA” because the cortex isn’t involved. In contrast to Parkinson’s Disease, where a majority develop dementia eventually. With PSP it’s worse than that. In Huntington’s Disease, there’s a lot of dementia.
Another part of the brain involved in MSA:
* cerebellum. See image of atrophic cerebellum and pons. Hot cross bun sign = scarring of pons. The image is an extreme case.
The autonomic nervous system is involved in MSA. When you see “autonomic,” think “automatic.” These are things we don’t think about. In MSA, there are problems with lots of these functions. (parasympathetic and sympathetic do opposite things.) In MSA, some of the cells in the spinal cord break down. There’s a problem with the connections from the spinal cord to the autonomic reflexes. So there are problems with organs. The most important ones in MSA are constipation, bladder control, and, in men, erectile function. Can be problems with constriction of the pupils, not enough tears, not enough saliva. Heart rate problems are more in Parkinson’s Disease. You can get breathing problems.
AGE OF ONSET, SURVIVAL, AND DIAGNOSIS
Chart from Stefanova, et al in Lancet Neurology 2009 showing MSA, PD, and PSP disease milestones:
* MSA starts earlier than PD. On average, MSA starts in mid-50s. Parkinson’s Disease tends to start later in the 50s, on average. PSP starts in early or mid-60s.
* width of green bar = survival
* on average, MSA survival is 8 years. This is similar to PSP. PD is longer: 15 years. Before there was medication for PD, it’s survival was similar to MSA and PSP.
* DX happens after several years, regardless of the disease. These leads to unnecessary diagnostic tests, inappropriate treatments, and a lot of stress not knowing your diagnosis.
* see chart for other disease milestones, including clinical diagnosis, frequent falls, cognitive disability, dysarthria or dysphagia, urinary catheter, wheelchair dependent, and residential care)
DIAGNOSIS AND CATALOG OF SYMPTOMS
Diagnosis is easy if there is parkinsonism, cerebellar symptoms, and autonomic symptoms. Diagnosis is harder if these symptoms aren’t all present.
This list of symptoms is a catalog of all the possible symptoms. Don’t think that you will get all of these symptoms. Your doctor should be aware of these symptoms. These symptoms may or may not be present but when they are, should raise suspicion of MSA.
Helpful diagnostic clues – Motor (other than parkinsonism and cerebellar ataxia):
* dystonia, which means an involuntary and inappropriate posture of a body part. Examples: forced smile; odd hand dystonia; disproportionate antecollis; “Pisa syndrome” – near constant bending of trunk to one side, sometimes w/enlargement of neck muscles
* jerky tremor or myoclonic tremor: on action or posture-holding of hands/fingers
* disproportionate speech problems, as compared to PD: high-pitched, pinched quality; low volume; tremulous. (“disproportionate” to parkinsonism)
Helpful diagnostic clues – Non-motor:
* abnormal ventilation: harsh, strained, noisy inhalations (imitated 18 minutes into presentation); irregular breathing rhythm (deep inspiratory sighs and periods of apnea)
* REM (rapid eye movement) behavioral disorder: acting out dreams (sometimes violent with punching or kicking of bed partner; sleepwalking); can precede other signs of MSA by years; also occurs in Parkinson’s Disease and other neurodegenerative disorders
* cold hands/feet: poor return of circulation after pressure on skin; constant purplish-blue discoloration of hand, feet, tip of nose; Raynaud’s phenomenon (when hand is exposed to cold, the hand goes through series of discoloration such as red, white, and blue)
* emotional incontinence (laughing or crying without true emotional content)
* daytime sleepiness
* restless leg syndrome
* dementia (4-5%….very rare)
Exclusion criteria: when one of these is present, MSA is unlikely –
* onset before age 30
* family history of similar disorder
* hallucinations unrelated to medication
* another explanation for the neurological symptoms (strokes, trauma, developmental abnormality)
* dementia (sign of DLB; very rare in MSA)
* disproportionate difficulty with downgaze (sign of PSP; “PSP” means trouble looking down)
* focal cortical problems — meaning problems related to speech or thinking — such as aphasia, alien limb, spatial perception difficulty (signs of CBD. CBD can mimic MSA sometimes.)
Glial cytoplastmic inclusions in MSA:
* glia = brain cells without electrical activity that support the electrically active cells (that are called neurons); they are more than waiters and janitors for neurons
* cytoplasm = the fluid in brain cells outside of the nucleus
* inclusions are dark things
* discovered in 1989 in people with SDS, SND, and OPCA. These three are all the same disease.
MSA: A tale of two (so far) proteins:
* alpha-synuclein: the important protein in MSA; also important in Parkinson’s Disease
* p25-alpha: much less important or studied; only recent discovered
Like other neurodegenerative disorders, proteins glom up and cause mischief.
Is MSA a prion disease? Are the other neurodegenerative diseases prion diseases? Misfolding problem “spreads” or propagates.
In the future, potential drug targets in the prion model of MSA: protective therapy
* antibodies against oligomers of alpha-synuclein or p25-alpha
* drugs inhibiting either the uptake of misfolded protein by healthy brain cells or the oligomer formation from single misfolded proteins
Rigidity and slowness = “parkinsonism”
* gets treated with carbidopa/levodopa and other Parkinson’s medications
* can aggravate low blood pressure!
* physical therapy
* balance re-training (tai chi, etc.)
* gait aids (cane, walker)
* wrist weights for tremor
* peripherally-acting anticholinergics, such as Oxybutinin, Detrol, Vesicare, and others. Can cause dry mouth, dry eyes, and constipation. Occasionally they can leak across the blood-brain barrier and cause brain side effects: they can cause confusion and sleepiness…but that doesn’t usually happen.
* alpha-adrenergic blockers, such as Flomax and others. Can aggravate low blood pressure.
* in extreme cases, urostomy
* consult a neuro-urologist
* docusate, fiber, hydration
* laxative as needed: try to minimize because the body can be habituated to them
Low blood pressure (this is a sub-specialty)
* non-drug measures: salt and fluid repletion (don’t limit your salt and fluid with MSA!); pressure stockings or Ted stockings; elevate head of bed 6 inches (put blocks under head of bed); full glass of water when feeling lightheaded
* drugs: fludrocortisone (Florinef), midodrine (ProAmatine), pyridostigmine (Mestinon), many others. These drugs don’t work if you don’t have enough salt and fluid onboard.
* cognitive-behavioral therapy
* other psychotherapy
* standard antidepressants: we don’t know which ones work best, if any. MDs have preferences; there’s no rational reason to prefer one over the other in MSA.
* anticholinesterases: Aricept, Exelon, Razadyne. Can aggravate the bladder problem (want to urinate more frequently). They can speed up the action of the GI tract which, in MSA, would be a good thing.
* insomnia: sleep hygiene is most important (regular schedule, even on the weekends); exercise; standard sleeping pills (no special ones are preferable in MSA; avoid ones that reduce blood pressure)
* REM behavioral disorder: clonazepam is very helpful, taken at bedtime every night. (Clonazepam is used in Psychiatry for mood stabilization.)
* obstructive sleep apnea: CPAP machine; may require tracheotomy (with a mechanical device keeping airway open – not a machine)
Dystonia (odd postures of hands or other body parts)
* bracing or splinting: often uncomfortable
* Keppra (seizure drug)
* Viagra, etc. Can really aggravate low blood pressure.
* penile injections of Caverject (alprostadil)
* consult a neuro-urologist
Restless legs syndrome
* Sinemet, Mirapex, Requip – PD medications (last two are expensive options)
* clonazepam (works at least as well as Mirapex and Requip)
* these are the only ones that are safe to use with MSA. But they can lower blood pressure too.
* measures for night-time insomnia
* Provigil, Nuvigil
EXPERIMENTAL DRUG TREATMENTS
Recent experimental treatments for MSA:
* rifampicin: results were just announced last week in San Diego (so he didn’t have time to update his chart); drug failed in MSA; phase 3 trial ended 12/12; drug is on the market.
* rasagiline: phase 2 trial ended 2/12; drug is on the market
* lithium: phase 2 trial was terminated because drug wasn’t tolerated; drug is on market (for mood disorders)
* IViG: phase 1 trial showed slight benefit; results published 11/12 in BMC Neurology 2012 (by Novak et al); drug is on market (for auto-immune diseases)
* autologous mesenchymal stem cells: phase 2 trial showed slight benefit; results published 7/12 in Ann. Neurol. 2012 (by Lee et al)
* Riluzole: phase 3 trial showed no benefit; results published 1/09 in Brain 2009 (by Bensimon et al); drug is on the market (for ALS)
Not a happy list.
* MSA, like PD, affects multiple areas of the brain and spinal cord.
* Three principal features of MSA, of which you can have one or more: parkinsonism (muscle stiffness, slowness); cerebellar deficits (tremor, incoordination); dysautonomic deficits (low blood pressure, bladder problems, constipation, etc).
* Outmoded terms: striatonigral degeneration, sporadic OPCA (olivopontocerebellar atrophy), and Shy-Drager syndrome. We now know these are all the same thing.
* Important additional features may include depression, disordered breathing, mild cognitive difficulties, emotional incontinence, changes in vocal quality, and sleep problems
* Hallmark of MSA is glial cytoplasmic inclusions. Seen under the microscope. The inclusions are aggregates of protein in certain brain cells, the astrocytes (the glial cells). Composed mainly of alpha-synuclein and p25-alpha.
* By analogy with some other neurodegenerative diseases, one or both of these two proteins:
* may aggregate as a result of mis-folding,
* may induce normally folded copies of the protein to mis-fold in a chain reaction (proteins that do this are called prions).
* If prion hypothesis is true, this opens up possibilities for new ways to slow or stop the progression of MSA.
* If the steps in the prion propagation process are similar for all neurodegenerative diseases, then a breakthrough for one disease could benefit them all. Lots of money is being devoted to researching Alzheimer’s. This could help MSA.
* Meanwhile, treatment of MSA is symptomatic, with each symptom treated as it would be as part of any other
condition. Exception: Some drugs for the parkinsonism, bladder problem and erectile dysfunction can aggravate the low blood pressure of MSA.
QUESTION AND ANSWER (42 minutes into the webinar)
Cartoon – “May I be excused? My brain is full.”
Robin’s Note: I’ve re-ordered these questions/answers so that the MSA-related questions are first, and then there are PSP and CBD questions.
Q: Is MSA an auto-immune disease?
A: No evidence of that. In all of the neurodegenerative diseases, there seems to be an immune component but it’s probably just a reaction to the damage. The brain is trying to clear away the damage using the immune system. That may contribute to the damage actually. But it is not at its origin an auto-immune disease.
Q: Will hot cross buns always appear in MSA?
A: No, not nearly. Less than half of everybody. Mainly in the cerebellar type of MSA.
Q: Regarding the 4-5% of those with MSA have dementia. Is that number from autopsy-confirmed research? How can a neurologist differentiate between the “rare” dementia of MSA and Dementia with Lewy Bodies?
A: Not from autopsy-confirmed series. It’s from a clinical series.
The patient already has MSA. It doesn’t look like they have Dementia with Lewy Bodies and they develop dementia. They still don’t look like they have Dementia with Lewy Bodies. DLB doesn’t produce cerebellar and dysautonomia very much. And then there’s all those other little features of MSA that don’t occur in DLB. So that’s how you’d tell.
Q: Is IViG helpful?
A: No, because MSA is not an auto-immune disease.
Q: Is the work Lilly is doing on proteins promising?
A: I don’t know what Lilly is working on. Trying to keep the alpha-synuclein from folding and misaggregating is a big part of ongoing research in MSA.
Q: What is the role of neuropathy or pins and needles-like numb-ness in MSA.
A: Very little of this in MSA. Yes, it can happen but I’d look for other causes of neuropathy in MSA.
Q: Are head tremors and jerkiness of hands and limbs more cerebellar or parkinsonian type?
Q: How about eyes that can’t be kept open?
A: That’s what botox is for. This is injected into the eyelid muscle by a specialist. It’s called blepharospasm. It happens in MSA, PSP, or all on its own.
Q: What about stem cell treatment?
A: It’s not ready for prime time.
Q: Is creatine and phosphotytyl serine (sp?) helpful?
A: Not for MSA.
Q: Jaw-clenching and teeth grinding. Will botox help?
A: Yes, but there is a danger that the botox will leak into the swallowing muscles. Yes, jaw closing dystonia can respond to botox.
Q: Biggest problem is speech.
A: Yes, this can happen in MSA.
Q: Stem cell replacement therapy?
A: Won’t happen anytime soon for any neurological diseases. Stem cells may be useful to deliver trophic factors that help the brain re-grow, rather than replacing cells that have been lost.
Q: Is MSA-Autonomic a type of MSA any more?
A: “Regular MSA” is mostly autonomic. Subclassifications are parkinsonian or cerebellar. It’s not any less common.
Q: I have a friend who is 46 and already in the advanced stages. What do I need to watch for?
A: Main potential complications – swallowing difficulty (getting food down the wrong pipe) and balance difficulty (falling and hurting yourself).
Q: Any indicators that show how fast the disease is progressing?
A: No. Just have to look at how fast it has progressed up to that point. There is an MSA Rating Scale that the doctor can use at each visit.
Q: Mis-folding of proteins.
A: We need to figure out how to stop the mis-folding.
Q: Is it common to slowly lose the ability to read in MSA?
A: Yes, on occasion. Reading is a complicated eye movement process. Can lose this ability with MSA or PSP.
Q: Where to go for specialized MSA medical care?
A: There are centers around the country where MSA is studied. Call the nearest medical school and ask if there’s a neurologist with particular interest in MSA. If no, call the second nearest medical school.
Q: Loss of empathy?
A: Might respond to an antidepressant or psychotherapy. Part of depression.
Q: What role does sweating or not play in the diagnosis of MSA?
A: This can establish the presence of dysautonomia. Can’t support the diagnosis all by itself.
Q: How do you regulate blood pressure in MSA?
A: The drugs I mentioned. Before resorting to drugs, it’s hydration and salt.
Q: At what point do you go to the hospital?
A: Fainting, or can’t walk due to low blood pressure, or lightheaded all the time that the person can’t function.
Q: Is handwriting a problem in early MSA?
A: Can be a problem, sometimes.
Q: Will stem cell surgery help in a few years?
A: Yes, I’m confident that in a few years…
Q: Are they testing lithium in depression?
A: Lithium is used in mania (the opposite of depression). It can be used for bipolar disorder.
Q: Special place to go for a more confirmed diagnosis of MSA? No Parkinson’s meds work.
A: If Parkinson’s meds don’t work, then MSA is a good possibility. I’ve already mentioned where you might find a movement disorder service.
Q: Can I carefully use my tree stand for deerhunting?
A: Depends on your balance. Balance problems tend to be an early and severe problem in MSA.
Q: Trying to get Ohio to open up funding for NIH.
A: Excellent idea to lobby your state legislature.
Any kind of activity is good – especially activity that maintains cardio conditioning.
Q: Is gene therapy a possibility?
A: Right now it’s not a possibility with MSA because we don’t know enough about the genes that cause MSA. Gene therapy could also be used to deliver proteins that are missing in MSA, but we don’t know enough about that.
Q: Should person with PSP limit salt intake?
A: This is a question for your internist.
Generally someone with MSA should not limit salt intake unless there’s some other reason to do so.
Q: My brother seems to be outside the standard deviation lines.
A: It sounds like your brother is inside the lines because he’s had MSA for 8 years and he’s in hospice.
Q: Are headaches part of MSA?
A: Can be because low blood pressure can cause headaches.
Q: My father has Parkinson’s Plus diagnosis at present. Will it change his care plan if we push for a specific diagnosis?
A: Not really because MSA, PSP, CBD, or DLB are treated all the same — they are treated symptomatically.
Q: Is internal shaking part of MSA?
A: Can have tremor in MSA. Tremor can be internal.
Q: Is anxiety part of MSA?
A: Yes, mood disorders are possible in MSA. (Not just depression.)
Q: Cognitive issues?
A: Dementia, in a few cases. Executive function is mainly affected, as opposed to memory or language.
Q: Do symptoms gradually come on? Slowly?
Q: Can someone have a mixture of all three types of the triangle?
A: Yes, definitely.
Q: Are alternative treatments — chelation, glutathione or diet — worth trying?
A: Not that we know of.
Q: Cannot vacate.
A: Talk to a gastro-enterologist. Things can be done about this.
Q: Is leg pain that cannot be diagnosed part of MSA?
A: Not so much. Sometimes with dystonia. In the legs, in MSA – not so much. This is more part of Parkinson’s.
Q: Why speech high and low within minutes?
A: Don’t know why. The control of speech in the brain stem.
Q: Any current drug trials in the works?
A: Yes, but there’s one but they aren’t recruiting at this point.
Q: Can botox help with feet turning in?
A: Yes, it can regardless of the cause.
Q: Research showed IViGs are helpful.
A: Well, that would be a surprise to me.
A: Good idea but be careful with balance and low blood pressure. But I encourage exercise.
Q: Non-response to PD drugs is a sign of MSA but you mention PD drugs are used to treat MSA symptoms. Can you correct or clarify?
A: PD drugs help some people with MSA – only a minority, only for a short time, and only at high dosages. I will add that refinement.
Q: Do you advocate not taking protein close to the time of taking meds?
A: It’s hardly relevant to MSA so this isn’t an issue. But even in Parkinson’s this isn’t an issue in many people.
Q: Absolute diagnosis through autopsy only?
Q: Do symptoms plateau for a few years?
A: Not really in MSA. This can happen in Parkinson’s Disease.
Q: You didn’t mention amantadine?
A: It’s one of the Parkinson’s drugs that can be used in MSA. Useful in some people.
Q: Eye movement coordination issues. Eyes do not track.
A: There can be these problems in some people with MSA.
Q: Is work being done on how to communicate long distance?
A: Talk to speech therapist. They often have devices that can help.
Q: What country is more involved in MSA?
A: All different countries. Not just the US.
Q: Is there any way a patient can help?
A: Yes, keep your eye on clinicaltrials.gov for treatment trials and observational trials.
Q: Copy of slides?
A: Will be posted to CurePSP website.
Q: Any PSP presentation?
A: I spend most of my life talking about PSP. The next PSP talk is in Peabody, MA on 4/27. (Bruce Janele notes that this conference will be recorded.)
Q: You didn’t talk about PSP.
A: No, I didn’t. PSP can look like the parkinsonian form of MSA.
Q: Is it possible to live 20 years with PSP if careful?
A: You are asking about PSP, not MSA. There are people with PSP who have lived 20 years but it’s rare.
Q: Death in PSP, if not pneumonia?
A: Some kind of infection – bladder infection, bed sores.
Q: Do high doses of CoQ10 help in CBD?
A: No. It hasn’t been tested in CBD. It has been tested in Parkinson’s and it doesn’t work there. It’s being tested in PSP; we don’t yet know.