George Huntington, On Chorea

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George Huntington (1850-1916) was a medical practitioner in Dutchess County New York.

His father and grandfather had both been doctors, and his family had lived on Long Island since 1797.

He gave his classic presentation, “On Chorea”, at the Meiga and Mason Academy of Medicine in Middleport Ohio in 1972, and this was subsequently published in the Medical and Surgical Reporter of Philadelphia on April 13, 1872.

This took place just one year after he graduated from his medical training at Columbia University.

He later explained his interest in the condition that now bears his name:

Over 50 years ago, in riding with my father on his rounds, I saw my first case of the “disorder”, which is the way the natives always referred to the dreaded disease.  I recall it as vividly as though it had just occurred but yesterday.  It made a most enduring impression on my boyish mind, an impression which was the very first impulse to my choosing chorea as my virgin contribution to the medical lore.  Driving with my father through a wooded road leading from East Hampton to Amagansett we suddenly came upon two women both bowing, twisting, grimacing.  I stared in wonderment, almost in fear.  What could it mean?  My father paused to speak with them and we passed on.  Then my Gamaliel-like instruction began; my medical instruction had its inception.  From this point on my interest in the disease has never wholly ceased.

Huntington’s disease (HD) is now know to be caused by a genetic mutation.  It is inherited in an autosomal dominant fashion, so that any child of an affected person typically has a 50% chance of inheriting the disease.  The mutation is a triplet repeat, so the genetics of HD lead to anticipation, a phenomenon whereby the disease may begin earlier and more severely in each successive generation.

HD can present at any age, but most often begins around 35-44 years with psychiatric disturbance such as depression or forgetfulness.  Neurological manifestations such as unsteady gait and the  jerky body movements (chorea) noted by George Huntington come later, followed by a progressive dementia.

Genetic testing is available, but pre-symptomatic testing for family members, who are at increased risk for the disease, is controversial since there is no treatment for HD.

Find out more about HD from the Huntington’s Disease Society of America.

Limbic Encephalitis

Post prepared by Precious Ramirez-Arao, Monmouth Medical Center PGY3

A 60 year-old female was found lethargic lying in a pool of feces by roommate.

EMS was called and was immediately brought to the hospital.

In the emergency department she had a witnessed generalized tonic-clonic seizure.

Her roommate relates she had episodes of confusion and short-term memory loss over the past few weeks.

She remained lethargic over the next 72 hours in the hospital.

48-hour EEG monitoring showed diffuse 2 to 3 Hz delta slowing with periodic lateralized epileptiform discharges emanating from the left frontal temporal region.

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T2 weighted image of the brain showed signal abnormality of the left mesial temporal lobe and the pulvinar with diffusion restriction in the left hippocampus consistent with limbic encephalitis.

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Limbic encephalitis (LE) is a subacute syndrome of seizures, personality change and cognitive dysfunction, typically evolving over days to weeks.

Autoimmune and paraneoplastic forms have been described. The most common neoplasms associated with paraneoplastic LE are lung cancer (usually small cell), thymoma, ovarian or testicular teratoma, breast cancer and Hodgkin lymphoma. The associated autoantibody depends on the tumor type. Lung cancer and thymomas are associated with anti-VGKC while ovarian or testicular teratomas are associated with antiNMDA antibodies.

Neurologic symptoms can precede oncologic diagnosis for several months to years and initial CT scans are typically unrevealing.

Nevertheless, prompt and thorough evaluation for malignancy including PET and CT scan of the chest, abdomen and pelvis should be initiated. Symptomatic treatment includes corticosteroids, plasmapharesis and intravenous immune globulin.

 

CJD – A downward spiral of depression into dementia and death

Post prepared by Dr Mariam Kemal, PGY-3 (Internal medicine), Monmouth Medical Center

Case History:

This 66 year old female had been living alone independently.  However, her neighbors became concerned when she had seemed more withdrawn than usual for about a month, and then stopped going out of the house and paying her utility bills.  Ultimately, one of them  noticed a dead cat in the house, and immediately called patient’s son who lived out-of- state, and he requested that she be admitted hospital.  At the time of her initial evaluation, she was depressed and had a urinary tract infection.  She was treated for the infection, and when she expressed suicidal ideation she was transferred to the psychiatric unit. While she was on the psychiatric unit she developed slurred speech, right arm clumsiness and and unsteady gait.   She was transferred back to the medical service and underwent a diagnostic evaluation.   Her brain MRI showed diffusion restriction in left putamen and caudate nucleus. Her EEG was also abnormal.  Her spinal fluid was ultimately positive for presence of Protein 14-3-3, indicating Creutzfeldt –Jacob disease.  She has progressed to a very debilitated state in just two week – Her speech was limited to a few intermittent slurred words, she was not able to walk and had diffuse myoclonic jerks. She was transferred to hospice.  Her brain was sent for autopsy to The National Prion Disease Pathology Surveillance Center which confirmed the presence of abnormal protease resistant prion protein (PrPSc), commonly identified as PrP 27-30, confirming the diagnosis of sporadic Creutzfeldt-Jacob disease.
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What is Creutzfeldt-Jakob disease?

Creutzfeldt-Jakob disease (“CJD”) is a rare brain disorder that causes rapidly progressive dementia with muscle twitching, leading to death within several months.

CJD usually affects older adults.


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It is caused by abnormal proteins called “prions” that infect the brain.

“Classic” CJD has been transmitted by infected organs during transplant surgery.

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“Variant” CJD (“mad cow disease”) has been transmitted by infected beef.

In addition to dementia and myoclonus, many CJD patients also exhibit behavioral change (including depression), balance problems, and sleep disturbance.

It is the presence of these unusual clinical features, and the rapid rate of clinical deterioration, that distinguish CJD from other dementias like Alzheimer’s disease.

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How is Creutzfeldt-Jakob disease diagnosed?

MRI imaging of the brain can show characteristic findings:

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The electroencephalogram (EEG) can show periodic complexes:

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The spinal fluid can show the 14-3-3 protein.

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However, a brain biopsy demonstrating spongiform change is still necessary to confirm the diagnosis in many cases:

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How is Creutzfeldt-Jakob disease treated?

Sadly, there are no treatments that can stop or cure the disease, and all affected patients die within several months.

Playing video games improves aging brain function

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We know from previous blogs that there is an escalating incidence of dementia.

We know that the strongest risk factor for developing dementia is old age.

However, we also know that dementia is not an inevitable consequence of old age.

Why do some older adults get dementia and others don’t?

Instead of looking for dementia risk factors, some researchers have turned the tables on this question, and looking at things that might be protective, reduce the likelihood of age related dementia.

This could translate into activities or behaviors  anyone could use to lower their dementia risk.

For example, regular exercise and social stimulation have been shown to lower dementia risk.

New research published in Nature looks at the relationship between brain function and video games performance in aging adults.

The investigators designed a game called NeuroRacer in which the player drives a virtual car along a track and must respond to the appearance of specific road signs by pressing a button. The trick is that the player has to attend to one type of sign only, ignore the others, and continue “driving” all the while.  Then, as the participants learned the game and improved their scores, the game gets harder and harder.

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The study had 46 participants, aged 60-85, engage in 12 hours of the training over the course of a month. During that time, they vastly improved their performance, and at the end of that study they played just as well as 20-year olds.  Furthermore, these gains in brain function persisted for more than 6-months, and more importantly weren’t limited to gaming – study participants also showed improved attention and working memory.

Click here to find out more.

New cure for dementia?

Probably not.

However, this study does demonstrate that older adults can still re-shape their brain connections, and also re-affirms that the old adage, if you don’t use it you lose it, also includes brain function!
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Maybe it’s time to start playing chess or BrainAge regularly?

Robots helping dementia patients live independently

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We have already blogged about the Alzheimer’s epidemic.

There are already more than 5 million affected patients, and Alzheimer’s is now the 6th leading cause of death in the US.

 Caregivers spend an average of 70 to 100 hours per week providing care to an affected family member.

Alzheimer’s patients cope better in familiar surroundings.   They get worse more quickly when socially isolated.   It is more cost effective to keep affected patients at home for as long as possible, avoiding expensive residential care.

However, many caregivers need to go to work, and cannot be at home with their affected family member 24/7.

New programs using robots to provide social contact and even supervision for Alzheimer’s patients on their own at home may provide a cost effective solution to this problem.

Robot “pets” have already been used to encourage emotional behaviors for socially isolated dementia patients.

Scotland’s National Health Service  is putting robots into the rural homes of some dementia patients in a pilot scheme to help them to continue to live independently.

A relative or carer – potentially hundreds of miles away – can drive the machine around the house to check that everything is all right. The pair can also have a chat through a two-way video call system.

The robots are about 5ft tall, on wheels and have a TV screen instead of a head.

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A relative or carer can connect to the robot with a computer from any location. Their face will appear on the screen allowing them to chat to the other person.

The operator can also drive the robot around the house to check that medication is being taken and that food is being eaten.

Find out more about this innovative program.

Ongoing studies are showing that robots can provide affordable personalized cognitive stimulation, motivation and companionship to dementia patients, and potentially keep them living independently longer.

Find out more about caring for Alzheimer’s patients at home.

Another reason to take snoring seriously! Sleep apnea linked to strokes.

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Sleep apnea, the disorder that causes a person to stop breathing suddenly while sleeping, is already known to increase the risk of high blood pressure, heart failure, and daytime sleepiness.

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A new study suggests that the sleep disorder is also linked with small brain lesions and a symptomless form of stroke, known as silent stroke.

In the study, 56 men and women ( aged 44 to 75 years) who’d had a recent stroke or TIA underwent overnight polysomnograms.  91% had sleep apnea.

Furthermore, having more than five episodes of sleep apnea in a night was linked with having multiple extra “silent strokes” on their brain imaging studies.

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Silent strokes don’t cause any symptoms as they occur, so a person typically doesn’t know he or she has suffered one, but they can eventually lead to memory loss and difficulties with walking, as their effects accumulate over the years.”

Yet another reason to take the on-line sleepiness test, and if your score is >10 see a sleep specialist and/or get an overnight polysomnogram in a certified sleep laboratory.

New Brain Imaging for Alzheimer’s Disease

Amyloid proteins in normal brains (left) and abnormal ones (right) visualized with GE Healthcare’s PET tracer flutemetamol.

Alzheimer’s disease is the commonest cause of dementia, and as the population is aging, it’s prevalence is increasing.

Alzheimer’s disease presently affects 5 million Americans aged 65 or older.  Without a major medical breakthrough, by 2025 this number is expected to have risen to 7 million, and by 2050 it could reach 14 million

The costs of caring for Alzheimer’s patients is also increasing, estimated at $203 billion in 2013, and $1.2 trillion by 2050,  including a 500% increase in combined Medicare and Medicaid spending.

Clearly, finding that major therapeutic breakthrough is crucial, and had been identified as a priority by the Obama Administration.

The first barrier to starting any clinical trial is accurate case ascertainment – we have to be able to correctly identify early Alzheimer’s patients for new experimental treatments.

So far, the only definitive test for Alzheimer’s disease is examination of brain tissue (usually obtained at autopsy) for identification of the characteristic pathologic changes of Amyloid paque and Neurofibrillary tangles:

Alzheimer’s disease is usually diagnosed based on  clinical criteria, but many patients diagnosed this way are later found to have other causes of dementia when their brains are examined at autopsy, in other words they were misdiagnosed as Alzheimer’s.

With more research trials and potential new effective therapies on the horizon, it is going to become more important to establish a diagnosis of Alzheimer’s more accurately and earlier, perhaps even pre-symptomatically (i.e. mild cognitive impairment or MCI), so that treatment to reverse the build up of plaque and tangles is more likely to be effective.

New positron emission tomography (PET) technology can actually quantify the amount of amyloid in affected patients’ brains.  A recently published small study showed a very high correlation between amyloid identified on PET scans and amyloid plaque demonstrated in brain biopsy specimens taken from demented patients.

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These tests are going to be very important for research studies.

However, don’t rush to your private doctor’s office asking to have one done just yet!

Although approved by the FDA, these test are not yet covered by Medicare or other insurance covering, and cost between $1500 and $3000.

Furthermore, these are new tests, and their role in clinical neurology practice in still unclear.

Some of these issues were recently clarified in a report by the Amyloid Imaging Taskforce convened by the Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging:

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This taskforce concluded that a Amyloid PET scan is indicated for:

Progressive memory impairment or dementia with atypical features, where a positive PET would indicate definite Alzheimer’s, and a negative scan would rule it out and lead to further testing for other possible causes.

Younger patients (aged 50-65) with suspected Alzheimer’s, in whom making a definitive diagnosis is crucial for log term planning and future medical decision making.

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The taskforce concluded that a Amyloid PET scan is unnecessary and/or unhelpful for:

Patients with typical Alzheimer’s disease,

Determining the severity of dementia,

Asymptomatic patients with a family history of dementia or positive apolipoprotein E4 status,

Patients who complain of memory loss but have no objective findings,

Testing purely for medico-legal, disability, insurance or employment related issues.

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Find out more:

Click here to find out more about Memory loss, Mild Cognitive Impairment and Alzheimer’s.

Click here to find out more about diagnosing Alzheimer’s.

Links to the Alzheimer’s Association, Alzheimer’s Foundation of America and CDC Healthy Brain Initiative

Prions: Could these zombie-like proteins be responsible for causing the most common form of Dementia?

Post courtesy of Dr Michael Chan, PGY2 Medicine Resident, Monmouth Medical Center.

ImageAs far as infectious diseases go, prions are a relatively new discovery. While humanity has known about parasites since ancient times, bacteria since the 1660s, and viruses since 1898, the first prion protein was only isolated in 1984. Since then, we’ve gotten to know a little more about these proteins, and we’ve found that its novelty is by no means the most interesting thing about it.
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So what are prions?

Prions are basically the misfolded version of a normal protein, PRP or Protease resistant protein. In the vast majority of instances, the body has mechanisms that adequately deal with misshapen proteins. These get tagged for destruction by antibodies or intracellularly by specific molecular signals and lysosomes. However, prions are not your run of the mill abnormal protein. They are resistant to degradation and exhibit the unique characteristic of causing other normal PRP proteins to misfold, which in turn causes even more misfolding. In this sense, prions behave like protein zombies.

And like zombies, they don’t begin their existence as malevolent molecules either. Indeed this is one of the characteristics which differentiate prions from most other infectious agents such as bacteria or viruses, majority of which are inherently disease causing. Studies have shown that normal PRP has functions in sleep, memory, neural development, and possibly the maintenance of the myelin sheath that surrounds neurons. Indeed, a mutation of PRP causes a very rare disease (only 8 cases have been diagnosed as of 2005) called Familial Fatal Insomnia which leads to progressively worse insomnia leading to dementia, hallucinations, and eventually death.

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Yes, complete inability to sleep kills.


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The connection to Alzheimer’s

Until recently, the most notable examples of prion diseases in humans are Creutzfeldt-Jakob disease and Kuru. Although spontaneous CJD does rarely occur, both these diseases are usually caused by ingestion of infected material, ie, eating infected meat (beef) for CJD and cannibalism for Kuru. Both exhibit progressive dementia, memory problems, gait and movement disturbances, and other unusual symptoms like uncontrolled laughter, hallucinations, and personality changes. Pathologically, the disease causes patients’ brains to develop tiny holes, much like a sponge. Thus the name for the disease in cows, Bovine Spongiform Encephalopathy, literally translates “cow spongy brain disease”.

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Brain of a CJD patient with multiple “holes”

However, over the past 5 years, research has shown that at least one major protein known to accumulate in Alzheimers disease, amyloid beta, behaves much like prions. Research conducted at UCSF showed that when mice brains are seeded with amyloid beta, after 300 days, the amyloid plaque is found all over the brain, not just the area seeded. A Yale university study in 2009 also showed that prion proteins of CJD interact with amyloid beta in some way to cause the dysfunction in neurons which lead to Alzheimer’s. Although there is no evidence that AD is contagious, it may open up new therapeutic avenues to think of its pathology as like that of prion diseases.

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Amyloid plaques and Neurofibrillary tangles in Alzheimer’s disease

How Alzheimer’s spreads in the brain.

Indeed, last year, a British team accidentally stumbled on a discovery that antibodies designed to treat CJD were found to block Alzheimer’s disease. These antibodies, ICSM-35 and ICSM-18, blocked the interaction between the PRP prion and amyloid beta in mice brains, resulting in decreased hippocampal nerve cell disruption. ICSM-18 and ICSM-35 are presently undergoing human trials for the treatment of CJD. With this finding, it’s likely they will be tested for Alzheimer’s as well, and we, for the first time, might have an effective and specific treatment for this disease which affects roughly 20 million people worldwide.

To see just how significant any form of treatment might be, check out the facts and figures provided by http://www.alz.org below:

References:

Jucker M, Walker LC. Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. 2011:70, 532–540.

Prusiner SB: A unifying role for prions in neurodegenerative diseases. 2012:336, 1511–1513.

Freir DB, Nicoll AJ, Klyubin I et alInteraction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sitesNature Communications, June 7 2011

Cortical Basal Ganglionic Degeneration

This post is provided courtesy of K. T. Weber, Drexel University College of Medicine Class of 2013:

Cortical Basal Ganglionic Degeneration (CBGD) is a rare neurodegenerative disorder that affects both the cerebral cortex and basal ganglia, resulting in a rapidly progressive and devastating combination of movement disorder and dementia.

CBGD shares features with other, more common, neurologic illnesses: Like Parkinson’s disease, it often presents asymmetrically, with a tremor, rigidity or dystonia. Like Alzheimer’s disease, there are subtle early cognitive and behavioral changes. However, CBGD progresses more rapidly than these other conditions, ultimately involving the other limbs and causing more cognitive dysfunction. Furthermore the Parkinsonian features of CBGD tend not to respond to dopaminergic medications.

Patient with CBGD, showing rigidity, paucity of movement, and myoclonic jerks in the left arm

One of the distinctive features of CBGD is alien limb phenomenon. Alien limb is characterized by a “loss of agency” in the affected limb. The patient is able to feel sensation in the limb, and movement is preserved, but the patient no longer recognizes the limb as his or her own. This same aLien limb or (more commonly an alien hand) syndrome can also result from separation or dysregulation between the brain’s hemispheres, for example after surgical division of the corpus callosum for severe epilepsy.

Patient with CBGD, showing rigidity, dystonic posturing and Alien limb phenomenon (the patient said the left arm was “moving on it’s own”)

In popular media, Dr. Strangelove struggled with an alien limb that was no longer under his control.

However, the movement disorder is only half the story, and symptoms also include behavioral changes, cognitive decline, and abnormal speech. Behavioral changes may involve personality changes, mood problems, like depression and agitation, or the development of new compulsive behaviors. Language problems often begin with difficulty finding words (“anomia“) and may progress to an inability to speak.

The disorder is currently classified as a “tauopathy” in the same family of diseases as Pick’s disease, progressive supranuclear palsy (PSP), and even Alzheimer’s disease.

Although the diagnosis of CBGD is mostly clinical, there are some diagnostic tests that may helpful, such as asymmetric cortical atrophy on brain imaging or asymmetric slowing on EEG.

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MRI showing right hemispheric atrophy

EEG showing L hemispheric slowing

EEG showing R hemispheric slowing

However, a definitive diagnosis can only be made by examining brain tissue at autopsy.

Pathology of CBGD (A) In the neocortex, ballooned neurons with displaced nuclei and pale cytoplasm (arrow) are common. (B) Immunostaining detects diffuse accumulations of tau protein in a peripheral distribution in a ballooned neuron. (C) Neuron loss and gliosis are often severe in deep nuclei, including the substantia nigra. (D) Diffuse cytoplasmic accumulation of tau protein is seen in neurons of various sizes in the neocortex (arrow, panel D), nucleus basalis (E) and striatum (F), as well as other locations. (Panels A,C from sections stained with H and E, remaining panels from sections immunostained with primary antibodies to tau).

Pathology of CBGD (A) In the neocortex, ballooned neurons with displaced nuclei and pale cytoplasm (arrow) are common. (B) Immunostaining detects diffuse accumulations of tau protein in a peripheral distribution in a ballooned neuron. (C) Neuron loss and gliosis are often severe in deep nuclei, including the substantia nigra. (D) Diffuse cytoplasmic accumulation of tau protein is seen in neurons of various sizes in the neocortex (arrow, panel D), nucleus basalis (E) and striatum (F), as well as other locations. (Panels A,C from sections stained with H and E, remaining panels from sections immunostained with primary antibodies to tau).

There are no effective treatments for CBGD, and therapy is aimed at symptomatic relief. The movement disorder, unlike Parkinson’s disease, does NOT respond well to levadopa, so other medications are used to help control the tremors and stiffness in the limbs. Beta blockers (propanolol), benzodiazepines (clonazepam), and gabapentin may have some efficacy in controlling tremor. Baclofen (a GABA agonist) is used to treat spasticity of many different causes and may provide some relief to patients with CBGD. Additionally, the depression, anxiety and agitation due to degeneration the cortical areas of the brain are critical therapeutic targets, and often respond to the first line therapies, including SSRIs and other antidepressants.

In summary, CBGD is a rare, progressive neurodegenerative disease. Recognizing the constellation of symptoms of CBGD from its more common cousins helps patients by identifying all elements of the disease progression, and can improve quality of life by addressing each of the related symptoms.