Eye movement disturbances

I struggled with some of this abstract although the topic is very interesting — how eye movements are affected in PSP, what this means about where in the brain PSP might originate, and how this may help diagnose PSP and disorders that mimic PSP.

Here is one point I could grasp:

“Although some aspects of all forms of eye movements are affected in PSP, the predominant defects concern vertical saccades (slow and hypometric, both up and down), impaired vergence, and inability to modulate the linear vestibulo-ocular reflex appropriately for viewing distance. These vertical and vergence eye movements habitually work in concert to enable visuomotor skills that are important during locomotion with the hands free.”


Frontiers in Neurology. 2010 Dec 3;1:147.

The disturbance of gaze in progressive supranuclear palsy: implications for pathogenesis.

Chen AL, Riley DE, King SA, Joshi AC, Serra A, Liao K, Cohen ML, Otero-Millan J, Martinez-Conde S, Strupp M, Leigh RJ.
Veterans Affairs Medical Center, University Hospitals Case Medical Center, Cleveland, OH.

Progressive supranuclear palsy (PSP) is a disease of later life that is currently regarded as a form of neurodegenerative tauopathy. Disturbance of gaze is a cardinal clinical feature of PSP that often helps clinicians to establish the diagnosis. Since the neurobiology of gaze control is now well understood, it is possible to use eye movements as investigational tools to understand aspects of the pathogenesis of PSP.

In this review, we summarize each disorder of gaze control that occurs in PSP, drawing on our studies of 50 patients, and on reports from other laboratories that have measured the disturbances of eye movements. When these gaze disorders are approached by considering each functional class of eye movements and its neurobiological basis, a distinct pattern of eye movement deficits emerges that provides insight into the pathogenesis of PSP.

Although some aspects of all forms of eye movements are affected in PSP, the predominant defects concern vertical saccades (slow and hypometric, both up and down), impaired vergence, and inability to modulate the linear vestibulo-ocular reflex appropriately for viewing distance. These vertical and vergence eye movements habitually work in concert to enable visuomotor skills that are important during locomotion with the hands free.

Taken with the prominent early feature of falls, these findings suggest that PSP tauopathy impairs a recently evolved neural system concerned with bipedal locomotion in an erect posture and frequent gaze shifts between the distant environment and proximate hands. This approach provides a conceptual framework that can be used to address the nosological challenge posed by overlapping clinical and neuropathological features of neurodegenerative tauopathies.

PubMed ID#: 21188269 (see pubmed.gov for this abstract only)

MSA – Current and Future Treatments

This medical journal article on current and future approaches to the management of MSA was published in July 2010 but the abstract was just recently posted to PubMed.  The article reviews current symptomatic treatment, potential neuroprotective drugs, and future approaches to the management of MSA.  It was written by a French team of neurologists.

Wonderfully, the full article is available at no charge online via PubMed:


Therapeutic Advances in Neurological Disorders. 2010 Jul;3(4):249-63.
Multiple system atrophy: current and future approaches to management.
Flabeau O, Meissner WG, Tison F.
Department of Neurology, University Hospital of Bordeaux, Bordeaux, France.

Here are a few notes:


There is a nice table (Table 1) of current first-line treatment for various symptoms and alternative treatments.  I thought one symptom made no sense to include and its treatment also made no sense:  the treatment for “cognitive impairment” is “speech therapy.”  Table 1 is a good summary of all the first half of the article.  In the article, it seems that what is meant by “cognitive impairment” is “verbal fluency”; I’m unclear if speech therapy will help with verbal fluency.

Here’s a very short summary of the current treatments:

“Current symptomatic management in MSA should target motor impairment, autonomic failure and depression, as these features are associated with a poor quality of life. Levodopa remains the main treatment for MSA, despite its modest and nonsustained effect. Among the several treatments available for OH, only midodrine meets the criteria of evidence-based medicine. Strategies for urinary disorders are well standardized, while other symptoms such as breathing disorders, RBD, depression or dystonia remain out of consensus.”

Here are some things I learned from the current treatment section of the article:

* “Although levodopa induces less delirium and hallucinations in MSA than in PD, it can lead to adverse effects such as … pathological hypersexuality.”

I hear from many PD caregivers about Sinemet causing hypersexuality but I’ve never heard this from MSA caregivers.

* “According to consensus criteria, levodopa unresponsiveness should only be accepted after a treatment with at least 1 g of levodopa per day for at least 3 months.”

* “Clean intermittent self- catheterization (CISC) is recommended as the first-line treatment when the postvoid residual is above 100 ml. Thus, the residual volume should be regularly monitored, for example with a portable ultrasound device. The critical threshold of 100 ml is reached in a mean of 2 years after disease diagnosis.”

* “To reduce the risk of infection due to permanent catheterization, surgery such as sphincterotomy or sphincteric wall stenting can be considered as a last option in MSA” [for the treatment of urinary incontinence].

* RBD (REM sleep behavior disorder) “is observed in 69-100% of systematic polysomnography recordings in MSA patients.”


All clinical trials investigating neuroprotective strategies — riluzole, minocycline, growth hormone, and estrogen (tested in MSA-C only) — have failed to show any disease-modifying benefits.  The authors advocated for further trials of growth hormone at higher doses and with more patients.


For neuroprotection, several drugs are being tested in MSA:  lithium, rasagiline, and intravenous immunoglobulins.  The lithium study is taking place in Italy.  The rasagiline (Azilect) trial has been going on in the US for a year or more.

The IVIg trial is going on at the University of Massachusetts (Peter Novak, MD, PhD is the principal investigator).  The authors say:  “a former clinical report [on IVIg] does not support any therapeutic effect in MSA.”

The authors mention rifampicin (“no human trial has been yet planned”) and NSAIDs (“the harmful adverse effects of long-term use may limit their evaluation until the development of safer drugs”).

For neurorestoration, three treatments are described:
* transplantation of fetal dopaminergic cells
* injection of bone marrow mesenchymal stem cells
* injection of granulocyte colony stimulating factor (GCSF)

In the “Future Therapies” section, the authors discuss the importance of researching unexplained sudden death in MSA. The authors say:  “Occurrence of sudden death is a common cause of mortality in MSA and may happen in the early stages while disability remains acceptable. The origin of sudden death in MSA remains unknown, although clinical reports, experimental and neuropathological evidence suggest that respiratory dysfunction may be the leading cause.”

The importance of the clinical diagnostic criteria and biomarkers is discussed.



Advanced MRI Techniques to Diagnose PSP

Philipps University in Marburg, Germany is very active in PSP research. This is a good review article of various advanced MRI techniques being used to help in the diagnosis of PSP. Many of the studies reviewed are related to a differential diagnosis between PSP, CBD, and MSA. MSA-P is described as the “most relevant clinical differential diagnosis” for PSP.

I learned a few things from this article:

1. For every study that shows good results from a technique, there is typically a later study showing not-as-good results.

2. All of the PSP imaging studies include patients with the Richardsons’s syndrome form of PSP. The clinical diagnostic criteria is based upon this “classic” form of PSP. So, these imaging studies really only apply to those with RS (or PSP-RS). Nearly half of those with PSP are excluded from these studies!

3. The “humming bird sign” (also known as the “penguin-silhouette sign”) for PSP on conventional MRI is described as “controversial.”

4. Voxel-based morphometry seems to be a good technique for differentiating PSP and CBD.


Journal of Neurology. 2010 Dec 22. [Epub ahead of print]

Magnetic resonance imaging in progressive supranuclear palsy.

Stamelou M, Knake S, Oertel WH, Höglinger GU.
Department of Neurology, Philipps University, Marburg, Germany.

Progressive supranuclear palsy (PSP) is a tauopathy, presenting clinically most often with a symmetrical akinetic-rigid syndrome, postural instability, supranuclear gaze palsy and frontal dementia.

In the absence of reliably validated biomarkers, the diagnosis of PSP in vivo is presently based on clinical criteria, which to date do not include supporting imaging findings, as is accepted for other neurodegenerative diseases.

However, data from conventional magnetic resonance imaging (MRI) and various advanced MRI techniques including magnetic resonance volumetry, voxel-based morphometry, diffusion-weighted and diffusion-tensor imaging, magnetization transfer imaging and proton resonance spectroscopy suggest that MRI can contribute valuable information for the differential diagnosis of PSP.

We review here the presently published literature concerning MRI in PSP and discuss the potential role of MRI in differentiating PSP from other parkinsonian syndromes.

PubMed ID#: 21181185 (see pubmed.gov for this abstract only)

Autonomic dysfunction in PSP (a few excerpts)

This sentence from the article summarizes what is known about dysautonomia and PSP: “Although autonomic dysfunction is accepted to be an important clinical symptom in MSA and PD patients, the role of autonomic dysfunction in progressive supranuclear palsy (PSP) patients is still quite unclear because of contradictory data on this issue.”

Here’s the abstract of an article and the (few) PSP-related excerpts.


Therapeutic Advances in Neurological Disorders. 2010 Jan;3(1):53-67.

Treatment of dysautonomia in extrapyramidal disorders.

Ziemssen T, Reichmann H.
ANF Laboratory, Department of Neurology, University Clinic Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.

Although extrapyramidal diseases are commonly thought to solely affect the extrapyramidal motor system, nonmotor symptoms such as behavioural abnormalities, dysautonomia, sleep disturbances and sensory dysfunctions are also frequently observed.

Autonomic dysfunction as an important clinical component of extrapyramidal disease (idiopathic Parkinson’s disease, multiple system atrophy, progressive supranuclear palsy, dementia with Lewy bodies) is often not formally assessed and thus frequently misdiagnosed.

Symptoms of autonomic dysfunction in general impact more on quality of life than motor symptoms. Appropriate symptom-oriented diagnosis and symptomatic treatment as part of an interdisciplinary approach can greatly benefit the patient.

Unfortunately, double-blind, randomized, controlled studies are scarce with the consequence that most recommendations are not based on the highest level of evidence.

This review elaborates a limited overview on the treatment of cardiovascular, gastrointestinal, urogenital and sudomotor autonomic dysfunction in various extrapyramidal syndromes.

PubMed ID#: 21180636 (see pubmed.gov for this abstract only)

Here are excerpts:

“As we have recently shown, 71% of PSP patients presented with pathologically small pupils in darkness at least in one eye in comparison to 32% MSA, 16% PD patients and 7% healthy controls. In an additional study, we could demonstrate that PSP patients frequently present with significant autonomic dysfunction. The parasympathetic cardiovascular system seems to be involved to a similar extent in PD and PSP patients, whereas sympathetic cardiovascular dysfunction is more frequent and severe in PD patients, but can also be found in PSP patients.”

“In PSP, significant pathologies in autonomic brainstem centres of PSP patients have already been demonstrated.”

Case Report of CBDer with Alien Hand Syndrome

This article on alien hand syndrome is available at no charge online. See:

http://www.plosone.org/article/info%3Ad … ne.0015010

It contains an interesting case report of someone diagnosed clinically with CBD on the basis of alien hand syndrome and declining response to levodopa (Sinemet). The case report describes in great detail how the features of this patient’s alien hand.

I’ve copied the (understandable) introduction and case report below. Further down is the abstract.


Here are excerpts:

“The alien hand syndrome (AHS) is a very rare movement disorder. Patients with AHS experience one of their limbs as alien, which acts autonomously and performs meaningful movements without being guided by the intention of the patient. The patients find themselves unable to stop the alien hand from reaching and grabbing objects without using their other hand. Patients are aware that the limb is still part of their body, but they report the feeling as if an external agent is controlling the limb. Consequently, they often describe it in the third person.”

“The phenomenon of AHS is complex and has various clinical manifestations, possibly related to different lesion sites. … The neural mechanisms of this movement disorder still remain unclear. It has been proposed that unwanted movements may arise because of a release of the primary motor cortex (M1) from conscious control by intentional planning systems.”

“Here we report data of a patient diagnosed with corticobasal degeneration and left hand AHS. His left hand showed relatively preserved volitional motor functions. Although there were spontaneous movements of the alien hand, we also had the possibility to elicit alien movements of the hand in a controlled way. We were able to evoke movements of the hand by slightly pushing the hand away from the patient’s body, which then resulted in a small movement into the opposite direction. This behavior is also known as “Gegenarbeiten”, meaning counteracting or working against. Using this reliable behavioural effect we conducted a functional magnetic resonance imaging (fMRI) study to further examine the neural correlates of unconscious or alien movements.”

“The study consisted out of two fMRI experiments. We first examined unwanted movements the way described above. The second experiment was a motor localizer scan to assess brain areas associated with conscious movements.”

Case report
“The 75-year-old right-handed gentleman (WH) was diagnosed with Parkinson’s syndrome five years ago. Within the last six months he reported a rapid loss of control of his left hand. It became much more stiffed and lost fine motor skills. When he walked down a stair he was not able to release the railway voluntary. Playing table tennis became awful. He was not able to serve because the left hand did not loose the grip of the ball. Dopaminergic medication was not as efficient as it used to be at the beginning of disease.”

“Clinically we saw an uplifted arm and reduced arm swing on the left side, strongly left sided rigidity and intermitted irregular myoclonus of the left arm. There were no signs of sensory deficit; reflexes were obtained symmetrical. Tracer studies (DAT Scan and IBZM Spect) revealed loss of presynaptic dopamine as well as a reduction of the post-synaptic dopaminergic receptor state. Structural MRI showed increased and asymmetrical ventricles. Based on the clinic and imaging we diagnosed an atypical Parkinsonian syndrome by possible corticobasal degeneration.”

“After increasing of dopaminergic medication rigidity improved but by now WH reported attacks of his left hand toward his body: the hand grabbed into his face and he could not loose the grip voluntary. When he used his right hand to release the left hand from his face the grip of the left hand became even stronger and he got scratched. He then controlled his hand during night covering up the left arm and keeping the bedside lamp turned on. Neuropsychological testing revealed intermanual conflict (the left hand did not let go objects), transitive dyspraxia using an object (i.e. hole-puncher), only slightly reduced tactile sensory, and tonic grasping. No mirror movements or synkinesis was observed.”

Here’s the abstract:

PLoS One. 2010 Dec 13;5(12):e15010.

Alien Hand Syndrome: Neural Correlates of Movements without Conscious Will.

Schaefer M, Heinze HJ, Galazky I.
Department of Neurology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.

BACKGROUND: The alien hand syndrome is a striking phenomenon characterized by purposeful and autonomous movements that are not voluntarily initiated. This study aimed to examine neural correlates of this rare neurological disorder in a patient with corticobasal degeneration and alien hand syndrome of the left hand.

METHODOLOGY/PRINCIPAL FINDINGS: We employed functional magnetic resonance imaging to investigate brain responses associated with unwanted movements in a case study. Results revealed that alien hand movements involved a network of brain activations including the primary motor cortex, premotor cortex, precuneus, and right inferior frontal gyrus. Conscious and voluntary movements of the alien hand elicited a similar network of brain responses but lacked an activation of the inferior frontal gyrus. The results demonstrate that alien and unwanted movements may engage similar brain networks than voluntary movements, but also imply different functional contributions of prefrontal areas. Since the inferior frontal gyrus was uniquely activated during alien movements, the results provide further support for a specific role of this brain region in inhibitory control over involuntary motor responses.

CONCLUSIONS/SIGNIFICANCE: We discuss the outcome of this study as providing evidence for a distributed neural network associated with unwanted movements in alien hand syndrome, including brain regions known to be related to movement execution and planning as well as areas that have been linked to inhibition control (inferior frontal gyrus) and experience of agency (precuneus).

PMID: 21179436