The Neurology of Fright Night

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Everybody knows October is the month of horror movies, haunted houses and Halloween parades.

But, have you ever wondered why we find fear so exciting?

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It turns out that distress and delight are closely related – both are mediated by same deep brain circuit known as the Limbic System.  This system is intimately associated with human emotional behaviors and memory.

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The limbic system is highly interconnected with the brain’s pleasure center, responsible for sexual arousal and the “high” derived from recreational drug use,  The Kluver-Bucy Syndrome, caused by bilateral limbic lesioning, includes heightened sex drive and/or a tendency to seek sexual stimulation from unusual or inappropriate objects.

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Animals with surgical lesions to the limbic system develop abnormal sexual behaviors

Recent studies  have shown these same circuits are responsible for associating fear with memories and the emotional responses that result from triggering those memories.  Patients affected by the extremely rare genetic condition  Urbach-Wiethe disease can develop selective atrophy of the amygdala, becoming fearless, with little or no emotional response to horror films, large spiders or snakes.

This probably explains why horror movies are most popular with younger audiences, mostly teens and twenty-somethings with raging hormones looking for intense experiences:
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So, we go to horror movies to be scared, triggering deep seated pleasure centers within the brain, knowing that we’re actually quite safe from harm, because in an hour or two we’re going to walk out of the theater with no permanent harm done.

Narcolep…… ZZZZZZ

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Posted by Ayushi Desai, MSIV, Drexel University College of Medicine

Fatigue. I imagine it ranks highly among the most unifying experiences shared by Americans in this day and age. Amidst torturously busy schedules, sleep deprivation, taxes, and the unyielding restraints of a day comprised of only 24 hours, I can blame no one for being tired, just, ALL the time.

Sometimes I wonder whether those of us who are affected by this obnoxious, unremitting daily fatigue secretly have undiagnosed narcolepsy.

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Let’s be serious — how many of us can really sit through some performance in a dark theater without catching even a few Zs? And aren’t we all jealous of kindergarteners, whose workday includes a mandatory scheduled nap?

I’m embellishing, of course, but I may not be too far off. As we delve further into the study of sleep, we are starting to realize that narcolepsy is, indeed, hopelessly underdiagnosed.

Down to the basics, narcolepsy is a sleep disorder characterized by the early intrusion of REM in the sleep cycle, which eventually translates into excessive daytime fatigue and resultant episodes of irrepressible need to sleep.

How this happens is slightly complicated and represents an unfortunately vicious cycle:

In a nutshell, restful sleep occurs during stages 3 and 4 — at this time brain waves are slow, and we are allowed to recuperate in so-called “deep sleep.”  In contrast, brain waves seen on polysomnography during the REM stage are fast and essentially the same as those seen when someone is awake with their eyes closed… Which means that in REM, our brains act as if we are awake. It becomes easier, then, to imagine how (8 hours or not) a night spent predominantly in REM equates to extremely poor sleep quality. This poor sleep quality in a narcoleptic leads to the aforementioned characteristic excessive daytime fatigue, and suddenly, we have a person who is almost involuntarily taking REM naps and doing other sorts of REM things throughout the day, everyday.

These other REM things? During REM, we have “awake” brains, we have dreams, and our bodies lose all muscle tone (USUALLY rendering us completely unable to move). Those suffering from narcolepsy manifest the latter two during the day and undergo peculiar experiences: CataplexyHypnaGOgic Hallucinations (vivid dream-like hallucinations experienced while GOing to sleep), and the ever-terrifying Sleep Paralysis.

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Sleep Paralysis (yikes)

As we can imagine, these key sleep pathologies are likely a source of significant embarrassment and suboptimal quality of life in sufferers of narcolepsy.

So how do we treat it? The most important aspect is, of course, in diagnosing it! Which means recognizing when a patient might have it — a ballgame in which it seems we have been falling behind. Unless the disease process is frank and severe, it may be difficult for a narcoleptic patient to recognize the characteristic “buzzword” signs and symptoms (or even that there may actually be something underlying their round-the-clock tiredness). So perhaps it might be prudent to consider the diagnosis of narcolepsy in a person experiencing chronic daily fatigue, with the first step being simply to ask if our perpetually half-awake patient sometimes experiences symptoms that sound somewhat like cataplexy, hypnagogic hallucinations, or sleep paralysis. We can throw in an Epworth Sleepiness Scale to get a baseline of how terribly the tiredness affects activities of daily living, and after that, sleep studies are the way to go.

Besides the obvious, though, traditional treatments are aimed largely at helping to improve symptoms (as we’ve not yet struck the gold in finding a cure). CNS stimulants such as methylphenidate (Ritalin), amphetamine (Adderall), modafinil (Provigil), and armodafinil (Nuvigil) have achieved moderate success in eliminating the chronic fatigue. We’ve even used tricyclic antidepressants (clomipramine/imipramine) and other medications with anticholinergic side effects to alleviate cataplexy. However, I am most intrigued by the eventual advent of an orexin-receptor agonist. While we aren’t yet quite sure how exactly narcolepsy develops, it is widely believed that the neurotransmitter orexin (aka hypocretin) is deficient in narcoleptics. It is hypothesized that finding a way to upregulate the production of orexin in narcoleptic patients may lead to disease remission without all the nasty side effects of medications.

So… are most of us realistically secret narcolepsy victims? Probably not. But here’s a link to the Epworth Sleepiness Scale in case you want to assess how well you’ve fared in the fight against fatigue.

Based on my results, I’ve likely been asleep during this entire blogging experience.

Ticked off at Neuro Lyme Disease

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Post Prepared by Dr. Mohammed Nasir Yousuf Shah,

PGY-3 Internal Medicine, Monmouth Medical Center

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Case Report

A 36 year old otherwise healthy male noticed a facial droop when he woke up one morning and looked in the mirror. There was associated pain at the angle of the right jaw like a “toothache” and also numbness to along right side of tongue.

He had been experiencing occipital headache with neck pain for the previous 3 days.  The headache was throbbing in character, worse when laying his head back on a pillow. He denied any other neurological symptoms.

Further questioning revealed that 2 months ago he suffered 2 tick bites on his thigh; but did not experience any fever, chills or rash at that time.

Physical examination showed prominent facial droop in the lower half of the right side of the face with inability to puff the cheek on the right and some mild weakness in the upper half of the right side of the face with reduced wrinkling of the forehead. He also had impaired taste sensation along the right side of the tongue. The rest of the neurological exam was normal.

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His brain imaging study was normal, but CSF analysis revealed low glucose and elevated protein and pleocytosis with increased lymphocytes indicating a diagnosis of aseptic meningitis.

Given the history of tick bite 2 months prior and the characteristic 7th cranial nerve palsy, a presumptive diagnosis of neurological Lyme disease was made and the patient was started on intravenous ceftriaxone.

Meanwhile Lyme serologies and antibodies to B. Burgdorferi in CSF were tested and the patient was discharged on IV ceftriaxone.

The results of the serological and CSF testing returned positive for Lyme disease a few days later.

Discussion

Background:

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Borrelia burgdorferi is the organism responsible for Lyme disease which affects several organ systems and is transmitted by the bite of infected ticks belonging to the genus Ixodes.

Skin, the site of inoculation, is involved in 80 percent or more of infected individuals followed by joint involvement.

The third most common site is the nervous system, which is involved in 10 to 15 percent.

Clinical manifestations:

Nervous system involvement begins during early disseminated Lyme disease, when spread of the spirochetes can result in meningeal seeding. Acute neurologic involvement usually occurs weeks to several months after the tick bite and may be the first manifestation of Lyme disease. In contrast, certain neurologic problems, such as a more indolent, disseminated polyneuropathy, may develop months to a few years after the initial infection.

Lymphocytic meningitis, cranial neuropathy and radiculoneuritis constitute the classic triad of acute, early neurologic Lyme disease.

Clinical findings of nervous system Lyme disease are divided into disorders of the peripheral vs. central nervous system.

Peripheral nervous system

In early disease, two peripheral nerve manifestations are particularly common and form part of the classic triad.

Cranial neuropathies: These tend to occur early in infection and are usually abrupt in onset. Virtually any cranial nerve can be involved, but the seventh (facial) is by far the most common, occurring in 8 percent of cases.

Since facial nerve palsy is uncommon in young children, Lyme disease should be strongly considered as the cause of facial nerve palsy affecting a child who has been in an endemic area. In adults in endemic areas, during spring through fall, a significant percentage of facial nerve palsies are attributable to Lyme disease. Involvement can be bilateral and because bilateral facial nerve palsies are generally uncommon, Lyme disease should be suspected in patients with potential recent exposure.

Radiculoneuritis: This is reported in 3 percent of cases of Lyme disease and is often missed. It can mimic a mechanical radiculopathy (eg, sciatica) with radicular pain in one or several dermatomes, accompanied by corresponding sensory, motor and reflex changes. This disorder should be considered in patients in endemic areas presenting in spring through autumn with severe limb or truncal radicular pain without an apparent mechanical precipitant.

Central nervous system

The most common form of CNS involvement is lymphocytic meningitis. Rarely, inflammation of the brain and/or spinal cord parenchyma (an encephalomyelitis) can occur.

Meningitis: Lymphocytic meningitis, alone or in combination with cranial nerve or spinal nerve root involvement, represents the most common form of central nervous system involvement. Clinically it is indistinguishable from viral meningitis, with headache, fever, other systemic symptoms, photosensitivity, and neck stiffness.

Encephalopathy: Patients may experience fatigue, cognitive slowing, and memory difficulty. However, these symptoms are nonspecific and are frequent concomitants of many inflammatory disorders.

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Diagnosis

The diagnosis of nervous system Lyme disease rests on three elements:

  • Since the disease is transmitted exclusively by bites of Ixodes ticks, there must be the possibility of exposure
  • The clinical disorder should include objective evidence of nervous system Lyme disease
  • Laboratory testing (positive two tier Lyme serologies with or without positive CSF Lyme antibodies)

Serologic testing: With the exception of the first 4 to 6 weeks of infection, when the specific immune response may not yet have developed sufficiently to provide a measurable antibody response, serologic testing for antibodies to B. burgdorferi is highly sensitive and specific for the diagnosis of Lyme disease and thus in such cases the absence of detectable antibodies in the serum is strong evidence against the diagnosis.

The two-tier strategy, which is recommended by the US Centers for Disease Control and Prevention, uses a sensitive enzyme-linked immunosorbent assay (ELISA) followed by a Western blot. If the ELISA is positive or equivocal, then the same serum sample should be tested by Western blot. If the ELISA is negative, the sample needs no further testing.

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CSF analysis: In Lyme meningitis the CSF typically has a modest pleocytosis of up to several hundred lymphocytes and/or monocytes per microL. The CSF protein concentration is usually moderately elevated, and is typically no greater than about 200 to 300 mg/dL (2 to 3 g/L).

CSF antibodies: The sensitivity for testing the CSF for intrathecal production of antibodies to B. burgdorferi is poor and a negative test does not exclude CNS Lyme disease if clinical circumstances support the diagnosis.

Imaging:  Since Lyme encephalomyelitis is so rare, MRI of the brain and spine is only rarely abnormal in Lyme disease. When present, the MRI reveals areas of increased signal on T2 and FLAIR sequences.

Electrophysiologic testing: In patients with a peripheral neuropathy, electrophysiologic assessment (electromyography and nerve conduction studies) can be helpful and typically reveal findings consistent with a patchy axonal polyneuropathy (ie, a mononeuropathy multiplex).

Approach to diagnostic testing

Assessment of the patient with possible nervous system Lyme disease must be tailored to the specific presentation. It can be sufficient to simply administer oral antibiotics to patients with recent exposure, a positive serology and an appropriate clinical syndrome.  However a lumbar puncture may still be necessary if there is a strong clinical suspicion of meningitis, primarily to exclude other, potentially more dangerous pathogens.

CSF studies should include cell count, protein and glucose concentrations, and gram stain and bacterial cultures.

CSF and serum should both be sent for anti-B. burgdorferi antibodies and VDRL should be measured.

Neuroimaging, preferably by MRI, should precede the lumbar puncture if the patient has clinical evidence of parenchymal brain involvement. Depending on the findings on imaging,

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Treatment

Lyme meningitis is generally self-limited, even without treatment.

Oral doxycycline is effective for early disseminated Lyme disease with neurologic manifestations, including meningitis. Doxycycline has moderately good penetration into the CSF and has oral bioavailability >98 percent, making oral dosing equivalent to intravenous dosing.

Lyme patients with isolated facial nerve palsy are treated with oral doxycycline (100 mg orally twice daily). Antibiotic therapy does not have a major impact on the outcome of facial palsy. However, treatment is recommended to prevent other complications of disseminated Lyme disease. The majority of patients with Lyme facial palsy recover. The prognosis is worse for patients with bilateral facial palsy compared with unilateral palsy.

Lyme patients with radiculoneuritis, meningitis or other neurologic complications are typically treated using parenteral therapy with ceftriaxone (2 g intravenously once daily) for at least 14 days.

There are no diagnostic tests that can determine clearance of infection or predict the success of therapy. Resolution of neurological symptoms is often delayed and persistence of symptoms is not necessarily indicative of treatment failure.

Treatment recommendations are the same for both the early and late neurologic manifestations of Lyme disease.

 

Synesthesia: Boy that word tastes good, huh?

Posted by Deepak H. Singh, MS IV Drexel University College of Medicine

Putting my intense desire to describe the mauve affect of a patient, or the loud shirt that a colleague is wearing aside, synesthesia is a fascinating phenomenon in which two or more senses in certain individuals are overlapped, meaning that the experience of both senses is connected in someway.

This has been described in terms of various different senses including forms such as grapheme-color synesthesia in which letters and numbers are perceived as colors, chromesthesia in which sounds are perceived as color, or lexical-gustatory synesthesia in which individual words are perceived as taste sensations in the mouth as alluded to in the title of this blog post.

Click here to find out more about word-taste synesthesia from the BBC.

Some notable supposed synesthetes to perhaps pique your interest are inventor Nikola Tesla, Muscians Eddie Van Halen, Billy Joel, Pharell Williams, and Actor Geoffrey Rush, among others.

This condition has long perplexed neuroscientists who are only touching the surface of the unique neural pathways that may account for the various experiences described by synesthetes.

One school of thought that has gained some traction is the concept of cross-activation, which is made possible by a failure of the physiological process of “synaptic pruning” that occurs in all of our brains during the initial developmental stages.  Synaptic pruning refers to a series of regulatory processes during which various axonal networks that were functional in one stage of development are outcompeted and subsequently eliminated as other synaptic connections become more frequently used as maturation occurs. In synesthetes  it is hypothesized that certain of these connections fail to regress leading to atypical connections between two sensory regions of the brain, thereby opening the door for some pretty vivid sensorial experiences. This, however, has only really held up for sensory regions directly adjacent to one another, as was demonstrated by fMRI studies showing significant brain activity in both the auditory cortex and the fusiform gyrus (responsible for color perception) in synesthetes while no such congruous activity was seen in age-matched controls. Similarly, in one study on lexical-gustatory synesthesia, the lateral sulcus (responsible for taste processing) was activated simultaneously with the auditory cortex in synesthetes.

Another prevailing hypothesis is the concept of “disinhibited feedback“. Normally, signals are travelling in both directions between the primary sensory regions of the brain and those that are involved in organizing that information, and feedback (both positive and negative) is constantly occurring to reconcile all of the different sensory input. If this balance were disrupted, however, it would be possible for signals encountered in the later stage of processing to influence those that were encountered earlier, resulting in the overlapping sensations that are perceived by synesthetes. This, too, may make more sense of the case reports in which individuals with temporal lobe epilepsy or individuals who have just experienced head trauma or stroke to “acquire” a synesthesia-like experience due to some disruption in those pathways, though no concrete studies have been done to test that theory.

Perhaps we’ll never know what is truly occurring at a neuroanatomical level that causes such a curious phenotype. In the meantime, looking at the accomplished list of puported “sufferers” of this condition, it may be worthwhile to pose the following question: which came first the synesthesia or the visionary?

GDNF and Parkinson’s Disease

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We have already blogged about the difficulties in treating advanced Parkinson’s Disease, and the need for new strategies including stem cell therapy.

Another therapeutic approach is use of a trophic factor to replenish or prevent the loss of those dopamine producing cells in the first place.

Glial cell-derived neurotrophic factor (GDNF) has been considered a potential therapy for Parkinson’s Disease for many years.

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GDNF has been known to protect and restore these cells in animal models of Parkinson’s Disease since the 1990s.

However, human studies have shown mixed results so far:

Early small open label studies of GDNF infusions into the putamen showed promising results:

These results were not confirmed in a larger double blind study, although this study has been criticized for early termination and other issues:

Furthermore, subsequent studies have confirmed the clinical benefits of GDNF infusions in Parkinson’s patients, and have even shown a sustained benefit after the infusions were discontinued in one patient.

There are ongoing trials of direct infusions of GDNF into the putamen in the UK using a novel infusion pump:

Another potential approach is to use gene therapydelivering a virus that carries the DNA to make GDNF directly into the putamen by a single injection. The “infected” neurons will make GDNF on their own to treat the disease.

So, at this point the jury is still out on GDNF and Parkinson’s, watch this space for more information!