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.

 

Do you take an antidepressant medicine? – If the answer is yes, you should know about serotonin syndrome

Post written by Dr. Hadi Razjouyan, PGY III Internal Medicine Resident at Monmouth Medical Center

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Introduction

Serotonin syndrome is a rare and potentially life-threatening toxic state caused by excessive serotonergic activity in the nervous system.
It was first described in 1960s in studies of antidepressant medications and classically consists of a triad of mental status changes, abnormalities of muscle tone, and autonomic hyperactivity. However, clinical manifestations can be diverse and nonspecific, leading to misdiagnosis. Most reported cases are in patients using multiple serotonergic drugs, or who have had considerable exposure to a single serotonin-augmenting drug:

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Medications that may contribute to serotonin syndrome. (Ables AZ, Nagubilli R. Prevention, recognition, and management of serotonin syndrome. Am Fam Physician. 2010 May 1; 81(9):1139-42).

Epidemiologic features

It can happen in all age groups.
Its incidence is rising as the number and use of available serotonergic drugs are increased in clinical practice.

Mechanism

Potential mechanisms include increased serotonin synthesis or release; reduced serotonin uptake or metabolism; and direct serotonin receptor activation. Addition of drugs that inhibit the cytochromes (e.g. CYP 2D6 and/or 3A4) to therapeutic regimens of selective serotonin reuptake inhibitors (SSRIs) could be another mechanism.
The majority of cases are iatrogenic from synergistic medication use, although cases of self-poisoning with serotonergic agents also occur.

Diagnosis

Diagnosis can be made using the Hunter Serotonin Toxicity Criteria:

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Hunter’s rules for diagnosis of serotonin syndrome. (Ables AZ, Nagubilli R. Prevention, recognition, and management of serotonin syndrome. Am Fam Physician. 2010 May 1; 81(9):1139-42).

Symptoms can include anxiety, restlessness, confusion, sweating, muscle spasm or rigidity, rapid back and forth eye movement, shaking, fever, rapid heart rate, vomiting and diarrhea.

Symptoms can develop rapidly, within minutes of taking the drug, however, most patients present within couple of hours after a medication change or overdose.

Differential Diagnosis

The primary differential diagnosis of serotonin syndrome includes malignant hyperthermia, neuroleptic malignant syndrome, and anticholinergic syndrome. A complete history of the drugs or substances is helpful in ruling out these conditions. It is necessary to rule out initiation or change of dosage of dopaminergic drugs and other possibilities, such as infection, metabolic disorder, substance intoxication, or withdrawal. Other potential diagnoses include heat stroke, overdose of sympathomimetic drugs, delirium tremens, meningitis, encephalitis, thyroid storm, sepsis, or tetanus.

Treatment

First, Recognize the disease
Next, Stop the offending agent(s)
In the meantime, Supportive care (treat hyperthermia, autonomic dysfunction)
Benzodiazepines may be used to treat agitation and tremor.
Sometimes may administer serotonin antagonists, cyproheptadine or chlorpromazine.
Patients with moderate or severe cases of serotonin syndrome require hospitalization.
Critically ill patients may require neuromuscular paralysis, sedation, and intubation.

Prognosis

If serotonin syndrome is recognized and complications are managed appropriately, the prognosis is favorable. The severity of the disease can range from mild to life-threatening situation. However, most cases are mild and do not require hospitalization and generally resolve within 1 to 3 days by withdrawal of the offending agent and supportive care. Patients with moderate and severe cases may require hospitalization.

Prevention

Awareness of physicians and patients of the potential for toxicity from serotonergic drugs.
Always tell any doctor who prescribes you about all medications, herbal products and street drug you take.
When starting new medicine, have the pharmacist check for drug interaction
Avoiding the combined use of serotonin-augmenting drugs.
If you are already on medicine, do not take a new herbal or over-the-counter medicine without first checking with your doctor

Warning

If you have any symptoms of serotonin syndrome, please call your primary care physician and inform him/her of your suspicion before taking any steps.

Prosopagnosia

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Memo to Hollywood: Don’t take it personally if Brad Pitt has no memory of meeting you. The World War Z actor, 49, apparently has a difficult time recognizing people’s faces. In fact, he thinks he may suffer from prosopagnosia, or face blindness.

Speaking about the problem in his much-talked-about interview for Esquire magazine’s June/July issue, Pitt says that even if he’s had a “real conversation” with someone, he’ll forget what the person looks like almost as soon as he or she walks away. “So many people hate me because they think I’m disrespecting them,” the actor confesses to the mag.

Prosopagnosia is a rare brain disorder that impairs the ability to recognize faces without affecting other aspects of visual processing.  It is usually caused by a lesion affecting the fusiform gyrus such as stroke or head trauma, although there are even rarer congenital cases.

Perhaps the best known case is “Dr. P.” in Oliver Sacks‘ 1985 book The Man Who Mistook His Wife for a Hat:

Dr P. was a musician of distinction, well-known for many years as a singer, and then, at the local School of Music, as a teacher. It was here, in relation to his students, that certain strange problems were first observed. Sometimes a student would present himself, and Dr P. would not recognize him; or, specifically, would not recognize his face. The moment the student spoke, he would be recognized by his voice …….. At first these odd mistakes were laughed off as jokes, not least by Dr P. himself …….. His musical powers were as dazzling as ever; he did not feel ill—he had never felt better ……. The notion of there being ‘something the matter’ did not emerge until some three years later, when diabetes developed. Well aware that diabetes could affect his eyes, Dr P. consulted an ophthalmologist, who took a careful history and examined his eyes closely. ‘There’s nothing the matter with your eyes,’ the doctor concluded. ‘But there is trouble with the visual parts of your brain ……… ‘What seems to be the matter?’ I asked him at length. ‘Nothing that I know of,’ he replied with a smile, ‘but people seem to think there’s something wrong with my eyes.’ ‘But you don’t recognize any visual problems?’ ‘No, not directly, but I occasionally make mistakes.’

Dr P. illustrates another important symptom in cognitive neurology, anosagnosia. Dr P. is himself completely unaware that he has a problem, he compensates without even knowing it.  It is his wife and students that encouraged him to seek medical attention.

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.

Memory Loss? Better check that medication list!

Memory Loss

Alzheimer’s disease is the commonest cause of memory loss and dementia.   We do not yet fully understand what causes Alzheimer’s.  However, we do know that the neurotransmitter acetylcholine is important in brain processing and memory.  We also know that the acetylcholinesterase inhibitors (drugs like Aricept<donezepil> , Exelon <rivastigmine> and Razadyne <galantamine>), which inhibit the breakdown of acetylcholine, do provide a symptomatic improvement in affected patients.

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acetylcholine

 

It is also known that many drugs can cause and/or exacerbate memory loss in elderly patients:

Anticholinergics block the effects of acetylcholine, causing confusion. They also negate the beneficial effects of aceylcholinesterase inhibitors in Alzheimer’s patients.  These drugs are commonly prescribed for urinary frequency and urgency, and include Ditropan <oxybutynin> and Vesicare <solifenacin>.  The tricyclics, including Elavil <amitriptyline> and Pamelor <nortriptyline>, commonly prescribed for insomnia and headaches, also have anticholinergic properties.

Benzodiazepine drugs like Xanax <alprazolam> Restoril <temazepam> and Klonopin <clonazepam>, most commonly prescribed for anxiety and insomnia, can also cause and/or exacerbate memory loss because of drowsiness and inattention.

A recent study of Alzheimer’s patients living independently in the community showed that as many 17% were taking anticholinergic drug and almost 9% were taking benzodiazepines.

As if that wasn’t bad enough, 16% of patients were taking both an acetycholineresterase (cholinergic) and an anticholinergic drug at the same time!

The bottom line here is that you should always bring a complete and updated list of all your medications with you to doctors appointments!

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Click here for a link to the full article.

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

Diagnostic testing for Alzheimer’s?

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:
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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.

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With more effective new 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.

There has been interest in Apoprotein E (APOE) genotype and Alzheimer’s risk. APOE genes come in 3 types (2-4).  If you have 2 copies of  APOE4 (1-2% of the population)  you are 15 times more likely to develop Alzheimer’s than averages, and if you have one copy of APOE4 you have are 3 times more likely to develop Alzheimer’s than average.   Clearly, there is an association between APOE4 genoytpe and Alzheimer’s.  However, not every patient with APOE4 develops Alzheimer’s, and you can develop Alzheimer’s without APOE4, so APOE genotyping is not recommended as a diagnostic test.

The ratio of cerebrospinal fluid levels of beta-amyloid and tau proteins can be predictive for Alzheimer’s, but this test requires a lumbar puncture, and is inconclusive in many cases.

Magnetic resonance imaging (MRI) of the brain has shown selective atrophy of the hippocampus in patients with early Alzheimer’s (a) vs. normal elderly controls (b), and this technique has been proposed as a diagnostic test for Alzheimer’s, but requires special computerized imaging processing not available at most imaging centers.
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Fluorodeoxyglucose posititon emission tomogrpahy (FDG-PET) shows reduced metabolic activity (uptake of sugar) in the temporal and parietal lobes of patients with early Alzheimer’s (these regions are darker) vs. normal elderly controls (these regions are brighter), and this test is FDA approved, covered by Medicare, and widely available at imaging centers around the counrty:
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A recent study compared the results of MRI, FDG-PET and analysis of CSF biomarkers  in 97 MCI patients, to see which was best for predicting who would convert to Alzheimer’s first. During a mean follow-up of almost 3-years, 43 patients progressed to AD and 54 did not. Of the 3 tests, an abnormal FDG-PET was most predictive.

Before you all rush out and get your FDG-PET to see if you are high risk for Alzheimer’s, be warned that results may be unreliable when the test is performed at an inexperienced center. Data presented at this year’s American Academy of Neurology meeting showed that up to 2/3 of patients referred to a University dementia program had been misdiagnosed with Alzheimer’s dementia based on misread FDG-PET scans performed at community imaging centers.

The Amyvid™ (Florbetapir F 18) PET scan, which was FDA approved this year, actually quantifies the amount of amyloid plaque in affected patients’ brains (bright), and is probably a more promising new PET technique for predicting Alzheimer’s disease. However, this test is not yet covered by Medicare or other insurance covering, and costs between $1500 and $3000:

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In sum, the hope for the future is that with earlier and more accurate diagnosis, future treatments could target Alzheimer’s in its earliest stages, before irreversible brain damage or mental decline has occurred.  However, it is clear that none of the available diagnostic tests are perfect, and although promising, amyloid plaque PET scans are not yet covered by Medicare, so for now we mostly continue to make do with clinical diagnostic criteria.