Neuro

Core IM Podcast: 5 pearls on Headaches

October 18, 2017

Listen to CORE IM’s first 5 Pearls segment on Headaches!

Time Stamps

  1.   What are the indications for imaging for HA? (1:36)
  2.   What is your approach to abortive therapy for migraines? (4:45)
  3.   How do you diagnose medication overuse HA? (6:41)
  4.  What is your approach to migraine prophylaxis? (8:29)
  5. What are some evidence based nonpharmacological therapies for migraines?  (10:42)

Show notes

Pearl 1:

  1. Think about both patient characteristics and alarming headache qualities to determine if your patient’s headache requires imaging to look for secondary cause.
  2. Important patient characteristics are age and high-risk comorbities.
  3. Worrisome headache qualities include headache that awaken patient from sleep and constitutional symptoms.
  4. Remember that unless you’re looking for an acute bleed, MRI is the preferred imaging modality.

Pearl 2:

  1. NSAIDs are the first-line abortive therapy for both tension and migraine headaches.
  2. For moderate to severe migraines or when NSAIDs don’t work, triptans are useful abortive therapies.
  3. Don’t be scared to try multiple types of triptans if the first fails to help your patient.

Pearl 3:

  1. If you notice your patient’s headache changes from intermittent to a chronic, daily headache while using lots of abortive therapy medications, consider medication overuse headache.
  2. To avoid medical overuse headache, encourage your patient to limit triptans and NSAIDs to less than 2 times per week on average.

Pearl 4:

  1. If patients are getting migraines requiring abortive therapy more than 2x/week or have a medical overuse headache, think about adding migraine prophylaxis.
  2. Beta blockers like propranolol and anti-seizure meds like topiramate are the mainstay of migraine prophylaxis.

Pearl 5:

  1. There is strong evidence to support nonpharmacologic headache treatment, such as CBT, progressive muscle relaxation regular sleep and exercise!

References:

  1. Loder, Elizabeth, et al. “Choosing wisely in headache medicine: the American Headache Society’s list of five things physicians and patients should question.” Headache: The Journal of Head and Face Pain 53.10 (2013): 1651-1659.
  2. Health Quality Ontario. Neuroimaging for the evaluation of chronic headaches: An evidence-based analysis. Ont Health Technol Assess Ser. 2010;10:1- 57.
  3. Detsky, Michael E., et al. “Does this patient with headache have a migraine or need neuroimaging?.” Jama 296.10 (2006): 1274-1283.
  4. Gilmore, Benjamin, and Magdalena Michael. “Treatment of acute migraine headache.” Am Fam Physician 83.3 (2011): 271-280.
  5. Munksgaard SB, Jensen RH. “Medication overuse headache.” Headache. 2014: 807-22.
  6. Pringsheim, Tamara, et al. “Canadian Headache Society guideline for migraine prophylaxis.” Can J Neurol Sci 39.2 Suppl 2 (2012): S1-59.
  7. Mauskop, Alexander. “Nonmedication, alternative, and complementary treatments for migraine.” CONTINUUM: Lifelong Learning in Neurology 18.4, Headache (2012): 796-806.
  8. Silberstein, S. D., et al. “Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society.” Neurology 78.17 (2012): 1337-1345.

Botox: Not Just for Wrinkles Anymore

July 28, 2016

Botulinum_toxin_3BTASamantha Kass Newman, MD

Peer Reviewed

You can get a Botox injection almost anywhere these days. Internists, dermatologists, and even gynecologists have capitalized on an aging group of baby boomers who aren’t fans of their wrinkles. And it’s true that with an impressive safety profile, few contraindications, rapid effectiveness, and positive cash return for providers, botulinum toxin injections for cosmetic purposes can make everyone happy.

Botulinim toxin is produced by the anaerobic bacterium, Clostridium botulinum. This is the strongest toxin found in nature. When injected into muscle, it is taken up by neurons via endocytosis, and then travels to the neuromuscular junction and prevents calcium-dependent release of acetylcholine [1]. This blocks nerve impulses, resulting in flaccid paralysis of the injected muscle.

Facial wrinkles are caused by dermal atrophy and repetitive contraction of the underlying facial muscles, especially around the forehead and periocular areas [2]. Injection of botulinum toxin into specific overactive muscles causes relaxation, and subsequent smoothing over the overlying skin. This procedure is FDA-approved, has predictable results and few adverse events, and is generally associated with high patient satisfaction [2]. For these reasons, botulinum toxin injections for frown lines and crow’s feet are among the most common dermatologic procedures performed in this country.

Yet, the powerful neuromuscular blocking agent has many non-cosmetic uses. Many specialties of medicine, including neurology and urology, have capitalized on botulinum toxin’s ability to selectively paralyze small muscles. In particular, it is frequently used for the treatment of another common problem: migraine.

Botulinum toxin has the ability to block the release of many pain neurotransmitters, including substance P, glutamate, and calcitonin gene-related peptide (CGRP) from the pre-synaptic nerve terminal [3]. The details surrounding this are poorly understood, but some evidence suggests that the toxin can diffuse into the nerve endings and inhibit neurotransmitter release to modulate pain at the level of the trigeminal-occipital-cervical complex [4]. The analgesic effects of botulinum toxin injections are well established, both within clinical trial data and anecdotally; these effects are distinctly different from those of muscle relaxation [4]. Although data on the use of botulinum toxin in episodic migraine were inconclusive, more promising results have been shown for its use in individuals suffering from chronic migraine. In the PREEMPT 1 and 2 studies, onabotulinum toxin A was shown to be significantly superior to placebo with regard to decreasing the frequency of headache days in patients with chronic migraine [4, 5]. It was also shown to be safe and well-tolerated. The FDA approved botulinum toxin as a treatment for chronic migraine in May 2013 [6].

Practically, treatment of migraine with botulinum toxin targets the supraorbital, supratrochlear, and auriculotemporal branches of the trigeminal nerve [4]. These peripheral sensory nerves are accessed by injecting the procerus, corrugator, and frontalis muscles in the forehead – many of the same muscles that are injected for cosmetic purposes. It is also common practice to inject the neck and shoulder region to target cervical sensory rami from C2, C3, C4, and C5 [4].

Botulinum toxin is also used in the treatment of cervical dystonia. Also known as spasmodic torticollis, this is a focal dystonia characterized by abnormal cervical muscle spasms causing significant pain and involuntary posturing of the head and neck. The most common muscles involved are the sternocleidomastoid, trapezius, and splenius capitus, although the scalenes and platysma may also be involved [7]. By blocking the release of acetylcholine at the neuromuscular junction, the toxin has the ability to temporarily weaken the muscle in spasm, alleviate the associated pain, and correct posture. In a double-blind, placebo-controlled trial, onabotulinum toxin A produced significant improvement in the severity of torticollis and in the disability and pain associated with it [8]. While generally safe for this indication, dysphagia is commonly reported, especially for individuals whose dystonia requires injection of the sternocleidomastoid and/or platysma muscles. Also, patients with pre-existing swallowing or breathing disorders are more susceptible to dysphagia [14]. Dry mouth and muscle weakness have also been reported, although these side effects vary based on formulation and dose [7]. Whereas many cases of cervical dystonia are refractory to systemic medications like anticholinergics, baclofen, skeletal muscle relaxants, and benzodiazepines—all of which come with potentially serious side effects—botulinum toxin is now considered first-line treatment. It is also FDA-approved for blepharospasm and other focal spasticities, including upper and lower extremity muscle spasticity following stroke, or in children with cerebral palsy.

A less intuitive use for botulinum toxin is the treatment of hyperhidrosis. More commonly known as excessive sweating, hyperhidrosis is an autonomic and typically idiopathic disorder that can lead to social embarrassment and occupational and psychological disability [9]. Although it most commonly occurs in the axillary region, it can also be seen in the palms, soles, and groin. As discussed above, onabotulinum toxin A inhibits release of acetylcholine from the sympathetic nerve endings, thereby effectively paralyzing eccrine glands. Accordingly, local injection of the toxin directly into the axilla has been shown to significantly reduce sweating in multiple clinical trials [10]. Botulinum toxin is FDA-approved as first-line therapy for patients with severe axillary hyperhidrosis and as second-line therapy in those who have failed alternative treatments [11].

Botulinum toxin also has several indications in the genitourinary realm. In particular, it is effective in treating detrusor muscle overactivity, the most common culprit of urge incontinence. Although occasionally due to neurologic disease, involuntary contractions of the detrusor muscle are commonly idiopathic [12]. While first-line treatment for overactive bladder is lifestyle changes and behavioral therapy, botulinum toxin can also be used in those patients whose symptoms are refractory to more conservative measures. A major limitation, however, is urinary retention, not surprisingly caused by detrusor muscle paralysis secondary to toxin injection [12]. In a randomized, double blind, placebo-controlled trial of botulinum toxin A for refractory overactive bladder, 27% of participants experienced post-void residuals of greater than 200 cc of urine at 6 weeks of follow up, including some who required intermittent self-catheterization [13]. Urinary infection and hematuria have also been reported, but in general, patient satisfaction remains high. Botulinum toxin has also been used for benign prostatic hypertrophy, excessive urethral sphincter tone, and pelvic floor dysfunction [12]. More studies are needed to determine the toxin’s precise role in other genitourinary conditions, such as vaginismus.

The effects of botulinum toxin injection typically last 3-4 months, regardless of the anatomical site [14]. Although there are few safety risks, it may rarely cause anaphylaxis or other allergic reactions. If used in very high doses or very frequently, antibodies may form which can reduce the effectiveness of future injections, though this depends on the specific toxin utilized [14]. As with any injection, there may be lingering pain and redness at the injection site. Contraindications include hypersensitivity to botulinum toxin, active infection at the injection site, and concurrent urinary retention or infection in patients receiving a detrusor injection [14]. Furthermore, there could be specific adverse reactions based on the targeted muscle group: dysphagia after injections in the platysma or sternocleidomastoid and urinary retention for injections in the detrusor muscle [14], as discussed above. There is a phenomenon known as “spread of toxin effect” where its effects are observed beyond the site of local injection; this is rare and poorly understood, but seen most commonly in children treated for spasticity [14].

This review has only skimmed the surface of the potential uses for botulinum toxin in modern medicine. It has been studied as an alternative to surgery in patients with achalasia [15]. It has been used to manage painful muscle contraction in neurological conditions like cerebral palsy and tardive dyskinesia. It has been shown to be effective in the management of strabismus [17]. It has been used off-label to manage a wide range of conditions from trigeminal neuralgia to temporomandibular joint syndrome to anal fissures. While botulinum toxin remains most recognized for its cosmetic uses, its effects extend far beyond frown lines, and much work is needed to fully elucidate its potential for alternative therapeutic medical uses.

Dr. Samantha Kass Newman is an internal medicine resident at NYU Langone Medical Center

Peer reviewed by Jason Siefferman, MD, Anesthesiology, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References

  1. Montecucco C, Molgó J. Botulinal neurotoxins: revival of an old killer. Current Opinion in Pharmacology. 2005; (3): 274–279. https://www.researchgate.net/publication/7833487_Botulinal_neurotoxins_revival_of_an_old_killer_Curr_Opin_Pharmacol_5274-279
  2. Small R. Botulinim toxin injection for facial wrinkles. Am Fam Physician. 2014 Aug 1:90(3):168-75. http://www.aafp.org/afp/2014/0801/p168.html
  3. Ashkenazi A, Blumenfeld A. OnabotulinumtoxinA for the treatment of headache. Headache. 2013 Sep; 54 Suppl 2:54-61. http://www.ncbi.nlm.nih.gov/pubmed/24024603
  4. Szok D, Csati A, Vecsei L, Tajti J. Treatment of chronic migraine with onabotulinumtoxinA: mode of action, efficacy, and safety. Toxins (basel). 2015 Jul 17; 7(7):2659-73.
  5. Aurora SK, Dodick DW, Turkel CC, et al. OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia. 2010;30:793-803. http://www.ncbi.nlm.nih.gov/pubmed/20487038
  6. FDA approves Botox to treat chronic migraine. Available at: http://www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm229782.htm 2013. (accessed May 11, 2013)
  7. Mills RR and Pagan FL. Patient considerations in the treatment of cervical dystonia: focus on botulinum toxin type A. Patient Prefer Adherence. 2015; 9: 725–731.
  8. Greene P, Kang U, Fahn S, Brin M, Moskowitz C, Flaster E. Double-blind, placebo-controlled trial of botulinum toxin injections for the treatment of spasmodic torticollis. Neurology. 1990 Aug; 40(8):1213-8.
  9. Lakrai AA, Moghimi N, Jabbari B. Hyperhidrosis: anatomy, pathophysiology and treatment with emphasis on the role of botulinum toxins. Toxins (Basel). 2013 Apr 23:5(4):821-40.
  10. de Almeida AR, Montagner S. Botulinum toxin for axillary hyperhidrosis. Dermatol Clin. 2014 Oct. 32(4):495-504.
  11. An JS, Hyun Won C, Si Han J, Park HS, Seo KK. Comparison of OnabotulinumtoxinA and RimabotulinumtoxinB for the Treatment of Axillary Hyperhidrosis. Dermatol Surg.2015 Aug;41(8):960-7. http://www.nejm.org/doi/full/10.1056/NEJM200102153440704
  12. Apostolidis A, Dasgupta P, Denys P, et al. Recommendations on the use of botulinum toxin in the treatment of lower urinary tract disorders and pelvic floor dysfunctions: a European consensus report. Eur Urol. 2009; 55:100.
  13. Flynn MK, Amundsen CL, Perevich M, Liu F, Webster GD. Outcome of a randomized, double-blind, placebo controlled trial of botulinum A toxin for refractory overactive bladder. J Urol. 2009;181(6):2608.
  14. Botox (OnabotulinumtoxinA) [prescribing information]. Irvine, CA: Allergan; April 2015. http://www.allergan.com/assets/pdf/botox_pi.pdf 
  15. Zhu Q, Liu J, Yang C. Clinical study on combined therapy of botulinum toxin injection and small balloon dilation in patients with esophageal achalasia. Dig Surg. 2009;26(6):493.
  16.  Jost WH, Benecke R, Hauschke D, Jankovic J, Kaňovský P, Roggenkämper P, Simpson DM, Comella CL. Clinical and pharmacological properties of incobotulinumtoxinA and its use in neurological disorders. Drug Des Devel Ther. 2015 Apr 1;9:1913-26
  17. Donahue SP. Botulinum toxin treatment for esotropia. Am Orthopt J. 2013(63):29-31. http://www.nzosi.com/uploads/1/0/2/6/10263349/botox_4_and_against_in_eso_aoj_2014.full1.pdf

 

 

Stroke 2.0: Novel methods of Detection, Selection and Intervention in Acute Cerebral Ischemia

June 29, 2016

Stroke_ischemicBy David Valentine, MD

Peer Reviewed

Stroke is among the costliest disorders in the world for both individuals and society. Every hour of an evolving stroke kills 120 million neurons, destroys 830 billion synapses and degrades 714 kilometers of myelinated fibers, aging the brain by 3.6 years in those 60 minutes1. It is the leading cause of adult disability in the USA, currently costing $70 billion a year2 with $2.2 trillion more projected over the next forty years3. The global burden is even higher.

Despite this increasingly severe problem, our approaches to the treatment of acute ischemic stroke (AIS) have changed remarkably little since the introduction of tissue plasminogen activator (tPA) in the mid-1990s4. Yet we are in the midst of a veritable renaissance in the management of AIS, with communities and clinicians implementing innovative ways of earlier detection and intervention, new pharmaceuticals for both thrombolysis and neuroprotection, improved stenting and clot dispersal devices, and more streamlined critical care after an ischemic event. Together, these new technologies offer hope for stroke patients and may return quality of life and productive years to both individuals and society.

The mantra of “time is brain” is entirely accurate in the management of AIS, and so shortening the time from detection to treatment is critical to improve outcomes. To this point, community outreach efforts to improve recognition, response to and understanding of stroke have been promising. The “Hip Hop Stroke” initiative, for example, seeks to teach school children the cardinal signs of stroke and how to immediately respond to them via interactive song and game based didactics, and then communicate that information to parents via homework and other activities5-7. Using this approach with a sample of 182 children in New York City, rates of recognition of the cardinal signs of stroke, along with knowledge of an action plan in response to them, went up from less than 4% to nearly 30% among families5.

The Hip Hop Stroke program and other similar initiatives hope to significantly decrease the time between stroke onset and intervention by empowering the community. These efforts are critical, as many patients currently arrive to the ED after the 3-4.5 hour window for tPA8,9, and while door-to-needle time can be reduced to 20 minutes in a well run stroke center10, patients often wait far longer for evaluation and treatment after arrival. There are several approaches being taken to reduce such time, including improved stroke triage education, EMS bringing stroke patients “straight to CT”, telestroke evaluation, and mobile stroke units that begin treatment before the patient even arrives to the hospital.

Multiple centers in the past few years have begun to mobilize specialized ambulances—“mobile stroke units,” or MSUs–with a full suite of equipment for diagnosis and treatment of stroke11,12. A recently published 21 month study equipped ambulances with an onboard CT scanner, blood testing (for INR, CBC and glucose), stroke-trained neurologist, radiology technician, and paramedic, allowing the start of tPA therapy en-route to a hospital13. The authors report that the tPA treatment rate increased by 50%, from 21.2% to 32.6% with these specialized ambulances. This may have come down to the alarm-to-treatment time being 25 minutes shorter with the MSU, allowing 58% of the MSU patients, versus 37% of controls, to be treated within 90 minutes of symptom onset. This mobile approach, however, is not perfect. Investigators found no significant difference in rates of ICH or death, and the scalability may be limited by cost; each unit costs approximately $1.4 million to outfit, and having a stroke-trained neurologist, radiographic technician and more on call for such ambulances may not be realistic for many areas.

In smaller or rural hospitals, or even overcrowded urban community centers, the issue may not be arrival time or nursing evaluation, but availability of stroke-trained physicians. Therefore, telestroke evaluation is a promising avenue. According to a study of smaller urban hospitals in California, by using telestroke with a stroke faculty at a larger center, the median time from initial ED call to stroke consult was 5 minutes, with the average tele-exam taking 30 minutes. With such expediency, tPA use rate increased between 2 and 6 times the normal at these hospitals, with limited burden on the off-site faculty14.

Once a diagnosis of acute ischemic stroke is confirmed, therapy has traditionally relied on pharmaceutical intervention. This focus goes back to 1996, when the NINDS-2 trial led to FDA approval for t-PA for acute ischemic stroke if symptom onset was within a 3-hour window. Patients in the study received 0.9mg/kg with 10% bolused and the rest given over the following 60 minutes4. Since that time, most major stroke centers have extended the time window from 3 to 4.5 hours, but even this extension fails to capture many stroke patients (significant limitations remain for diabetics and those over 80 years of age, a large proportion of the population at risk for stroke15) and the utility of tPA is diminished with each passing minute. In addition, a minority of patients even arrive to the ED in time to receive tPA16. Aside from these logistical issues, there are physiologic limitations to tPA. It often fails to cause rapid reperfusion and puts patients at increased risk of bleeding. A less discussed issue is the neurotoxicity that seems to be associated with its use, possibly due to blood-brain-barrier disturbance and interaction with NMDA receptors17. Therefore, improvements in drug efficacy, the therapeutic window and post-administration toxicity are essential to improving patient outcomes.

For the past decade, a wide range of alternatives to tPA have been sought, but thus far only tenecteplase and desmoteplase show clinical promise. First described in 1995 18, tenecteplase was not studied in the context of AIS until 200519. While this first study was stopped prematurely when doses over 0.5mg were found to cause increased risk of ICH, it was later shown that 0.25mg/kg of tenecteplase was superior to standard tPA per 24 hour and 90 day outcomes (72% showed excellent recovery at 90 days in the tenecteplase group, vs 44% in the tPA group), with no difference in bleeding risk or other complications and with a longer treatment window20 21. With such a promising set of studies, a phase III trial for the use of TNK in AIS in now in progress.

Perhaps even more promising, however, is desmoteplase, a compound first isolated from vampire bat saliva in 199122. It has a theoretical affinity for fibrin nearly 200 times higher than that of tPA23, and several studies have shown both its comparative efficacy and safety24,25, with a lower rate of neurotoxic complications than tPA26. The benefit over tPA may be higher for patients with severe rather than mild/moderate stenosis27, but phase III and IV studies are now ongoing regarding a single 90microgram/kg bolus of desmoteplase within a 3-9 hour window for treatment of AIS28.

Aside from pharmaceutical innovation, the past few years have seen substantial progress in novel devices that allow for localized administration of thrombolytics, stenting, and mechanical removal of a clot. In the early 2000s a series of studies initially suggested such interventions were ineffective or harmful. More recent trials, however, provide strongly evidence that interventional approaches are safe, efficacious and superior to the use of tPA alone. Of these trials, the MR CLEAN stands out as perhaps the most influential.

Enrolling 500 patients across the Netherlands, MR CLEAN29 randomly divided confirmed ischemic stroke patients into either a control group that received tPA alone or an interventional group that received intra-arterial treatment with either local delivery of tPA or urokinase (decision up to the provider), and/or mechanical thrombectomy with or without IV tPA. Inclusion criteria were relatively strict: eligibility required an NIHSS of >2 along with a CT, MRA or DSA-confirmed occlusion in a distal intracranial carotid artery, the MCA (M1 or M2), or the ACA (A1 or A2). Primary outcome was the modified Rankin scale score (mRSS) at 90 days, with secondary outcomes including the NIH Stroke Scale (NIHSS) at 24 hours and 5 or 7 days, or at discharge. By classifying a mRSS of 0-2 as a good outcome (indicative of functional independence after stroke) and a score of >3 as a poor outcome (functional dependence or death), the number needed treat for endovascular therapy to provide additional benefit over tPA alone was 5.3—a strikingly positive result. Aside from this primary outcome, the interventional group showed a positive “shift analysis” for mRSS, in which more patients scored lower on the scale than in the control group, as seen below. While the interventional group had a higher rate of new ischemic stroke in a different vascular territory (13/233 vs 1/267 in control), there was no difference in mortality at 7, 30 or 90 days, thus the authors concluded that treatment of proximal intracranial arterial occlusions within 6 hours of symptom onset by endovascular intervention leads to improved outcomes relative to tPA alone.

stroke 1

 

 

 

 

 

 

 

Since MR CLEAN, the SWIFT-PRIME, ACCORD, and REVASCAT trials have all shown similar efficacy to interventional thrombolysis over tPA alone, prompting the AHA to update their official guidelines for management of acute ischemic stroke to include endovascular procedures30. What changed, then, between the original negative studies on this topic and these newer positive ones? The answer likely lies in both study design and technology used. Earlier trials had limitations in design such as an overly long interval before treatment, absence of pretreatment imaging to confirm a proximal occlusion, and older, less nuanced devices. The IMS-III trial, for example, the most recent of the negative studies, did not use CT imaging to select patients appropriate for thrombolytic intervention until nearly 300 participants had been randomized, and used a smaller dose of tPA in the interventional group than the control for most of the participants.

Newer interventional devices also offer improved efficacy and safety through debulking, aspiration and direct extraction of a thrombus with a lower risk for clot displacement. The Solitaire Flow Restoration Device, for instance, has a 90-day mortality odds ratio of 0.34 compared to older devices such as the MERCI31. Others, like the Penumbra device, show similar improvements in efficacy per improvement on the NIHSS at discharge and 30-day modified Rankin scores32. Complication rates, including vasospasm, ICH and stroke in a new territory, are similar to current pharmaceutical therapy. In short, these new devices offer superior clot retrieval potential with similar or less risk than prior tools.

These advances in treatment options offer significant hope for improvement of patient outcomes, but also make selection of patients for a particular treatment approach all the more important. It has been well documented, for instance, that tPA is most effective in distal intracranial occlusions whereas intra-arterial thrombolysis is more effective in proximal occlusions with ischemic areas less than a certain size33,34. As such, improved imaging technologies may help to stratify patients and improve the outcome of those for whom treatment would be beneficial, while preventing unnecessary procedures and complications in those for whom it would not. While there is much on the horizon, however, for now the current AIS guidelines for imaging of stroke remain quite simple: non-contrast head CT prior to any intervention, be it tPA alone or endovascular thrombolysis. Other modalities, such as MRI, MRA, or CT perfusion/diffusion weight imaging, require further study but promise to more effectively differentiate between the infarct core and the potentially salvageable tissue around the core, termed the penumbra. Of these methods, CT perfusion is already the most widely used, as it can quickly and accurately help to select patients for endovascular therapy beyond the recommended 4.5 hours post-symptom onset. CT perfusion relies on three variables to determine the core and penumbra of an ischemic stroke: mean transit time (MTT), cerebral blood flow (CBF) and cerebral blood volume (CBV). Both the infarct core and penumbra have a prolonged MTT, but the core has a significantly lower CBF and CBV, whereas the penumbra typically has only a marginally decreased CBF with a normal or somewhat elevated CBV (secondary to reactive vasodilation)35.

As interventions and selection for stroke treatment improve, it is equally important to prevent lasting neurologic damage during and after the infarct. The effort to prevent ischemic neurotoxicity in AIS has been extremely challenging. Traditional approaches have assumed glutamate toxicity to be the primary cause of neurotoxicity, and have targeted NMDA receptors to prevent the extracellular calcium buildup that leads to enzyme activation with reactive oxygen species proliferation and subsequent cell death. The problem with this approach is that glutamate release happens very early in the ischemic cascade, and thus NMDA antagonists must be given within 30 minutes of stroke onset, which is rarely achievable in clinical practice. Targeting NMDA receptors is made more complicated by the fact that they seem to have contrary effects depending on location– synaptic NMDA receptors cause calcium influx that make neurons more resistant to ischemia, but extrasynaptic NMDA stimulation initiates apoptotic pathways36.

Given these issues with targeting NMDA receptors, recent studies have shifted focus onto other targets, the most promising of which is TRPM7, a newly discovered Ca+ permeable channel that strongly influences cell survival, as both over and under-expression of the gene lead to cell death37. Oxidative stress, decreased pH, and increased extracellular calcium and magnesium—which all occur in cerebral ischemia—activate TRPM7 independent of glutamate, and in vitro studies suggest this activation plays a large role in oxygen/glucose-deprivation cell death36,37. Interestingly, in vivo rat studies show that TRPM7 suppression makes neurons more resistant to death, maintains normal structural integrity, and allows better functional outcomes in the presence of oxidative stress38. Still, while these findings are promising, current TRPM7 inhibitors are nonselective and further study is needed before any clinical trials are considered.

While pharmaceutical and endovascular treatments have improved, sonothrombolysis, or high-intensity focused ultrasound, might someday offer an alternative approach to AIS. It is theorized to either boost drug transport into the clot to facilitate enzymatic fibrinolysis causing capillary vasodilation and enhanced tissue perfusion, or cause acoustic cavitation of the clot to promote dissolution 39. Initial studies found it to enhance the effect of tPA without affecting clot degradation independently40,41. Recent meta-analyses, however, show an odds ratio of 2.95 for complete recanalization in 1-2 hours, and 2.20 for minimal lasting deficit 90 days post-stroke, relative to intervention without sonothrombolysis39,42. Injectable intravascular microbubbles may further enhance this by oscillating when exposed to an ultrasound beam, mechanically disrupting the clot tissue; thus far, microbubbles appears to double the efficacy of sonothrombolysis without increased bleeding or endothelial and extravascular damage42. The use of sonothrombolysis, however, is still highly experimental with many limitations and, given the proven efficacy of intravascular devices, may not ultimately be clinically relevant.

Aside from the topics discussed above, there are significant opportunities to improve stroke at the preventive level, as well as in the days to weeks after stroke via a neurological ICU and intensive rehabilitation. For the acute management, however, what is clear is that after nearly two decades of relative stagnancy in stroke treatment, major inroads are being made to ensure timely identification, stratification, and safe, effective treatment of ischemic stroke, allowing patients to retain as much of their life—in quality and in years—as possible.

Dr. David Valentine is an Internist at NYU Langone Medical Center

Peer reviewed by Aaron Lord, MD, department of neurology, NYU Langone Medical Center  

Image courtesy of Wikimedia Commons

References 

  1. Saver JL. Time is brain – Quantified. Stroke. 2006;37:263-266. http://stroke.ahajournals.org/content/37/1/263.full.pdf
  2. Go AS, Mozaffarian D, Roger VL, et al. Executive summary: heart disease and stroke statistics–2014 update: a report from the American Heart Association. Circulation. 2014;129(3):399-410. http://www.ncbi.nlm.nih.gov/pubmed/24446411
  3. Brown DL, Boden-Albala B, Langa KM, et al. Projected costs of ischemic stroke in the United States. Neurology. 2006;67:1390-1395. http://graphics.tx.ovid.com.ezproxy.med.nyu.edu/ovftpdfs/FPDDNCJCBFIFLL00/fs047/ovft/live/gv031/00006114/00006114-200610240-00018.pdf
  4. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333(24):1581-1587. http://www.ncbi.nlm.nih.gov/pubmed/7477192
  5. Williams O, DeSorbo A, Noble J, Gerin W. Child-Mediated Stroke Communication: findings from Hip Hop Stroke. Stroke. 2012;43(1):163-169. http://www.ncbi.nlm.nih.gov/pubmed/22033995,   http://stroke.ahajournals.org/content/43/1/163.full.pdf
  6. Williams O, DeSorbo A, Noble J, Shaffer M, Gerin W. Long-term learning of stroke knowledge among children in a high-risk community. Neurology. 2012;79(8):802-806. http://www.ncbi.nlm.nih.gov/pubmed/22875089 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3421152/pdf/znl802.pdf
  7. Williams O, Noble JM. ‘Hip-hop’ stroke: a stroke educational program for elementary school children living in a high-risk community. Stroke. 2008;39(10):2809-2816. http://www.ncbi.nlm.nih.gov/pubmed/18635851

http://stroke.ahajournals.org/content/39/10/2809.full.pdf

  1. Saver JL, Smith EE, Fonarow GC, et al. The “golden hour” and acute brain ischemia: Presenting features and lytic therapy in >30 000 patients arriving within 60 minutes of stroke onset. Stroke. 2010;41:1431-1439. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909671/pdf/nihms213423.pdf
  2. Byrne B, O’Halloran P, Cardwell C. Accuracy of stroke diagnosis by registered nurses using the ROSIER tool compared to doctors using neurological assessment on a stroke unit: A prospective audit. International Journal of Nursing Studies. 2011;48:979-985. http://ac.els-cdn.com/S0020748911000356/1-s2.0-S0020748911000356-main.pdf?_tid=79ff9040-2aae-11e5-9e83-00000aacb35d&acdnat=1436936637_08bab8853bd258b9c488fedba1f82bbc
  3. Meretoja A, Strbian D, Mustanoja S, Tatlisumak T, Lindsberg PJ, Kaste M. Reducing in-hospital delay to 20 minutes in stroke thrombolysis. Neurology. 2012;79:306-313. http://graphics.tx.ovid.com.ezproxy.med.nyu.edu/ovftpdfs/FPDDNCJCBFIFLL00/fs047/ovft/live/gv024/00006114/00006114-201207240-00007.pdf
  4. Rajan S, Baraniuk S, Parker S, Wu T-C, Bowry R, Grotta JC. Implementing a Mobile Stroke Unit Program in the United States. JAMA Neurology. 2015;72:229. http://archneur.jamanetwork.com/article.aspx?articleid=2020709
  5. Parker SA, Bowry R, Wu T-C, et al. Establishing the First Mobile Stroke Unit in the United States. Stroke. 2015;46:1384-1391. http://stroke.ahajournals.org/content/46/5/1384.long
  6. Ebinger M, Winter B, Wendt M, et al. Effect of the use of ambulance-based thrombolysis on time to thrombolysis in acute ischemic stroke: a randomized clinical trial. JAMA : the journal of the American Medical Association. 2014;311:1622-1631. http://jama.jamanetwork.com/article.aspx?articleid=1861800
  7. Cutting S, Conners JJ, Lee VH, Song S, Prabhakaran S. Telestroke in an Urban Setting. Telemedicine journal and e-health : the official journal of the American Telemedicine Association. 2014;20:855-857. http://online.liebertpub.com/doi/abs/10.1089/tmj.2013.0348
  8. Röther J, Ford Ga, Thijs VNS. Thrombolytics in acute ischaemic stroke: historical perspective and future opportunities. Cerebrovascular diseases (Basel, Switzerland). 2013;35:313-319. http://www.karger.com/Article/Pdf/348705
  9. Qureshi AI, Kirmani JF, Sayed MA, et al. Time to hospital arrival, use of thrombolytics, and in-hospital outcomes in ischemic stroke. Neurology. 2005;64(12):2115-2120. http://www.ncbi.nlm.nih.gov/pubmed/15985583
  10. Micieli G, Marcheselli S, Tosi PA. Safety and efficacy of alteplase in the treatment of acute ischemic stroke. Vascular Health and Risk Management. 2009;5:397-409. http://www.dovepress.com/getfile.php?fileID=4763
  11. Benedict CR, Refino CJ, Keyt BA, et al. New variant of human tissue plasminogen activator (TPA) with enhanced efficacy and lower incidence of bleeding compared with recombinant human TPA. Circulation. 1995;92:3032-3040. http://www.ncbi.nlm.nih.gov/pubmed/7586274
  12. Haley EC, Lyden PD, Johnston KC, Hemmen TM. A pilot dose-escalation safety study of tenecteplase in acute ischemic stroke. Stroke. 2005;36:607-612. http://stroke.ahajournals.org/content/36/3/607.full.pdf
  13. Parsons M, Spratt N, Bivard A, et al. A Randomized Trial of Tenecteplase versus Alteplase for Acute Ischemic Stroke. New England Journal of Medicine. 2012;366:1099-1107. http://www.nejm.org/doi/full/10.1056/NEJMoa1109842
  14. Parsons MW, Miteff F, Bateman Ga, et al. Acute ischemic stroke: Imaging-guided tenecteplase treatment in an extended time window. Neurology. 2009;72:915-921. http://www.neurology.org/content/72/10/915
  15. Kratzschmar J, Haendler B, Langer G, et al. The plasminogen activator family from the salivary gland of the vampire bat Dew&us rotundus: cloning and expression. Gene. 1991;105:229-237. http://www.ncbi.nlm.nih.gov/pubmed/1937019
  16. Bringmann P, Gruber D, Liese a, et al. Structural features mediating fibrin selectivity of vampire bat plasminogen activators. Journal of Biological Chemistry. 1995;270:25596-25603. http://www.jbc.org/content/270/43/25596.full.pdf
  17. Furlan AJ, Eyding D, Albers GW, et al. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): Evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke. 2006;37:1227-1231. http://stroke.ahajournals.org/content/37/5/1227.full.pdf
  18. Hacke W, Albers G, Al-Rawi Y, et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): A phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005;36:66-73. http://stroke.ahajournals.org/content/36/1/66.full.pdf
  19. Atalaya JL, Benchenane K, Castel H, Ali C, Petersen K-U, Vivien D. Desmoteplase (DSPA) does not interact with or cleave the NMDA receptor NR1 subunit: Possible molecular basis for improved tolerability in treatment of acute ischemic stroke. Journal of Cerebral Blood Flow & Metabolism. 2005;25:S578-S578. http://www.nature.com/jcbfm/journal/v25/n1s/full/9591524.0578a.html
  20. Fiebach JB, Al-Rawi Y, Wintermark M, et al. Vascular occlusion enables selecting acute ischemic stroke patients for treatment with desmoteplase. Stroke. 2012;43:1561-1566. http://stroke.ahajournals.org/content/43/6/1561.full.pdf
  21. von Kummer R, Albers GW, Mori E, et al. The Desmoteplase in Acute Ischemic Stroke (DIAS) clinical trial program. International Journal of Stroke. 2012;7:589-596. http://onlinelibrary.wiley.com/doi/10.1111/j.1747-4949.2012.00910.x/abstract
  22. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11-20. http://www.ncbi.nlm.nih.gov/pubmed/25517348

http://www.nejm.org/doi/pdf/10.1056/NEJMoa1411587

  1. Powers WJ, Derdeyn CP, Biller J, et al. 2015 American Heart Association/American Stroke Association Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2015;46(10):3020-3035. http://www.ncbi.nlm.nih.gov/pubmed/26123479
  2. Saver JL, Jahan R, Levy EI, et al. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. Lancet. 2012;380(9849):1241-1249. http://www.ncbi.nlm.nih.gov/pubmed/22932715
  3. Po Sit S. The penumbra pivotal stroke trial: Safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke. 2009;40:2761-2768. http://stroke.ahajournals.org/content/40/8/2761.full.pdf
  4. Davalos A, Pereira VM, Chapot R, et al. Retrospective multicenter study of Solitaire FR for revascularization in the treatment of acute ischemic stroke. Stroke. 2012;43(10):2699-2705. http://www.ncbi.nlm.nih.gov/pubmed/22851547
  5. Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke. 2007;38(3):967-973. http://www.ncbi.nlm.nih.gov/pubmed/17272772
  6. Kurz KD, Ringstad G, Odland A, Advani R, Farbu E, Kurz MW. Radiological imaging in acute ischaemic stroke. Eur J Neurol. 2016;23 Suppl 1:8-17. http://www.ncbi.nlm.nih.gov/pubmed/26563093
  7. Bae CYJ, Sun H-S. Current understanding of TRPM7 pharmacology and drug development for stroke. Acta Pharmacologica Sinica. 2012;34:10-16. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086489/pdf/aps201294a.pdf
  8. Aarts M, Iihara K, Wei WL, et al. A Key Role for TRPM7 Channels in Anoxic Neuronal Death. Cell. 2003;115:863-877. http://ac.els-cdn.com/S0092867403010171/1-s2.0-S0092867403010171-main.pdf?_tid=2f9401e4-2aae-11e5-9662-00000aacb35e&acdnat=1436936511_87e2710d71fa488d6a36ed60b75460bb
  9. Sun H-S, Jackson MF, Martin LJ, et al. Suppression of hippocampal TRPM7 protein prevents delayed neuronal death in brain ischemia. Nature neuroscience. 2009;12:1300-1307. http://www.ncbi.nlm.nih.gov/pubmed/19734892

http://www.nature.com/neuro/journal/v12/n10/pdf/nn.2395.pdf

  1. Saqqur M, Tsivgoulis G, Nicoli F, et al. The role of sonolysis and sonothrombolysis in acute ischemic stroke: a systematic review and meta-analysis of randomized controlled trials and case-control studies. J Neuroimaging. 2014;24(3):209-220. http://www.ncbi.nlm.nih.gov/pubmed/23607713

http://onlinelibrary.wiley.com/doi/10.1111/jon.12026/abstract

  1. Frenkel V, Oberoi J, Stone MJ, et al. Pulsed high-intensity focused ultrasound enhances thrombolysis in an in vitro model. Radiology. 2006;239(1):86-93. http://www.ncbi.nlm.nih.gov/pubmed/16493016
  2. Stone MJ, Frenkel V, Dromi S, et al. Pulsed-high intensity focused ultrasound enhanced tPA mediated thrombolysis in a novel in vivo clot model, a pilot study. Thromb Res. 2007;121(2):193-202. http://www.ncbi.nlm.nih.gov/pubmed/17481699
  3. Lapchak Pa, Kikuchi K, Butte P, Holscher T. Development of transcranial sonothrombolysis as an alternative stroke therapy: incremental scientific advances toward overcoming substantial barriers. Expert Rev Med Devices. 2013;10:201-213. http://informahealthcare.com/doi/abs/10.1586/erd.12.88

 

The Brain’s Effect on the Heart After a Stroke

June 22, 2016

Composicion-CardiologiaBy Rory Abrams, MD

Peer Reviewed 

The heart and brain are hopelessly intertwined. Their connection is greater than the tissues and sinews that physically tether them to the human body, and can be understood in three ways: 1) how the heart affects the brain, 2) how the brain affects the heart, and 3) how the heart and brain are both affected by various neuro-cardiac syndromes.  The heart’s effects on the brain are illustrated when there is hypoperfusion of the brain resulting in syncope, or when the heart shoots off emboli to the brain in a dreaded consequence of atrial fibrillation.  Neuro-cardiac syndromes can be thought of as congenital disorders that affect both organs, such as Down’s syndrome or Friedreich’s Ataxia.  These syndromes can also include conditions that occur because of certain shared biological characteristics, such as defects of ion channels and gap junction proteins that both organs possess.  For example,  neurogenic deafness can sometimes be seen in heritable Long QT syndrome type 1.1 What is less well-known and understood are the effects incurred on the heart by the brain, and the mechanisms of these interactions.

As early as the 1940s, QT-prolongation and T-wave/U-wave abnormalities have been reported after acute strokes.2 It is estimated that 15-40% of patients presenting with an acute ischemic stroke, 60-70% of patients presenting with intracranial hemorrhage, and 40-70% of patients presenting with subarachnoid hemorrhage have ECG alterations.3 After acute ischemic stroke, these ECG alterations include, but are not limited to, T-wave abnormalities such as flattening, inverting, peaking and/or widening, the presence of U-waves and/or Q-waves, ST-segment depression or elevation, peaked P-waves, and an increased amplitude of the QRS complex.3,6 However, QT prolongation is by far the most commonly reported ECG finding after ischemic/hemorrhage strokes and subarachnoid hemorrhage (SAH), and this may never normalize after the initial cerebral insult.2,3,6 These ECG findings can occur regardless of whether or not pre-existing cardiac or coronary artery disease is present.4,5

In addition to these expected ECG changes, about 20-40% of patients with ischemic/hemorrhage stroke and nearly 100% of patients with SAH have reported experiencing some form of cardiac arrhythmia in the acute setting, including bradycardia, atrial fibrillation, atrial flutter, paroxysmal SVT, VT and VF.3 These arrhythmias can occur regardless of whether they precipitated the stroke (e.g. embolus formation from atrial fibrillation).  It is therefore of paramount importance to carefully monitor any patient with QT prolongation and T- and U-wave abnormalities (regardless of serum potassium levels), as they have  an increased  risk of VT/VF, Torsade de pointes, and sudden death.  This is especially true in stroke and SAH patients who have an elevated likelihood of concomitant cardiac or coronary disease given similar chronic risk factors.2,7 These cardiac findings can be so pronounced in stroke or SAH that these patients may actually be misdiagnosed with a primary cardiac insult.5 As such, it is crucial  to determine the presenting disease entity.

At least two theories have tried to explain this connection between the brain and heart. Both the multi-vessel coronary artery vasospasm theory and the cardiac microvascular dysfunction theory, though supported by animal models, have little clinical evidence in humans.5 The most well regarded theory, however, is the catecholamine hypothesis, which suggests that alterations in the autonomic nervous system may mediate deleterious changes in both cardiac and cerebral function and metabolism.5,8-10 The autonomic nervous system is regulated by a network of both cortical and subcortical sites in the brain.  The chief hubs that regulate this network include the insular cortex, amygdala, hypothalamus, and paraventricular nucleus.  It is thought that after a stroke, direct damage or secondary metabolic changes to any of these areas alter the regulatory balance of the sympathetic and parasympathetic nervous systems.  In particular, the insular cortex is extremely susceptible to elevated intracranial pressure, irritation from blood products, or direct active ischemia from the middle cerebral artery, and is believed to play a central role in catecholamine surge after ischemic strokes.3,4,9,11 Revved up sympathetic activity is then secondarily triggered by adrenal gland stimulation, which releases excess catecholamines that modulate cardiovascular function.3-5,8,10,11 Excess catecholamines produce hyper-excitable cardiomyocytes through the activation of calcium channels, yielding increased contractility, decreased muscle relaxation, and a propensity for tachyarrhythmias.5,6  This reflex clinically manifests as feeling the heart “racing” or “pounding” and is commonly experienced as a normal reaction to getting nervous or becoming startled, though this sensation is usually quite short-lived. When the heart encounters a powerful and prolonged catecholamine surge, patients may develop demand ischemia through subendocardial lesions that include contraction band necrosis, coagulative myocytolysis, and myofibrillar degeneration.  Of note, these pathologic changes are typically seen in the region of cardiac nerves rather than near the coronary macrovasculature that is typically affected in an MI.2 It is also important to consider that increased parasympathetic/vagal tone and depression of sympathetic stimulation has also been shown to cause bradyarrhythmias and even asystole/sudden cardiac death, which was seen in about 4% of SAH patients in one study.2,9

There is growing evidence to support a model of autonomic dysfunction in this process. A study in 2000 directly measured circulating catecholamine levels in the blood through isotope analysis in 18 patients with non-traumatic SAH as compared to two different control groups.  The study revealed that there was an approximate 3-fold increase of circulating serum catecholamines acutely in the SAH group as compared to either control group (10.2 ± 1.4 nmol/L in SAH group vs. 3.2 ± 0.3 and 4.2 ± 0.7 nmol/L in the control groups, p<0.05).  This catecholamine elevation persisted during the 7-10 day acute study period and only normalized after 6 months of follow-up.8 Other studies typically examine surrogate measures of autonomic dysfunction in association with stroke.  One study that sought to examine autonomic dysfunction after an ischemic stroke, evaluated 77 patients (on average 6 months post-stroke) and compared them to age-matched controls on a variety of autonomic function tests (including Ewing’s battery autonomic function, heart rate variability in response to Valsalva, deep-breathing, and the sit-to-stand maneuver).  The study revealed autonomic dysfunction in 82% of patients with large-artery and 63% of patients with small-artery strokes, as compared to only 21% of controls.   Patients with large artery infarcts demonstrated decreased function of all parasympathetic tests performed (p<0.05), and patients with small artery infarcts only showed impairment in two parasympathetic tests (heart rate response to deep breathing, p=0.01, and heart rate response to standing, p=0.004).12

Catecholamine surges are believed to mediate functional and structural cardiac disturbances. Neurocardiogenic damage is believed to directly manifest as left ventricular dysfunction.13 LV systolic dysfunction has been reported after SAH in up to 28% of patients.2 In a retrospective study of 169 aneurysmal SAH patients who underwent echocardiography, 15% were shown to have LV wall-motion abnormalities.  The specific abnormalities included apical hypokinesis (28%), non-apical hypokinesis (48%), and global hypokinesis (24%).10 Perhaps the best known example of catecholamine-induced cardiomyopathy is Takotsubo cardiomyopathy.  Takotsubo cardiomyopathy is also known as apical ballooning, “broken heart,” or “stress cardiomyopathy,” and is believed to result from physical or emotional stress.  These patients present in a manner resembling acute ST-segment MI on ECG, with elevated cardiac enzymes and evidence of LV dysfunction, however, angiography of these patients reveals normal coronaries.  Remarkably, these patients experience less than 1% in-hospital mortality and the structural and functional changes in the heart tend to be completely reversible within 6 months.2,5,14 The fact that the cardiac changes in Takotsubos tend to be transient and reversible with conservative measures speaks to the possibility that catecholamine surges trigger the initial process of myocardial dysfunction and remodeling, and then correct after normalization of catecholamine levels.

Given the profound electrocardiographic and functional cardiac changes that occur with intracranial pathology, it is not surprising to find other evidence of cardiac damage as well. Creatine kinase-MB (CK-MB) is reported to be elevated in 30-45% of stroke patients, even in the absence of clinically apparent or electrocardiographically detectable  myocardial injury.  In fact, CK-MB has even been proposed as a marker of cerebral infarction.2-4 CK-MB has been mostly replaced by cardiac troponin, as CK-MB is far less sensitive and specific for myocardial damage.4,5,9 Cardiac troponin is estimated to be elevated in 20-30% of patients with SAH and in 36-54% of patients with acute ischemic strokes.2,5,9,13 The AHA/ASA guidelines recommend assessing cardiac biomarkers in all patients presenting with acute ischemic stroke to evaluate for concurrent cardiac disease.7 Cardiac troponin is so highly implicated in cerebrovascular disease that it has also been used as a predictor of death from stroke.  In the Scottish Heart Health Cohort, in which 15,340 patients were followed over 20 years, it was found that elevated high-sensitivity troponin I of just 7.0 pg/mL in men and 4.7 pg/mL in women was predictive of a 2.5-times elevated risk of cardiovascular events (2,171 in total), death from MI (714) and stroke (797) as compared to the general population.15 It is important to note, however, that the numbers of stroke/intracranial hemorrhage patients with elevated troponin reported in more recent studies are in general higher than older studies.  This is due in large part to the increased sensitivities to serum troponin levels of newer assays.9,16

While more sensitive assays may improve the detection of cardiac ischemia, interpretation of elevated serum troponin levels in the setting of an acute stroke can be confusing. Given this difficulty the TRELAS (TRoponin Elevation in Acute ischemic Stroke) trial was conducted to improve the management of ischemic stroke patients with an incidentally noted troponin.  The study was completed in late 2014 and was designed to include all consecutive patients presenting to a single large medical center with imaging confirmed infarcts.  These patients were screened for troponin elevation (>0.05µg/L) on admission and hospital day 2.  Patients with elevated troponin and normal serum creatinine were referred for coronary angiography within 72 hours of admission.  Comparing the findings of these patients to age- and gender-matched NSTEMI patients could reveal culprit lesion patterns that may result in LV dysfunction.13 The results of this trial are pending.

Although the ECG alterations and enzyme elevations seen after stroke or intracranial bleed are alarming, it is important to first stabilize these patients. Consultation with neurology and neurosurgery, as well as prompt administration of thrombolytics when appropriate, should not be delayed.  This does not mean, however, that ECG changes following a stroke should be ignored.  With the notable exception of aneurysmal SAH, stroke patients often share the same cardiovascular risk factors as patients presenting with acute MI, such as diabetes, hypertension, dyslipidemia, or a history of smoking.7 Concomitant coronary, carotid, and peripheral vascular disease should also not be ignored in these patients and at the very least should be worked up and managed as an outpatient following the acute period.2 Cardiac arrhythmias causing hemodynamic instability require prompt stabilization to prevent further end organ damage.  Patients presenting with ischemic stroke should undergo embolic stroke workup to identify potential underlying arrhythmias (as up to 24% of patients with ischemic stroke have unrecognized underlying afib), and be started on anticoagulation when deemed safe to prevent hemorrhagic conversion.17-19 Much remains to be learned about the brain-heart connection, but a greater awareness of cardiac manifestations of cerebrovascular disease can improve diagnostic yield and aid in patient management decisions.

Dr. Rory Abrams is a  resident, internal medicine at NYU Langone Medical Center

Peer reviewed by Robert Donnino, MD, cardiologist, NYU Langone Medical Center

Image courtesy of Wikimedia Commons 

References

  1. Schwartz PJ, Spazzolini C, Crotti L, et al. The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome. Circulation. 2006;113(6):783-790. http://www.ncbi.nlm.nih.gov/pubmed/16461811
  2. Kopelnik A, Zaroff JG. Neurocardiogenic injury in neurovascular disorders. Crit Care Clin. 2006;22(4):733-752.
  3. Cheung RT, Hachinski V. Cardiac Effects of Stroke. Curr Treat Options Cardiovasc Med. 2004;6(3):199-207. http://www.ncbi.nlm.nih.gov/pubmed/15096311
  4. Manea MM, Comsa M, Minca A, Dragos D, Popa C. Brain-heart axis – Review Article. J Med Life. 2015;8(3):266-271. http://www.ncbi.nlm.nih.gov/pubmed/26351525
  5. Lee VH, Oh JK, Mulvagh SL, Wijdicks EF. Mechanisms in neurogenic stress cardiomyopathy after aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2006;5(3):243-249.  http://www.ncbi.nlm.nih.gov/pubmed/17290097
  6. Ibrahim GM, Macdonald RL. Electrocardiographic changes predict angiographic vasospasm after aneurysmal subarachnoid hemorrhage. Stroke. 2012;43(8):2102-2107.
  7. Jauch EC, Saver JL, Adams HP, Jr., et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870-947.
  8. Naredi S, Lambert G, Eden E, et al. Increased sympathetic nervous activity in patients with nontraumatic subarachnoid hemorrhage. Stroke. 2000;31(4):901-906.
  9. Scheitz JF, Nolte CH, Laufs U, Endres M. Application and interpretation of high-sensitivity cardiac troponin assays in patients with acute ischemic stroke. Stroke. 2015;46(4):1132-1140.
  10. Malik AN, Gross BA, Rosalind Lai PM, Moses ZB, Du R. Neurogenic Stress Cardiomyopathy After Aneurysmal Subarachnoid Hemorrhage. World Neurosurg. 2015;83(6):880-885.
  11. Nagai M, Hoshide S, Kario K. The insular cortex and cardiovascular system: a new insight into the brain-heart axis. J Am Soc Hypertens. 2010;4(4):174-182.
  12. Xiong L, Leung HW, Chen XY, Leung WH, Soo OY, Wong KS. Autonomic dysfunction in different subtypes of post-acute ischemic stroke. J Neurol Sci. 2014;337(1-2):141-146. http://www.ncbi.nlm.nih.gov/pubmed/24326200
  13. Scheitz JF, Mochmann HC, Nolte CH, et al. Troponin elevation in acute ischemic stroke (TRELAS)–protocol of a prospective observational trial. BMC Neurol. 2011;11:98.
  14. Maekawa H, Hadeishi H. Takotsubo cardiomyopathy following subarachnoid haemorrhage. Pract Neurol. 2014;14(4):252-255.
  15. Zeller T, Tunstall-Pedoe H, Saarela O, et al. High population prevalence of cardiac troponin I measured by a high-sensitivity assay and cardiovascular risk estimation: the MORGAM Biomarker Project Scottish Cohort. European heart journal. 2014;35(5):271-281.  http://eurheartj.oxfordjournals.org/content/35/5/271
  16. Faiz KW, Thommessen B, Einvik G, Brekke PH, Omland T, Ronning OM. Determinants of high sensitivity cardiac troponin T elevation in acute ischemic stroke. BMC Neurol. 2014;14:96.
  17. Sposato LA, Cipriano LE, Saposnik G, Ruiz Vargas E, Riccio PM, Hachinski V. Diagnosis of atrial fibrillation after stroke and transient ischaemic attack: a systematic review and meta-analysis. Lancet Neurol. 2015;14(4):377-387.
  18. Gladstone DJ, Spring M, Dorian P, et al. Atrial fibrillation in patients with cryptogenic stroke. The New England journal of medicine. 2014;370(26):2467-2477. http://www.ncbi.nlm.nih.gov/pubmed/24963566
  19. Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. The New England journal of medicine. 2014;370(26):2478-2486.

 

The Great Marijuana Debate – Effects on Psychosis and Cognition

August 13, 2015

cannabisBy Kristina Cieslak, MD

Peer Reviewed 

The heavily debated gradual decriminalization and legalization of marijuana will likely result in easier access for all ages. An informed debate has been stymied, however, by a lack of prospective data examining the various long-term effects of marijuana use on the brain, particularly among adolescents who use it heavily. This year, the National Institute on Drug Abuse (NIDA) initiated the “National Longitudinal Study of the Neurodevelopmental Consequences of Substance Use.” This study will follow a large cohort of children from age 10 onward and will examine the effects of exposure to nicotine, marijuana, alcohol, and other drugs on the developing brain. Though likely to provide a wealth of information, these data will not be available for many years.

The link between marijuana use and acute psychiatric symptoms has been known for years. Although transient psychosis and paranoia have been reported, the contribution of marijuana use to the development and exacerbation of chronic psychotic disorders remains under investigation. Several studies have shown that exposure to cannabis increases the likelihood of developing an overt psychotic state among individuals already at high risk for a psychotic disorder [1-2]. Additionally, Henquet et al demonstrated a negative impact of tetrahydrocannabinol (THC) on cognition and psychosis, conditional on an individual’s psychotic liability. There was also the suggestion of potential gene-environment interactions [3]. In a review examining 5 of the largest population-based studies, Arseneault et al found associations between cannabis use, particularly early and heavy use, and later schizophrenia outcomes, with an overall 2-fold increased risk of developing schizophrenia or schizophreniform disorder [2, 4-8].

Although a strong association has been observed, there is a lack of evidence demonstrating that marijuana use is necessary or sufficient grounds for the development of psychotic illness. Additionally, the vast majority of individuals who use marijuana do not develop a psychotic disorder. A recent study by Proal et al posited that the increased familial risk for schizophrenia was the driving force behind incident schizophrenia among those who use marijuana, not the use of marijuana itself [9]. This raises the question of whether marijuana use directly increases the risk of psychosis or if a genetic predisposition to schizophrenia escalates the likelihood of using marijuana. Last year Power et al demonstrated that at least part of the association between marijuana use and schizophrenia is indeed due to a shared underlying genetic etiology [10]. Future studies may be able to elucidate specific gene-environment interactions and identify which of the numerous compounds in marijuana is associated with schizophrenia and affects brain structure and development.

Current factors that have been shown to play a role in the influence of marijuana on psychosis include the age and plasticity of the brain, vulnerability to mental illness, and combination with other drugs. A large body of evidence already demonstrates the acute and non-acute effects of marijuana on learning, memory, attention, concentration, and abstract reasoning, though the underlying mechanisms and potential reversibility require further elucidation [11]. Harvey et al reported on a significant relationship between the frequency of cannabis use in adolescents aged 13-18 years and a decline in cognitive function [12]. Similarly, Meier et al found that persistent cannabis use in adolescence was associated with broad neuropsychological decline and lower IQ later in life, an association not confounded by additional drug use, socioeconomic status, education, or personality differences [13-14]. Furthermore, evidence of gross morphological brain changes among individuals with chronic, heavy cannabis use was recently reported by Lorenzetti et al, including evidence of smaller hippocampal and amygdala volumes [15].

The current data highlight concern for the potential detrimental effects of heavy marijuana use on the developing brain and the increased risk for, and exacerbation of, psychiatric disorders, particularly schizophrenia. Identifying those individuals with the propensity to develop cannabis dependence or addiction, particularly in adolescence, remains a challenge. Large gaps in our knowledge undoubtedly persist; however, it may be prudent to focus our efforts on keeping marijuana away from the brains of vulnerable youth. Doing so may prevent future neurological and psychiatric morbidities.

Dr. Kristina Cieslak is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Ishmeal Bradley, MD, Section Editor, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References

  1. Verdoux H, Gindre C, Sorbara F, Tournier M, Swendsen J. Effects of cannabis and psychosis vulnerability in daily life: an experience sampling test study. Psychological medicine 2003; 33(01): 23-32.  http://f1000.com/prime/717968257

 

  1. Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Wittchen H-U et al. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. BMJ 2005; 330(7481): 11.

 

  1. Henquet C, Rosa A, Krabbendam L, Papiol S, Fananas L, Drukker M et al. An Experimental Study of Catechol-O-Methyltransferase Val158Met Moderation of [Delta]-9-Tetrahydrocannabinol-Induced Effects on Psychosis and Cognition. Neuropsychopharmacology 2006; 31(12): 2748-2757. http://www.ncbi.nlm.nih.gov/pubmed/16936704

 

  1. Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE. Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ 2002; 325(7374): 1212-1213.  http://www.ncbi.nlm.nih.gov/pubmed/12446537

 

  1. Andreasson S, Allebeck P, Engstrom A, Rydberg U. Cannabis and schizophrenia. A longitudinal study of Swedish conscripts. Lancet 1987; 2(8574): 1483-1486.

 

  1. Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G. Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. BMJ 2002; 325(7374): 1199.

 

  1. van Os J, Bak M, Hanssen M, Bijl RV, de Graaf R, Verdoux H. Cannabis use and psychosis: a longitudinal population-based study. American journal of epidemiology 2002; 156(4): 319-327.

 

  1. Fergusson DM, Horwood LJ, Swain-Campbell NR. Cannabis dependence and psychotic symptoms in young people. Psychological medicine 2003; 33(1): 15-21.

 

  1. Proal AC, Fleming J, Galvez-Buccollini JA, DeLisi LE. A controlled family study of cannabis users with and without psychosis. Schizophrenia research 2014; 152(1): 283-288. http://www.ncbi.nlm.nih.gov/pubmed/24309013

 

  1. Power RA, Verweij KJH, Zuhair M, Montgomery GW, Henders AK, Heath AC et al. Genetic predisposition to schizophrenia associated with increased use of cannabis. Mol Psychiatry 2014; 19(11): 1201-1204.  http://www.ncbi.nlm.nih.gov/pubmed/24957864

 

  1. Crane NA, Schuster RM, Fusar-Poli P, Gonzalez R. Effects of cannabis on neurocognitive functioning: recent advances, neurodevelopmental influences, and sex differences. Neuropsychology Review 2013; 23(2): 117-137.  http://www.ncbi.nlm.nih.gov/pubmed/23129391

 

  1. Harvey MA, Sellman JD, Porter RJ, Frampton CM. The relationship between non-acute adolescent cannabis use and cognition. Drug & Alcohol Review 2007; 26(3): 309-319.

 

  1. Meier MH, Caspi A, Ambler A, Harrington H, Houts R, Keefe RSE et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proceedings of the National Academy of Sciences 2012; 109(40): E2657–E2664.  http://www.ncbi.nlm.nih.gov/pubmed/22927402

 

  1. Moffitt TE, Meier MH, Caspi A, Poulton R. Reply to Rogeberg and Daly: No evidence that socioeconomic status or personality differences confound the association between cannabis use and IQ decline. Proceedings of the National Academy of Sciences 2013; 110(11): E980-E982.

 

  1. Lorenzetti V, Solowij N, Whittle S, Fornito A, Lubman DI, Pantelis C et al. Gross morphological brain changes with chronic, heavy cannabis use. The British Journal of Psychiatry 2014.  http://www.ncbi.nlm.nih.gov/pubmed/25431432

 

 

Help Versus Hope: Acetylcholinesterase Inhibitors in Alzheimer’s Disease

May 21, 2014

By Jonathan Gursky

Peer Reviewed

Approximately 5.2 million Americans are currently living with Alzheimer’s disease (AD) [1], with this number expected to triple by the year 2050 [2]. Alzheimer’s disease is now the sixth leading cause of death in the United States [3] and accounts for $100 billion in healthcare expenditures each year [1]. Nevertheless, the most devastating and far-reaching effects of Alzheimer’s disease hit close to home. While those with the disease progressively lose their memory, speech, and independence, it is the caretaker who often bears the brunt of the burden. Not surprisingly, an estimated 23.5% of spouses of a person with Alzheimer’s disease develop clinically significant anxiety and 10.5% develop depression [4]. Overall, the mortality from any cause among caretakers of patients with AD has been found to be higher than controls by up to 63% over 4 years[5].

Alzheimer’s disease is a slowly progressive disease of the brain that affects the hippocampus, frontal cortex and cingulate gyrus [6]. As the disease advances, patients require higher levels of care that often extend beyond the capabilities of family caretakers and result in high rates of patient placement in nursing homes. Preventing and reversing the dementia seen in AD in order to increase quality of life among these patients is the goal of treatment. Nevertheless, the backbone of Alzheimer’s treatment remains acetylcholinesterase inhibitors (CIs) such as donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne). Memantine (Namenda), which is also approved for the treatment of Alzheimer’s disease, is an NMDA receptor antagonist. These drugs do not target the beta-amyloid plaques and neurofibrillary tangles associated with AD, but function by inhibiting the acetylcholinesterase enzyme and thus reducing the rate at which acetylcholine is broken down in the neural synaptic cleft. This net increase in free acetylcholine has been argued to increase memory and other cognitive functions [7]. Doctors have long suspected that these drugs neither reverse pre-existing cognitive damage nor slow down the development of new damage. Instead, CIs temporarily enhance the remaining cognitive function of the patient and mask the full presentation of the existing disease.

Many patients with a new diagnosis of AD are eager to begin treatment with CIs. Often these patients have great expectations regarding the extent to which these drugs will affect their course of illness. It is imperative that prescribing physicians counsel patients and their families about CIs so that patient expectations align with probable outcomes. What does the evidence show about the benefits of acetylcholinesterase inhibitors in the treatment of Alzheimer’s disease?

Numerous studies investigating the effects of CI treatment on AD progression have yielded results that many find disappointing. One such study followed 2853 persons with Alzheimer’s disease to assess for changes in Mini-Mental State Examination (MMSE) score after treatment with donepezil, rivastigmine, or galantamine [8]. By 9 months, only 15.7% of patients responded to treatment, with two-thirds of patients actually demonstrating further deterioration in MMSE score. The strongest predictor of obtaining a positive response to CIs was the presence of an improvement by 3 months. After this time period, the likelihood of clinical improvement was much reduced. Furthermore, increasing doses of CIs were less likely to result in a response to treatment and more likely to cause adverse drug reactions such as heart block, stroke, gastrointestinal distress, and adverse psychiatric changes such as hallucinations. Furthermore, the CRONOS study reported in 2005 that CI treatment has no effect on patients’ abilities to perform the activities of daily living or the instrumental activities of daily living [9], which for many are felt to be among the most debilitating effects of the disease. Of note, many studies that suggest CIs provide significant improvements in cognition often have unclear endpoints or are initiated and funded by pharmaceutical companies with clear incentives to show the efficacy of CIs. The AD2000 study was the first non-pharmaceutically funded study to compare donepezil to placebo, and it found no significant difference in patients’ progression to institutional care, disability, behavioral and psychological symptoms, and other measures of AD severity [10]. When one considers that generic CIs cost an average of approximately $200 per month, it is reasonable to conclude that CIs don’t work well enough to validate their costs, even before one considers their numerous side effects.

Despite these limitations, CIs may have valuable benefits. Studies show that when a person with AD dies while living in a nursing home, the spouse experiences more grief than do the spouses of patients who died while living at home [11]. Fortunately, patients taking donepezil, rivastigmine, or galantamine are more likely to avoid or delay nursing home placement and are thus more likely to continue living at home [12,13]. On average, patients receiving CIs may remain at home under the care of their spouses for almost 2 years longer than non-treated patients [12]. This delay in nursing home placement may be due in part to the fact that patients on CIs are less likely than non-treated patients to experience behavioral disturbances such as destroying property, threatening others, and shouting, and consequently require sedation less often [14]. This prolonged ability to remain at home may help to mitigate the effects of guilt, grief, and depression that caretakers too often experience when they become unable to care for a loved one.

In one study assessing the effect of CIs on the level of distress among caretakers, it was found that the caretakers of patients receiving donepezil reported lower levels of burden of care, even though demand for care remained unchanged from that of patients not receiving the drug [15]. Prior research showed that the ethnicity of caretakers affects reported levels of distress: white parents and siblings of patients with severe mental illness reported a higher level of burden than their black counterparts with the same responsibilities [16]. It is therefore possible that simply reducing the perceived helplessness and loss of hope associated with caring for a loved one with AD, in this case by treating with CIs, is enough to improve the quality of life for caretakers even when no clinical improvements are seen in the patient.

CIs are different than most other drugs in that their effects may benefit the caretaker more than the patient. Providers must consider the ethics of offering CIs for their placebo-like effects or for the benefit of a person who is not the patient. In such a scenario, other potentially safer drug alternatives can be considered. Some evidence shows that memantine may be equivalent to donepezil in slowing decline in neuronal density, dementia scales and other markers of dementia [18]. In turn, Vitamin E, a natural, cheap, and safe alternative, has been shown to be superior to memantine in slowing decline in patients with mild-to-moderate AD [17]. If a prescriber or family members wish to use CIs, most commonly a trial of benefit will be used in order to gauge whether the drug should be continued. With grey lines separating helpful from harmful, it is important to make the distinction between disease as a biological process and illness as a human experience. In this case, we may not be able to treat the disease, but we can ease the experience. Perhaps most important to patients and caregivers dealing with AD is practical advice and help through support groups and advocacy organizations such as the Alzheimer’s Association, that can reduce frustration and assist families during challenging times. Although science continues to work towards developing a drug that will treat the pathology behind AD and more effectively slow decline among patients with AD, the benefits of CIs, their alternatives, and strong social support not only include improved quality of life for patients and their caretakers, but also the immeasurable benefits of hope and empowerment that render the effort therapeutic.

Jonathan Gursky is a 4th year medical student at NYU School of Medicine

Peer Reviewed by Laura Boylan, MD, Neurology, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References

1. Alzheimer’s Association. Alzheimer’s disease facts and figures. http://www.alz.org/alzheimers_disease_facts_and_figures.asp#quickFacts.  Updated 2014. Accessed May 11, 2014.

2. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003;60(8):1119-1122.  http://www.ncbi.nlm.nih.gov/pubmed/12925369

3. Murphy SL, Xu J, Kochanek KD. Deaths: preliminary data for 2010. Nat Vital Stat Rep. 2012;60(4):1-68.

4. Mahoney R, Regan C, Katona C, Livingston G. Anxiety and depression in family caregivers of people with Alzheimer disease: the LASER-AD study. Am J Geriatr Psychiatry. 2005;13(9):795-801. http://www.ncbi.nlm.nih.gov/pubmed/16166409

5. Schulz R, Beach SR. Caregiving as a risk factor for mortality: the Caregiver Health Effects Study. JAMA. 1999;282(23):2215-2219.  http://www.ncbi.nlm.nih.gov/pubmed/10605972

6. Wenk GL. Neuropathologic changes in Alzheimer’s disease. J Clin Psychiatry. 2003;64 Suppl 9:7-10.  http://www.ncbi.nlm.nih.gov/pubmed/12934968

7. Camps P, Muñoz-Torrero D. Cholinergic drugs in pharmacotherapy of Alzheimer’s disease. Mini Rev Med Chem. 2002;2(1):11–25.  http://www.ncbi.nlm.nih.gov/pubmed/12369954

8. Raschetti R, Maggini M, Sorrentino GC, Martini N, Caffari B, Vanacore N. A cohort study of effectiveness of acetylcholinesterase inhibitors in Alzheimer’s disease. Eur J Clin Pharmacol. 2005;61(5-6):361-368. http://www.ncbi.nlm.nih.gov/pubmed/15912389

9. Bellelli G, Lucchi E, Minicuci N, et al. Results of a multi-level therapeutic approach for Alzheimer’s disease subjects in the “real world” (CRONOS project): a 36-week follow-up study. Aging Clin Exp Res. 2005;17(1):54-61.

10. Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double-blind trial. Lancet. 2004;363(9427):2105-2115.  http://www.ncbi.nlm.nih.gov/pubmed/15220031

11. Rudd MG, Viney LL, Preston CA. The grief experienced by spousal caregivers of dementia patients: the role of place of care of patient and gender of caregiver. Int J Aging Hum Dev. 1999;48(8):217-240.

12. Geldmacher DS, Provenzano G, McRae T, Mastey V, Ieni JR. Donepezil is associated with delayed nursing home placement in patients with Alzheimer’s disease. J Am Geriatr Soc. 2003;51(7):937-944.

13. Knopman D, Schneider L, Davis K, et al. Long-term tacrine (Cognex) treatment: effects on nursing home placement and mortality, Tacrine Study Group. Neurology. 1996;47(1):166-177.

14. Cummings JL, Donohue JA, Brooks RL. The relationship between donepezil and behavioral disturbances in patients with Alzheimer’s disease. Am J Geriatr Psychiatry. 2000;8(2):134-140.

15. Fillit HM, Gutterman EM, Brooks RL. Impact of donepezil on caregiving burden for patients with Alzheimer’s disease. Int Psychogeriatr. 2000;12(3):389-401.

16. Horwitz AV, Reinhard SC. Ethnic differences in caregiving duties and burdens among parents and siblings of persons with severe mental illness. J Health and Social Behavior. 1995;36:138-150.  http://www.ncbi.nlm.nih.gov/pubmed/9113139

17. Modrego PJ, Fayed N, Errea JM, Rios C, Pina MA, Sarasa M. Memantine versus donepezil in mild to moderate Alzheimer’s disease: a randomized trial with magnetic resonance spectroscopy. Eur J Neurol. 2010;17(3)405-412.

18. Dysken MW, Sano M, Asthana S, et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014;311(1):33

 

 

 

Can crossword puzzles prevent dementia?

March 12, 2014

By Theresa Sumberac, MD

Peer Reviewed

The 2008 US Census Bureau reported that 14 to 16 percent of the adult population enjoyed crossword puzzles and that half of them played crossword puzzles at least twice a week. [1] Wouldn’t it be wonderful if all those hours spent finishing the Sunday crossword puzzle were good for your health? Recent evidence shows that this may be the case. By 2030 the US population over 65 will double to more than 70 million, highlighting the need to investigate whether non-pharmacological interventions such as crossword puzzles may delay the onset of dementia.[2] The puzzles would serve as a form of cognitive training in which repeated tasks with an inherent problem aim to improve a specific aspect of cognition such as memory, reasoning, and speed processing.[2] By improving brain function, one would ideally create a “cognitive reserve” that would delay the clinical onset of dementia by years even though brain pathology in the form of Lewy bodies, neurofibrillary tangles of hyperphosphorylated tau protein, and β-amyloid plaques may be increasing.[2, 4, 5]

In an observational study by Pillai et al., 488 community dwelling elderly volunteers without evidence of cognitive impairment at baseline underwent cognitive assessment testing their delayed free recall and cognition every 12 to 18 months as part of the Bronx Aging Study. Pillai et al. identified 101 participants who subsequently developed dementia and analyzed the self-reported frequency of participation in crossword puzzles. They found that any amount of crossword puzzle activity delayed the onset of accelerated memory decline by 2.54 years. However, once begun, crossword puzzle users were subject to a steeper rate of memory decline than non-users. These findings support the theory that cognitive reserve delays the onset of dementia up to a certain point, after which the brain’s ability to compensate is overcome, resulting in the steeper decline in memory.[1, 4]

Seven other randomized controlled trials have found a beneficial effect of cognitive exercise on mental activity, with four reaching statistical significance.[6] For example, Mahncke et al. divided 162 elderly participants into three groups, with the experimental group receiving computer based training on six tasks including speed of processing, word recognition, digit span, and working memory for 40 one hour sessions over ten weeks.[11] The two control groups received either active contact with computers or no contact with computers. Mahncke et al. found a significant improvement in the speed of processing between pre-training and post-training performance, with a difference of 176 ±32milliseconds (P‹0.001).[11] Global auditory memory score also improved, as measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), with an increase of 2.3 summed standard score points in the experimental group (P=0.019).[11] Importantly, they were able to show that improvements in digit span persisted after 3 months of a no contact period (P=0.044 immediately post-training and P=0.034 three months after training).[11] Upon closer inspection, however, each of the seven randomized control studies tested different combinations of brain function areas such as general knowledge, memory, reasoning, and speed processing, making it difficult to form generalized guidelines for conducting cognitive therapy. [6]

Does cognitive exercise in one area translate to improvement in other areas of cognition, especially everyday functioning such as instrumental activities of daily living (IADLS)?

In a trial by Ball et al. together with the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study group, 2832 volunteers from the community aged 65 to 94 years old were randomized to ten group sessions of training for memory, reasoning, speed processing, or placebo (no intervention) with 60% offered a four session booster training eleven months later.[7] Each group improved in their targeted area two years later but not in the other domains or in IADLS. However, in a five year follow up to the ACTIVE study, the reasoning group demonstrated an effect size of 0.29 (99% confidence interval 0.03-0.55; P=0.008) compared to the control group, where a positive effect size indicates improvement.[8] A randomized control trial by Cheng et al. demonstrated that immediate memory proficiency as measured by RBANS is improved by multi-domain cognitive therapy, with a net effect size of 0.530 (P=0.002).[9] It is not significantly improved by single domain therapy with a net effect size of 0.216 (P value not reported).[9] Contrastingly, visuospatial and attention abilities improve more after single domain therapy with a net effect size of 0.356 (P=0.031) than multi-domain cognitive therapy with a net effect size of 0.263 (P value not reported). [9]

Is this something grandpa can do at home?

Traditional cognitive training programs tend to be comprised of expensive group sessions in the realm of $100 for one occupational therapy session. Often, the targeted audience may not be able to make it to the session, such as elderly individuals who lack access to public transportation or live in a nursing home. The emergence of computer based cognitive therapy may offer a cheaper, more accessible and exciting alternative.[3, 5, 10] Computer based products are currently a $300 million worldwide industry and is estimated to achieve between $2 and $8 billion by 2015.[10] Kueider et al. performed a systematic review of computerized cognitive training studies including classic cognitive training programs, neuropsychological software, and video games. They also evaluated whether these interventions actually affect cognitive outcome measures in global and domain specific areas. Classic cognitive training appeared to have the greatest benefit on working memory, executive function, and processing speed while neuropsychological software was most able to improve memory and visual spatial ability. Video and computer games included Nintendo Wii’s Big Brain Academy, Microsoft’s Rise of Nations, Medal of Honor, and classic video games such as Pac Man, Donkey-Kong, and Tetris. They had their largest effect on enhancing reaction time, processing speed, executive function, and global cognition in older adults. Additionally, the magnitude of cognitive functioning improvement between computer based and classic cognitive training was similar, showing that either is a viable option for older adults.[3, 10] Despite initial reservations by elderly participants about unfamiliar technology, most adjusted to the new media and stated that it may even help them connect with their grandchildren.[10]

What is the optimal dosing and duration of cognitive therapy?

Review of the current literature reveals studies that differ based on cognitive therapies used, duration of therapy, and longitudinal follow up. The best estimate was ventured in the meta-analysis by Valenzuela, where a “dose” of cognitive therapy lasting two to three months may have effects on healthy community dwelling elderly for years with a relative improvement of 1.2/2.6 points on the mini mental state examination (MMSE).[6] Future trials need to focus on larger sample sizes, randomization, and longer follow up periods to detect lasting effects on cognition.[6]

The Bottom Line

Leisure activities such as crossword puzzles, card games, and reading provide an avenue to stimulate the mind thus delaying the onset of dementia with relatively few negative consequences. These activities should be recommended to our healthy elderly patients. In the future, targeted computerized cognitive training in the form of video games may accompany a daily aspirin in our armamentarium as we strive to prevent disease.

Dr. Theresa Sumberac is an Internal Medicine Resident at NYU Langone Medical Center

Peer reviewed by Martin Sadowski, MD, Neurology, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

1. Pillai, J.A., et al., Association of crossword puzzle participation with memory decline in persons who develop dementia. J Int Neuropsychol Soc, 2011. 17(6): p. 1006-13.  http://www.ncbi.nlm.nih.gov/pubmed/22040899

2. Daffner, K.R., Promoting successful cognitive aging: a comprehensive review. J Alzheimers Dis, 2010. 19(4): p. 1101-22.  http://www.ncbi.nlm.nih.gov/pubmed/20308777

3. Gates, N. and M. Valenzuela, Cognitive exercise and its role in cognitive function in older adults. Curr Psychiatry Rep, 2010. 12(1): p. 20-7.

4. Wilson, R.S., et al., Life-span cognitive activity, neuropathologic burden, and cognitive aging. Neurology, 2013. 81(4): p. 314-21.

5. Mitchell, M.B., et al., Cognitively Stimulating Activities: Effects on Cognition across Four Studies with up to 21 Years of Longitudinal Data. J Aging Res, 2012. 2012: p. 461592.  http://www.hindawi.com/journals/jar/2012/461592/

6. Valenzuela, M. and P. Sachdev, Can cognitive exercise prevent the onset of dementia? Systematic review of randomized clinical trials with longitudinal follow-up. Am J Geriatr Psychiatry, 2009. 17(3): p. 179-87.  http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0028725/

7. Ball, K., et al., Effects of cognitive training interventions with older adults: a randomized controlled trial. Jama, 2002. 288(18): p. 2271-81.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2916176/

8. Willis, S.L., et al., Long-term effects of cognitive training on everyday functional outcomes in older adults. Jama, 2006. 296(23): p. 2805-14. http://www.ncbi.nlm.nih.gov/pubmed/17179457

9. Cheng, Y., et al., The effects of multi-domain versus single-domain cognitive training in non-demented older people: a randomized controlled trial. BMC Medicine, 2012. 10(1): p. 1-13.  http://www.biomedcentral.com/1741-7015/10/30

10. Kueider, A.M., et al., Computerized cognitive training with older adults: a systematic review. PLoS One, 2012. 7(7): p. e40588. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0040588

11. Mahncke, H.W., et al., Memory enhancement in healthy older adults using a brain plasticity-based training program: A randomized, controlled study. Proc Natl Acad Sci USA, 2006. 103(33): p. 12523-8  http://www.ncbi.nlm.nih.gov/pubmed/16888038

 

 

Concussions and Football By The Numbers

December 6, 2013

By Benjamin G. Wu

Peer Reviewed

The news of a large $675 million dollar settlement on concussions has headlined on both the sports news channels and in popular media during this 2013 National Football League (N.F.L.) season [1]. Heralded as a victory mainly for the N.F.L., the settlement not only allows the league to avoid larger amounts in potential liability payments but also the public scrutiny of a discovery phase if a case were to move forward [1]. In the wake of this settlement there are many lingering questions regarding the research of sports-related concussions, helmet design, and safety regulations to protect players at all levels of the popular American pastime.

As concern grew that concussive and sub-concussive impacts may contribute to mild traumatic brain injury (MTBI) and concussive traumatic encephalopathy (CTE) high school, college, and professional football leagues have started tracking the prevalence of concussions over the past decade. [2,4]. High profile cases have the medical and legal world paying more attention to the response and actions taken by the N.FL. [1,4]. The death of the ex-N.F.L. player Andre Waters made national headlines in 2006 as a partial autopsy by Dr. Bennet Omalu revealed diffuse cerebral taupathy [5,6]. Even the United States Congress has attempted to pass a bill to create national guidelines for concussions in young athletes. The bill currently sits in Committee [7,8].

The question is: how widespread are concussions in sports? Surprisingly, an estimated 3.8 million concussions happen every year during competitive and recreational activities [2,9-10]. The rate of concussions found in high school and collegiate sports is 2.4-2.5 concussions per 10,000 athletic exposures [10]. The highest rate of concussions for females occurred in soccer. Predictably, male football players had the highest incidence of concussions [10]. The overall incidence of concussions in sports is estimated to be much higher secondary to under-reporting; an estimated 50% of concussions may go un-reported [2]. A concussion is a clinical diagnosis and involves several criteria including a change in consciousness from confusion or amnesia [11-13]. As we understand more about concussions and their sequelae, the threshold for diagnosis is lowered and the list of activities associated with concussions grows. This research also has clear implications beyond recreational and profressional sports for armed service members returning from Afghanistan and Iraq who have experienced repetitive explosions from improvised explosive devices (IEDs).

There have been many technological advances protecting players and service-members alike from the perils of concussion. The first football helmet was invented in 1896. The helmet had rudimentary strips of leather protecting the players’ skulls [14]. Despite the use of helmets over the past century there have been no substantial studies that show a decrease in concussions due to helmet use [2]. Researchers recorded a total of 101,944 impacts in a study of 95 high school football players in Michigan over 4 years using the Head Impact Telemetry System (HITS). The average player had 652 impacts over the course of the study [15]. The high school player study raised the question of sub-concussive impacts on the neurologic skills of football players. However, this was inconclusively addressed in a research study of 46 collegiate football players at the University of North Carolina, Chapel Hill. On average, the college players sustained more than 1000 impacts during the football season [16]. Neurological performance markers pre-season and post-season did not differ statistically in the study [16]. The researchers suggested that higher acceleration cutoffs may potentially discern changes, but their lower cutoffs for sub-concussive impacts was to discriminate between normal motions of the head to low intensity impacts. Thus, the authors implied that their threshold might be too low to study small and incremental effects of sub-concussive impacts in their cohort [16].

Despite this, data from the N.F.L. shows that there were a total of 887 MTBIs recorded from 1996-2001 and a total of 854 MTBIs recorded from 2002-2007 [17]. Of these concussions, 152 players had repeat concussions in 2002-2007 and 44 players had more than 3 head injuries [18]. Five players had concussions on the same day and 18 players reported concussions within the next seven days [18]. The data suggest that the most important risk factor of receiving concussions is a history of concussions, those players that receive concussions are at 2-5.8 risk of receiving another [2]. This does not imply that players have underlying physiological factors that promote concussions rather differences may likely be explained by riskier play and adherence to safety guidelines. Thankfully, the advances in the rules and technology have greatly improved the safety of football players.

Decreasing the risk of concussions addresses the immediate and short-term health of our athletes, but also begs the question of long-term effects of being punch-drunk. Health workers and researchers have long noted the connection of repeated blows to the head and dementia pugilistica. The first published description of being punch-drunk was in 1928 by Dr. Martland in New Jersey [19]. Since then, multiple studies have addressed the connection of pathological findings such as abnormal deposition of proteins, neuropathies, and other neurological disorders as a result of multiple concussions or MTBIs [20]. The association of concussions to CTE is not new, but while associations exist, the natural history of mild TBI and its progression to CTE is not well understood. Highly publicized cases and recent congressional hearings signal that there are changes coming to American football, and with this attention comes funding for research that may help us understand these challenges.

As a bellwether, the increasing incidence of concussions has been attributed less to risky play, but better and quicker recognition of concussions in the field [2]. In fact, researchers acknowledge that it is not only the force of the impact that dictates long term sequelae of concussions, but the consistency and repetitive nature of these injuries that lead to pathological damage [13]. In response to the attention, the American Academy of Neurology (AAN) has recommended expert involvement in the evaluation of concussions [21]. The benefit of heightened public attention and the involvement experts for concussions and MTBIs remain to be seen. Psychological factors and expectations of recovery influence the recovery from MTBI and the small implication of permanent brain damage currently colors the debate behind the concussion discussion. Research studies that prognosticate and predict trauma in athletes can help those who lack attention and advocacy to do so. Hopefully with better recognition, research, and rules we can eliminate dangerous head injuries in sports to make them not only safer for players, but also more enjoyable for players, their families, and their fans.

Dr. Benjamin Wu is a 3rd year resident at NYU Langone Medical Center

Peer reviewed by Laura Boylan, MD, Neurology, NYU Langone Medical Center

References:

1. Belson, Ken. “N.F.L. Agrees to Settle Concussion Suit for $765 Million“ New York Times on the Web. 29 Aug. 2013. Retrieved 5 Sept. 2013. http://www.nytimes.com/2013/08/30/sports/football/judge-announces-settlement-in-nfl-concussion-suit.html

2. Harmon KG, Drezner JA, Gammons M, et al. American Medical Society for Sports Medicine position statement: concussion in sport. British Journal of Sports Medicine (2013) vol. 47 (1) pp. 15-26. http://bjsm.bmj.com/content/47/1/15.long

3. Roehr B. Why the NFL is investing in health research. BMJ (2012) vol. 345 pp. e6626. http://www.bmj.com/content/345/bmj.e6626.pdf%2Bhtml

4. Belson, Ken. “Concussion Liability Costs May Rise, and Not Just for N.F.L.” New York Times on the Web. 10 Dec. 2012. Retrieved 3 Jan. 2013. http://www.nytimes.com/2012/12/11/sports/football/insurance-liability-in-nfl-concussion-suits-may-have-costly-consequences.html

5. Omalu BI, Hamilton RL, Kamboh MI, DeKosky ST, Bailes J. Chronic traumatic encephalopathy (CTE) in a National Football League Player: Case report and emerging medicolegal practice questions. J Forensic Nurs (2010) Spring 6 (1) pp. 40-6. http://onlinelibrary.wiley.com/doi/10.1111/j.1939-3938.2010.01078.x/abstract

6. Schwarz, Alan. Expert Ties Ex-Player’s Suicide to Brain Damage. New York Times on the Web. 18 Jan. 2007. Retrieved 3 Jan. 2013. http://www.nytimes.com/2007/01/18/sports/football/18waters.html

7. Schwarz, Alan. Congress Considers Concussion Protections. New York Times on the Web. 23 Sep. 2010. Retrieved 3 Jan. 2013. http://www.nytimes.com/2010/09/24/sports/football/24concussion.html

8. S. 2840–111th Congress: Concussion Treatment and Care Tools Act of 2009. (2009). In www.GovTrack.us. Retrieved January 5, 2013. http://www.govtrack.us/congress/bills/111/s2840

9. Browne GJ, Lam LT. Concussive head injury in children and adolescents related to sports and other leisure physical activities. Br J Sports Med 2006; 40 pp. 163 – 168. http://bjsm.bmj.com/content/40/2/163.long

10. Guerriero RM, Proctor MR, Mannix R, Meehan WP 3rd. Epidemiology, trends, assessment and management of sport-related concussion in United States high schools. Current Opinion in Pediatrics (2012) vol. 24 (6) pp. 696-701. http://journals.lww.com/co-pediatrics/pages/articleviewer.aspx?year=2012&issue=12000&article=00008&type=abstract

11. McCrory P, Johnston K, Meeuwisse W, et al. Summary and agreement statement of the 2nd International Conference on Concussion in Sport, Prague 2004. British Journal of Sports Medicine (2005) vol. 39 (4) pp. 196-204. https://physsportsmed.org/doi/10.3810/psm.2005.04.76

12. Casson IR, Pellman EJ, Viano DC.. Concussion in the national football league: an overview for neurologists. Neurol Clin (2008) vol. 26 (1) pp. 217-41; x-xi. http://www.sciencedirect.com/science/article/pii/S0733861907001284

13. Khurana VG, Kaye AH.. An overview of concussion in sport. J Clin Neurosci (2012) vol. 19 (1) pp. 1-11. http://www.jocn-journal.com/article/S0967-5868(11)00441-3/pdf

14. Levy ML, Ozgur BM, Berry C, Aryan HE, Apuzzo ML. Birth and evolution of the football helmet. Neurosurgery (2004) vol. 55 (3) pp. 656-61; discussion 661-2. http://journals.lww.com/neurosurgery/pages/articleviewer.aspx?year=2004&issue=09000&article=00022&type=abstract

15. Broglio SP, Eckner JT, Martini D, et al. Cumulative head impact burden in high school football. Journal of Neurotrauma (2011) vol. 28 (10) pp. 2069-78. http://online.liebertpub.com/doi/abs/10.1089/neu.2011.1825

16. Gysland SM, Mihalik JP, Register-Mihalik JK, Trulock SC, Shields EW, Guskiewicz KM. The relationship between subconcussive impacts and concussion history on clinical measures of neurologic function in collegiate football players. Ann Biomed Eng. 2012 Jan;40(1):14-22. http://link.springer.com/article/10.1007%2Fs10439-011-0421-3

17. Casson IR, Viano DC, Powell JW, Pellman EJ. Twelve years of national football league concussion data. Sports Health: A Multidisciplinary Approach (2010) vol. 2 (6) pp. 471-83. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3438866/

18. Casson IR, Viano DC, Powell JW, Pellman EJ. Repeat concussions in the national football league. Sports Health: A Multidisciplinary Approach (2011) vol. 3 (1) pp. 11-24. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3445193/

19. Martland HS. Punch drunk. Journal of the American Medical Association (1928) vol. 91 (15) pp. 1103-1107. http://jama.jamanetwork.com/article.aspx?articleid=260461

20. McKee AC, Cantu RC, Nowinski CJ, et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. Journal of Neuropathology and Experimental Neurology (2009) vol. 68 (7) pp. 709-35. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2945234/

21. Giza CG, Kutcher JS, Ashwal S, et al. Summary of evidence-based guideline update: evaluation and management of concussion in sports: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013 Jun 11;80(24):2250-7. doi: 10.1212/WNL.0b013e31828d57dd. Epub 2013 Mar 18. http://http://www.neurology.org/content/80/24/2250.long

 

Mystery Quiz- The Answer

June 29, 2012

Vivian Hayashi MD and Robert Smith MD, Mystery Quiz Section Editors

The answer to the mystery quiz is thymoma associated with myasthenia gravis. The clue to the case is the intermittent dysphagia and chewing difficulty. If one considers myasthenia in the differential, then an otherwise grossly normal appearing chest radiograph may be viewed more closely, with attention directed to the upper, anterior mediastinum. The chest radiograph shows the ascending aorta (image 3, arrow); on the lateral film, the retrosternal space, which normally contains air, appears opacified due to a soft tissue density (image 4, asterisk). The anterior ascending aorta on the lateral chest radiograph is not clearly seen because its border is obliterated by the mass which is in contact with it (image 5, arrow). The aorta also appears enlarged (image 5, arrowhead) which accounts for its prominence as seen on the PA chest radiograph. The mass appears encapsulated but the rough border on its left lateral aspect signifies possible invasion (image 6, arrow). Calcification, reported in 10-41% of patients, is also seen within the mass. Although more common in invasive disease, calcification can also be found in a significant minority of patients with benign disease.

Thymoma is the most common anterior mediastinal neoplasm in adult patients. About half of patients present with an incidental finding on chest imaging while the remaining half present with symptoms, most often muscle weakness associated with myasthenia gravis. This condition characteristically presents with waxing and waning weakness over long periods of time. Less commonly, patients present with other paraneoplastic syndromes such as pure red cell aplasia.

Our patient had an elevated level of acetylcholine receptor antibodies. (1.58, where a level >0.40 is considered positive). The resected specimen showed Type B Thymoma, B1 (lymphocyte-rich, organoid histology, as seen in low and high magnification, image 7 and 8 respectively). In addition, pathology revealed Stage la given the presence of microscopic transcapsular invasion (image 6, arrow). Based on the Masaoka staging classification, the pathology findings confer a predicted five year survival of 86-95%. Due to the presence of capsular invasion, adjuvant radiotherapy was also undertaken for our patient. Overall, there is a continuum of pathology from thymoma to the less common thymic carcinoma, with heterogeneous histology seen. Pathology, however, does correlate with biologic behavior and invasiveness.

Use it or Lose it- Do cognitive leisure activities protect against the development of Alzheimer’s?

March 30, 2012

By Courtney Cunningham, MD

Faculty Peer Reviewed

As the world population ages, enormous resources will be required to adequately care for persons suffering from Alzheimer’s disease. The disease is the fifth leading cause of death for adults aged 65 years and older, and is estimated to affect 1 in 8 persons in this age group.[1,2] Despite recent advances, the cause of Alzheimer’s disease is not well understood. The FDA-approved medications in common use—donepezil (Aricept), galantamine (Razadyne), rivastigmine (Exelon), and memantine (Namenda)–help to manage symptoms; however there are no treatments available shown to stop or reverse the progression of the disease.

In addition to medical therapy, researchers have begun to explore the utility of behavioral interventions in preventing and slowing the progression of dementia. Emerging evidence from observational studies suggest that participating in cognitive leisure activities may have a protective effect on the development of Alzheimer’s disease and other dementias.[3] Activities considered to require mental effort include reading books or newspapers, writing for pleasure, doing crossword puzzles, playing board games, and playing musical instruments. Studies suggest that increased participation in such activities in middle and late life is associated with slower rates of cognitive decline.[3]

Although the evidence is convincing, a causal relationship between participation in cognitive leisure activities and dementia has not been firmly established. A systematic review by Wilson and colleagues from 2010 included 13 observational studies that were grouped by the stage of adult life when cognitive interventions were taken. Results of this analysis showed that 5 out of 6 middle-adulthood and 6 out of 7 late-life interventions were significantly associated with a reduced risk of developing Alzheimer’s and other dementias. However, it is possible that reduced participation in leisure activities is itself an early maker of dementia that precedes decline on cognitive tests.[4]

In attempt to eliminate this important confounding factor, a study from the New England Journal of Medicine recruited 469 subjects over the age of 75 years who did not have dementia at baseline and evaluated the risk of dementia according to the baseline level of participation in leisure activities.[5] Advantages of this study include its prospective design and long (median 5.1 years) period of observation. The investigators found that participation in leisure activities conferred a protective effect that persisted after excluding from the analysis persons with possible early symptoms of dementia and adjusting for age, sex, educational level, and chronic medical illnesses. The protective effects were restricted to those activities requiring mental effort; activities involving mere physical activity did not show a significant effect. Nevertheless, controlled trials are still needed to establish causality in the observed association between cognitive stimulation and dementia.

If there is a causal role, two competing theories have been proposed to offer an explanation. The first is that is that of the “cognitive reserve.”[6] This theory suggests that individuals with higher educational or occupational attainment may compensate for early pathological changes of dementia by utilizing cognitive strategies or brain networks associated with increased reserve.[6] A cognitive reserve improved through cognitive enrichment would therefore delay the onset of symptoms without altering the biologic progression of dementia.[6,7] An alternative hypothesis is that participation in cognitive activities slows the pathological processes of the disease during the preclinical phase of dementia.[5] This view emphasizes the remarkable plasticity of the brain, and suggests that cognitive stimulation may play a role in strengthening existing synaptic connections as well as in generating new ones.[8,9] It has also been theorized that cognitive activities may stimulate neurogenesis, even during middle- or late-adult life.[7] The role of such biologic mechanisms underlying cognitive stimulation would have major implications for behavioral intervention in preventing dementia.

A few studies have employed neuroimaging techniques to unravel the brain mechanisms involved in cognitive stimulation interventions. A study by Belleville and colleagues was the first to use functional magnetic resonance imaging to measure the effect of memory training on brain activation in adults with mild cognitive impairment.[8] The aim of the study was to assess whether memory training can reverse brain changes seen in mild cognitive impairment, a precursor state to dementia. The patients participated in a memory-training program where they learned to use memory devices like mnemonics and word lists. Comparison of imaging before and after training revealed an increase in activation and new recruitment of brain regions typically implicated in memory. Furthermore, the majority of areas recruited after training in subjects with mild cognitive impairment were normal prior to training. These results indicate that the older brain is highly plastic and remains so even during the early stages of neurodegenerative disease.

The relative contribution of factors like effortful mental activity to the pathogenesis of dementia remains incompletely understood. A growing body of literature suggests that persistent engagement by the elderly in effortful mental activities may promote plastic changes in the brain that alter the clinical progression of dementia. However, further investigation is needed establish a causal relationship between participation in cognitive leisure activities and a slowed progression of disease. For the time being, elderly patients should nonetheless be encouraged to challenge themselves through crossword puzzles, card games, and stimulating social interactions.

References

1. Centers for Disease Control and Prevention Web site. Alzheimer’s Disease Statistics.http://www.cdc.gov/mentalhealth/data_stats/alzheimers.htm.  July 1, 2011.  Accessed November 15, 2011.

2. Alzheimer’s Association Web site. 2011 Alzheimer’s Disease Facts and Figures. www.alz.org/downloads/Facts_Figures_2011.pdf. Accessed November 15, 2011.

3. Stern C and Munn Z. Cognitive leisure activities and their role in preventing dementia: a systematic review. Int J Evid Based Healthc. 2010; 8(1): p. 2-17.  http://onlinelibrary.wiley.com/doi/10.1111/j.1744-1609.2010.00150.x/pdf

4. Wilson RS, Mendes De Leon CF, Barnes LL, et al. Participation in cognitively stimulating activities and risk of incident Alzheimer disease. JAMA. 2002; 287(6): p. 742-8.

5. Verghese J, Lipton RB, Katz MJ, et al. Leisure activities and the risk of dementia in the elderly. N Engl J Med. 2003; 348(25): p. 2508-16. http://www.nejm.org/doi/full/10.1056/NEJMoa022252

6. Stern Y, Albert S, Tang MX, and Tsai WY. Rate of memory decline in AD is related to education and occupation: cognitive reserve? Neurology. 1999; 53(9): p. 1942-7.  http://www.ncbi.nlm.nih.gov/pubmed/10599762

7. Milgram NW, Siwak-Tapp CT, Araujo J, and Head E. Neuroprotective effects of cognitive enrichment. Ageing Res Rev. 2006; 5(3): p. 354-69.

8. Belleville S, Clement F, Mellah S, Gilbert B, Fontaine F, and Gauthier S. Training-related brain plasticity in subjects at risk of developing Alzheimer’s disease. Brain. 2011; 134(Pt 6): p. 1623-34.

9. Coyle, JT. Use it or lose it-do effortful mental activities protect against dementia? N Engl J Med. 2003; 348(25): p. 2489-2490.

 

Commentary by David Sutin, MD

In April 2011 the National Institute of Aging and the Alzheimer’s Association workgroup published new criteria for Alzheimer’s diagnosis, the major difference being the recognition that clinical symptomatology may significantly lag behind pathological changes.

–The preclinical stage, for which the guidelines only apply in research settings.

–The mild cognitive impairment (MCI) stage, marked by memory problems severe enough to be noticed and measured, but not compromising a person’s independence. People with MCI may or may not progress to Alzheimer’s dementia.

–Alzheimer’s dementia. These criteria apply to the final stage of the disease.

As those of us who work with the elderly have realized, Alzheimer’s disease is not only catastrophic for the patient, but also has tremendous impacts on the family. Preventive strategies must start in the preclinical stage, well before the onset of dementia. While we wait for the availability of disease-modifying therapy and the development of risk stratification tools, it seems prudent to continue to recommend cognitively engaging activities to all.[2]

1. Alzheimer’s diagnostic guidelines updated for first time in decades, National Institute of Aging, last accessed December 9, 2011 at http://www.nia.nih.gov/NewsAndEvents/PressReleases/PR20110419guidelines.htm

2. Williams JW, Plassman BL, Burke J, et al. Preventing Alzheimer’s Disease and Cognitive Decline. Evidence Report/Technology Assessment no. 193. (prepared by the Duke Evidence-based Practice Center under Contract No. HHSA 290-2007-10066-1) AHRQ Publication No. 10-E005. Rockville, MD: Agency for Healthcare Research and Quality. April 2010.

Dr. Courtney Cunningham is a student at NYU School of Medicine

Peer reviewed by David Sutin, MD, Clinical Associate Professor, Section Chief Geriatrics, Bellevue Hospital Center

Image courtesy of Wikimedia Commons (Alois Alzheimer)


How Should You Choose the Best Anti-platelet Agents for Secondary Stroke Prevention?

February 16, 2012

By Demetrios Tzimas, MD

Faculty Peer Reviewed

You are about to discharge a 75-year-old female with hyperlipidemia, hypertension, peripheral vascular disease, who was admitted to the hospital for an ischemic stroke. Being an astute physician, you would like to mitigate this patient’s risk of having a second stroke. But you ask yourself, “with all of the agents available today, what anti-platelet agents should I put this patient on to decrease her risk for a second stroke?”

The etiology of an ischemic stroke, as defined by Adam’s and Victor’s Principles of Neurology, is thrombosis from atheromatous plaques in the cerebral arteries [1]. Thus, it makes sense that after a stroke, as in cardiovascular disease, anti-platelet therapy can help mitigate the onset of a second stroke. Although aspirin has traditionally been the anti-platelet agent of choice [2], currently, there are a variety of anti-platelet agents at our disposal to help in the secondary prevention of ischemic stroke, including: aspirin (irreversible inhibitor of platelet aggregation), aspirin-dipyridamole (inhibitor of platelet aggregation and adhesion), clopidogrel (inhibits adenosine diphosphate-induced platelet aggregation), and cilostazol (inhibits cellular phosphodiesterase and thus platelet aggregation).

In 2006, the American Heart Association and the American Stroke Association published “Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack.” This article describes the Class 1 A recommendations for secondary stroke prevention in patients with non-cardioembolic ischemic stroke or transient ischemic attacks, stating that aspirin (at any dose), aspirin-dipyridamole, and clopidogrel as all being acceptable options for secondary prophylaxis [3]; yet, this does not solve our dilemma of which agent to start in our patient. Therefore, you decide to look at the literature yourself to help come up with an answer of what anti-platelet agents to place your patient on post-hospitalization.

The CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) Trial, conducted by Gent et al in 1996, looked at clopidogrel 75 mg vs. aspirin 325 mg in 19,185 patients with recent ischemic stroke, myocardial infarction, or symptomatic peripheral vascular disease [4]. The primary outcomes were defined as the reduction of ischemic stroke, myocardial infarction, or vascular death. Investigators found an 8.7% significant relative-risk reduction in favor of clopidogrel in the primary outcomes (939 events in clopidogrel group versus 1021 events in aspirin group), although when looking specifically at recurrent stroke there was no difference between the aspirin and clopidogrel groups. Of note, gastrointestinal bleeding was significantly more common in the aspirin group.

Diner et al (2004) conducted the MATCH (Management of Atherothrombosis with Clopidogrel in High Risk Patients) Trial, which was a follow-up to CAPRIE. In this trial, authors investigated the efficacy of aspirin 75 mg plus clopidogrel 75mg vs. clopidogrel 75mg plus placebo in 7, 276 patients with risk factors for stroke (previous stroke, previous MI, angina, diabetes mellitus, or symptomatic peripheral artery disease) as well as previous manifestations of atheroembolic disease (previous transient ischemic attacks or ischemic stroke) [5]. The study’s primary endpoint was the first occurrence of ischemic stroke, myocardial infarction, vascular death, or rehospitalization for any ischemic event over 18 months. Although there was no difference between the two groups in reaching the primary endpoint (15.7% in aspirin plus clopidogrel vs. 16.7% in clopidogrel plus placebo), there was a significantly higher rate of life-threatening bleeding in the clopidogrel plus aspirin group than in the clopidogrel plus placebo (3% versus 1 %, respectively). The study demonstrated that the addition of aspirin to clopidogrel did not add any benefit in terms of prevention of stroke, and actually increased the rate of serious bleeding.

In a follow-up of the MATCH Trial, Bhatt et al (2006) followed 15, 603 patients at high risk for atherothrombotic events in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) Trial, who were randomized to either low-dose aspirin plus clopidogrel 75 mg or low-dose aspirin plus placebo[6]. The primary endpoint of the trial was the first occurrence of myocardial infarction, stroke, or death from cardiovascular causes in the median 28 month follow-up. Similar to the MATCH Trial, there was no difference between the two groups in the rates of the primary outcomes (6.8% in the aspirin plus clopidogrel group, and 7.3% in the aspirin plus placebo group). Unlike the MATCH Trial, in terms of bleeding, there were no differences in severe bleeding, but there was a significantly increased relative risk for moderate bleeding in the aspirin plus clopidogrel group when compared to the aspirin plus placebo group. Thus, as in MATCH, authors found no benefit with clopidogrel plus aspirin in reducing the rate of stroke in patients with multiple cardiovascular risk factors.

Although we have seen that the use of aspirin and clopidogrel together show no increased benefit, with the introduction of newer agents we are able to have more combination drugs. One such agent, dipyridamole, was studied in combination with aspirin in the ESPS2 (European Stroke Prevention Study) Trial in 1996 [7]. Authors studied the efficacy of low-dose aspirin, dipyridamole, and the agents in combination for the secondary prevention of ischemic stroke in 6, 602 patients with prior stroke or transient ischemic attacks. The primary endpoint was defined as stroke or death over two years. Investigators demonstrated that stroke risk was significantly reduced by 18.1% with aspirin 25 mg twice daily, 16.3% with dipyridamole 200 mg twice daily, and 37% with asprin/dipyridamole 25mg/200mg twice daily as compared with placebo; there was no significant difference on the stroke or transient ischemic attack rate between asprin alone or dipyridamole alone, but the combination pill was significantly better than both in regards to stroke reduction. In terms of bleeding, this study showed that all groups containing aspirin had significantly more bleeding than the non-aspirin groups (aspirin alone 8.4%, aspririn/dipyridamole 8.7%, dipyridamole alone 4.7%, placebo 4.5%).

The PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes) Trial in 2008 looked at 20, 332 patients who had an ischemic stroke in the previous 90 days and assigned them to either aspirin/dipyridamole 25mg/200mg twice daily with telmisartan 80 mg daily or placebo, and clopidogrel 75mg daily with telmisartan 80 mg or placebo, with the predefined primary endpoint being recurrent stroke of any kind [8]. In regards to the anti-platelet arms of the trial, authors found no significant differences in the number of recurrent strokes between the aspirin/dipyridamole group and clopidogrel group, but there were more major hemorrhagic events in the aspirin/dipyridamole group than the clopidogrel group (4.1 % vs 3.6%, hazard ratio 1.15).

A newer agent, cilostazol, was studied in the CSPS 2 (Cilostazol for the Prevention of Secondary Stroke) Trial, a non-inferiority study in The Lancet [9]. Authors compared cilostazol 100 mg versus aspirin 81 mg in preventing stroke in 2,757 patients who had a cerebral infarction in the previous 26 weeks. The primary endpoint was defined as the first occurrence of cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage over a mean of 29 months. Investigators found that compared with aspirin, cilistazol was not inferior in reducing the risk of recurrent stroke, but they did report that patients in the cilostazol group had significantly fewer hemorrhagic events (hazard ratio of 0.458 in comparison with aspirin).

These trials reviewed demonstrate that there are several options for us to use as secondary stroke prophylaxis. In summary:

Trial Anti-Platelet Agents Result Caveat
CAPRIE Clopidogrel vs Aspirin No difference in rates of stroke Increased bleeding with Aspirin
MATCH Aspirin + Clopidogrel vs Aspirin No difference in rates of stroke Increased bleeding with Aspirin + Clopidogrel
CHARISMA Aspirin + Clopidogrel vs Clopidogrel No difference in rates of stroke Increased bleeding with Aspirin + Clopidogrel
ESPS2 Aspirin + Dipyridamole vs Aspirin, Aspirin + Dipyridimole vs Dipyridamole Combination better than either agent alone in secondary stroke prevention More bleeding see in all Aspirin containing groups
PRoFESS Aspirin + Dipyridamole vs Clopidogrel No difference in rates of stroke More bleeding with Aspirin + Dipyridamole
CSPS 2 Aspirin vs Cilostazol No difference in rates of stroke More bleeding in Aspirin group

As the current guidelines for anti-platelet agents are not clear, it is our responsibility as physician-scientists to be knowledgeable on the current data, and to review each patient individually instead of relying on vague guidelines.  Upon this review of the literature, it seems that all of these anti-platelet agents have similar efficacy in reducing the incidences of recurrent strokes in high risk patients; a recurring theme of these trials is more bleeding in the aspirin groups and combination groups.  Since we always weigh the risks and benefits of our treatments to patients, in an older population we must seriously consider the risk of GI bleeding when placing our patients on secondary prophylaxis.  Since the combination groups mostly showed increased risk of bleeding with no real benefit, a single agent is probably the best method of secondary prevention.  Although aspirin was traditionally the anti-platelet agent of choice, this agent has been the culprit of bleeding in many trials.  Thus, since they all have similar efficacies in preventing recurrent strokes, whether we choose aspirin, clopidogrel, aspirin/dipyridamole, or cilostazol will depend on: the patient’s ability to tolerate the regimen, cost (aspirin pennies/pill, clopidogrel 5 dollars/pill, aspirin/dipyridamole 3 dollars/pill, cilostazol 1 dollar/pill), as well as compelling factors for certain anti-platelet agents (ie. having stents and requiring plavix).

Dr. Demetrios Tzimas is a contributing editor, Clinical Correlations and a 3rd year resident at NYU Langone Medical Center

Peer reviewed by Saran Jonas, Professor of Neurology, Director of Bellevue Department of Neurology

Image courtesy of Wikimedia Commons

References:

1. Ropper, Allan. Adams and Victor’s Principles of Neurology. 9. New York: McGraw Hill, 2009. 773. Print.

2. Antiplatlet Trialist’s Collaboration. Collaborative overview of randomised trials of antiplatelet therapy–I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration. British Medical Journal. 1994 Jan; 308:81-106. Web. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2539220/?tool=pubmed

3. Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke. Stroke. 2006; 37:577–561. Web. http://stroke.ahajournals.org/cgi/reprint/37/2/577

4. Gent M, Beaumont D, Blanchard J, et al. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). The Lancet. 1996; 348: 1329-1339. Web. http://www.sciencedirect.com.ezproxy.med.nyu.edu/science?_ob=MImg&_imagekey=B6T1B-3Y9GPP9-G1&_cdi=4886&_user=142623&_pii=S0140673696094573&_origin=search&_coverDate=11%2F16%2F1996&_sk=996510961&view=c&wchp=dGLbVtzzSkWb&md5=cdb48c26ac1fc872fe55a83dd0dac855&ie=/sdarticle.pdf

5. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. The Lancet. 2004 July; 364: 331-337. Web. http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6T1B4CXM224149&_cdi=4886&_user=142623&_pii=S0140673604167214&_origin=search&_coverDate=07%2F24%2F2004&_sk=996350568&view=c&wchp=dGLbVzzzSkWb&md5=23f76db79250bc04aeb0d15454516fb2&ie=/sdarticle .pdf

6. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. The New England Journal of Medicine. 2006 Apr; 354: 1706-1717. Web. http://www.nejm.org/doi/full/10.1056/NEJMoa060989

7. Diener HC, Cunha L, Forbes C, et al. Journal of the Neurological Sciences. 1996 Nov; 143: 1-13. Web. http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6T063YTCC2MS1&_cdi=4854&_user=142623&_pii=S0022510X96003085&_origin=search&_coverDate=11%2F30%2F1996&_sk=998569998&view=c&wchp=dGLbVlz-zSkWb&md5=3214efed51ae906c0281a6006414dae8&ie=/sdarticle.pdf

8. Sacco RL, Diener HC, Yusuf L, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. The New England Journal of Medicine. 2008; 359: 1238-1251. Web. http://www.nejm.org/doi/pdf/10.1056/NEJMoa0805002

9. Shinohara Y, Katayama Y, Uchiyama S, et al. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. The Lancet Neurology. 2010; 9: 959-968. Web. http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6X3F-511B43J-2-G&_cdi=7297&_user=142623&_pii=S1474442210701988&_origin=search&_coverDate=10%2F31%2F2010&_sk=999909989&view=c&wchp=dGLbVtzzSkWA&md5=0d7483198b97151accc6cea2893e3b0d&ie=/sdarticle.pdf

Dance Therapy in Parkinson’s Disease: Can the Argentine Tango Improve Motor Function?

December 2, 2011

By Neha Jindal

Faculty Peer Reviewed

Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder that affects over 1 million people in the United States. People with PD often demonstrate postural instability, gait difficulties, and impaired functional mobility, which can lead to falls and decreased quality of life.[1] Medical treatments for PD do not fully address gait and balance issues and, consequently, additional approaches are needed.[2] One approach that has recently emerged in clinical studies is the use of dance, particularly the Argentine tango, as therapy to improve motor function in Parkinson’s patients. Can this social partner dance rooted in the early nineteenth century brothels of Buenos Aires really help improve the motor disturbances of Parkinson’s disease?

In PD, there is an imbalance in neurotransmitters such as dopamine, gamma-aminobutyric acid (GABA), and acetylcholine in the basal ganglia, which compromises their role in the motor control of skilled voluntary movements.[3,4] As a result, patients develop bradykinesia with short, shuffling steps and flexed posture, and may have freezing of gait. Patients also have difficulties with balance, and dual tasking while walking, turning, and walking backwards.[5] Traditionally, physical therapy is prescribed along with medical treatment to address these symptoms. In 2007, Keus and colleagues made evidence-based recommendations regarding the four key components of physical therapy design for PD patients: 1) cueing strategies to improve gait; 2) cognitive movement strategies to improve transfers of weight; 3) exercises to improve balance; and 4) training of joint mobility and muscle power to improve physical capacity.[6] Based on these recommendations, it is clear why the Argentine tango may be an effective form of therapy in PD.

The Argentine tango is a partner dance in which the couple is embraced in each other’s arms, and the leader guides the follower, creating synchronized walking and body movement to the music. This form of dance uniquely addresses each of Keus’s recommendations.[7] First, all movement is done to music. Rhythmic auditory cues have been shown to be beneficial in gait training for PD patients.[8] Similarly, music in Argentine tango may act as an external cue to facilitate movement. Secondly, the Argentine tango teaches specific movement strategies for walking patterns that are particularly difficult for PD patients, like walking backwards. To walk backwards in the Argentine tango, dancers are taught to “keep the trunk over the supporting foot while reaching backward with the other foot, keeping the toe of that rear foot in contact with the floor as it slides back and shifting weight backward over the rear foot only after it is firmly planted.”[7] Balance, the third recommendation, is addressed though the partnered nature of the Argentine tango; the dancers must work to maintain balance dynamically while turning and in the midst of random external perturbation. Finally, similar to other forms of dance, if the Argentine tango is done with sufficient amount of intensity, it can be an aerobic workout and result in improved cardiovascular function and physical capacity.[7]

The benefits of Argentine tango in mild-to-moderate idiopathic PD were demonstrated by Hackney and colleagues in 2007.[9] Their study found significant improvements in balance based on an average improvement of 4 points on the Berg Balance Scale after patients completed 20 one-hour Argentine tango classes over 13 weeks. Interestingly, this improvement was only seen in the tango group and not the control group, who only participated in traditional exercise class. This finding of improved balance in PD patients after Argentine tango classes was also supported by two later studies, both showing comparable improvements in the average Berg Balance Scale.[1,10] Furthermore, a 2009 study by Madeleine and colleagues comparing effects of Argentine tango in PD to American Ballroom (waltz/foxtrot) demonstrated not only an improvement in balance after Argentine tango classes, but also a significant improvement in backward walking velocity, backward stride strength, and physical capacity. The study went on to show superiority of Argentine tango over American ballroom in improving forward walking velocity and functional motor control function, as evidenced by a 0.08 meter per second increase in forward walking velocity and 2 second decrease in the Timed Up & Go test.[1]

Based on this information, the Argentine tango appears to contain the four recommended components of physical therapy for individuals with PD and to be an effective form of movement therapy as well. Not only has Argentine tango proven to be beneficial for the motor function of patients with PD, it has also demonstrated superiority to exercise and American ballroom dance. The Argentine tango demands postural control, movement initiation, turning, and moving in close proximity to another individual. These fundamentals of Argentine dance can improve balance, difficulties in movement initiation, directional changes, and overall functional motor control. While there is currently a small number of studies looking at the Argentine tango and its effects in PD, the research to date is highly suggestive of a potential benefit for patients with mild-to-moderate PD with movement disturbances. If research continues in this direction, it may not be long before we see Parkinson’s patients practicing the Argentine tango up and down the halls of Neurology Clinic.

Neha Jindal is a 4th year medical student at NYU School of Medicine

Peer reviewed by Damara Gutnick, MD, Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

1. Hackney ME, Earhart G. Effects of dance on movement control in Parkinson’s Disease: a comparison of Argentine tango and American ballroom. J Rehabil Med. 2009;41(6):475-481.

2. Gage H, Storey L. Rehabilitation for Parkinson’s disease: a systematic review of available evidence. Clin Rehabil. 2004;18(5):463-482.  http://cre.sagepub.com/content/18/5/463.abstract

3. Marsden CD, Parkes JD. “On-off effects” in patients with Parkinson’s disease on chronic levodopa therapy. Lancet. 1976;1(7954):292-296. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(76)91416-1/abstract

4. Benecke R, Rothwell JC, Dick JP, Day BL, Marsden CD. Disturbance of sequential movements in patients with Parkinson’s disease. Brain. 1987;110(Pt 2):361-379.

5. Hackney ME, Earhart GM. Backward walking in Parkinson’s disease. Mov Disord. 2008;24(2):218-223.

6. Keus SH, Bloem BR, Hendriks EJ, Bredero-Cohen AB, Munneke M; Practice Recommendations Development Group. Evidence-based analysis of physical therapy in Parkinson’s disease with recommendations for practice and research. Mov Disord. 2007;22(4):451-460.

7. Earhart GM. Dance as therapy for individuals with Parkinson’s disease. Eur J Phys Rehabil Med. 2009;45(2):231-238.  http://www.mendeley.com/research/dance-as-therapy-for-individuals-with-parkinson-disease/

8. Thaut MH, McIntosh GC, Rice RR, Miller RA, Rathbun J, Brault JM. Rhythmic auditory stimulation in gait training for Parkinson’s disease patients. Mov Disord. 1996;11(2):193-200.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC486690/

9. Hackney ME, Kantorovich S, Levin R, Earhart GM. Effects of tango on functional mobility in Parkinson’s disease: a preliminary study. J Neurol Phys Ther. 2007;31(4):173-179.  http://nnr.sagepub.com/content/24/4/384.refs

10. Hackney ME, Kantorovich S, Earhart GM. A study on the effects of Argentine tango as a form of partnered dance for those with Parkinson’s disease and healthy elderly. Am J Dance Ther. 2007;29:109-127.