The Prostate Is On The Wrong End - Why Should We Worry?

There is always a lot of news about the prostate these days.  It has become the poster child of the evidence based crowd.  Just last week I saw the headline: "Men are more likely to die in a structure fire than from prostate cancer." This is all part of the political approach to epidemiology that emphasizes that even though most men will develop some type of prostate cancer by the age of 85, they are likely to die of other causes.  Therefore PSA screening is not useful because it leads to more invasive procedures with complications like prostate biopsy and then procedures with even more complications like radical prostatectomy. The sordid aspect of this business has been pointing out the options that several celebrities who made decisions about prostate cancer and therapies.  Depending on the side you take - you will cheer the representative decision.  I noticed that the celebrities who died from prostate cancer including misdiagnosis are omitted from that equation.

In clinical practice, young men with recurrent prostatitis have always been a red flag for me. They often end up on very long courses of antibiotics and seem to have chronic symptoms.  The symptoms don't match descriptions of acute prostatitis that are more similar to an acute urinary tract infection. The anatomy of the male urinary tract often needs to be reviewed, especially the relationship of the prostate and the urethra.  I have treated many young men who were very angry at their Urologists because of these chronic symptoms even though they were not medically explained.  If I see these situations today - I typically call the Urologist and suggest treatment only for a clear cut case of prostatitis and whether they have noticed any changes in the patient's behavior.

My focus in this post is bladder outlet obstruction and all of the associated phenomenon due to benign prostatic hyperplasia.  According to UpToDate (10) it is more common in men and  10% of men greater than the age of 70 and 1/3 of men over the age of 80 will develop it.  Treatment is necessary to prevent renal complications, bladder dysfunction, infection and in severe cases delirium.  I don't intent to focus on the urological treatment - only as required to explain the situation.  I am more interested in what happens with this disorder and how the presentation may appear to be psychiatric.  I think that this is a neglected are in the literature.  Please send me any references that I may have missed.

The neuroanatomy and physiology of micturation is a complicated process.  At the local level, micturation is innervated by both the sympathetic and parasympathetic nerves.  The sympathetic efferent innervation inhibits  β3 adrenoreceptors to relax the detrussor muscle of the bladder and activates α1 receptors at the level of the urethra.  Parasympathetic efferent innervation activates M3 muscarinic receptors in bladder smooth muscle and motor neurons stimulate acetylcholine nicotinic receptors in the external urethral sphincter to cause contraction.  Relaxation of that sphincter muscle is facilitated by postsynaptic parasympathetic neurons that release ATP and nitric oxide.  The efferent arm of micturation requires close coordination of that combination of motor and sympathetic nervous system components.

The afferent side of this function begins at the level of the bladder epithelium.  These cells have complex signalling functions that can lead to local vascular and muscular responses in addition to sensory information being sent to higher centers. Bladder epithelium and underlying myelofibroblasts may function to send a stretch signal as the bladder fills. The actual mechanism that initiates that signal was not clear from the review I read.  A local acetylcholine based mechanism was thought to led to local bladder contractions.  This was thought to be the reason that antimuscarinic agents were used for bladder spasticity.   

This process was not delineated very well until about the past 10-15 years.  A combination of brain imaging during micturation and neuroscience techniques applied to determine the anatomic pathways.  One of those techniques was the application of pseudorabies virus to the wall of the rat  bladder.  This technique leads to retrograde transport of the virus into affected structures.  Viral markers go to structures in both the peripheral and central nervous system. A wide variety of cortical and subcortical structures are involved including the raphe nuclei, locus ceruleus, red nucleus, periaqueductal grey area, pontine micturation center, and cerebral cortex are involved.  The parasympathetic excitatory reflex pathway  is presented in the diagram below (1).

The circuits controlling continence and micturation are shown below. The diagram on the left is the storage reflex consisting of negative feedback to inhibit detrusor contractions and increase urethral sphincter activity. In the voiding phase intense afferent activity in the spinobulbospinal reflex pathways passes the pontine micturation center. That leads to descending parasympathetic activity stimulates detrusor muscle and inhibits urethral sphincter activity at the bladder outlet. Associated structures at the brain level have been suggested by functional imaging studies. The central mechanism suggested is release of tonic inhibition of the micturation center by the frontal cortex. Some of the associated structures are important limbic structures and have connectivity to other organ systems by sympathetic tracts. 

In the case of BPH, there is increased intraluminal pressure in the proximal urethra or bladder outlet. This alters the set point of the system. Voluntary voiding occurs but at higher residual volume and detrussor pressure. That leads to typical symptoms of frequent voiding, decreased urine flow, and small volumes. In extreme cases total obstruction can occur on at least a temporary basis requiring temporary catheter insertion to maintain urine flow. 

Getting back to psychiatry, let me illustrate the relevance of the problem. 

Case 1: JD - a 68 yr old man in fairly good health until about 3 months earlier. At that time he started to experience profound sleep problems. He has obstructive sleep apnea (OSA) and uses CPAP - but his parameters looking at the AHI and air leakage are unchanged. He now has frequent nocturnal panic attacks that awaken him.  Upon waking his heart is pounding and he has palpitations. He purchased a single lead hand held ECG device that takes a 30 second rhythm strip and recorded one ventricular premature contraction in 30 seconds. He consulted both his pulmonologist and cardiologist involved in the original OSA diagnosis. The pulmonologist looks at his CPAP parameters and concludes that he does not need another sleep study. The cardiologist tells him that these VPCs are benign and there is nothing to worry about. JD is concerned because this is a definite change in his health status and neither physician is concerned. 

He went in to see his primary care physician who examines him and jokes about the cardiac-bladder connection. He does a prostate exam and concludes that his prostate is "about the 90th percentile". No further evaluation or treatment is recommended. 

His wife notices that he is sitting up in a chair in the bedroom a lot more at night. He explains that he is having palpitations and is very anxious at night. His wife tells him to see the psychiatrist who is treating her for panic attacks. He makes an appointment and goes in about 2 weeks later. 

The psychiatrist does a complete history and sleep assessment and concludes that these are not typical panic attacks. JD recalls a number of dreams where he is running, exerting himself, or very fearful in the dreams. He awakens with his heart pounding and experiencing the irregular beats. As soon as he is able to void, the tachycardia and palpitations resolve. The psychiatrist thinks they are related to the episodes of urinary frequency and urgency associated with BPH and that therapy targeted to address the bladder outlet obstruction will lead to a resolution of the sleep problems and panic attacks. Since seeing his primary care physician JD has acquired a wrist watch with a vibrating alarm. He uses it to wake himself up at 2AM and 4AM and finds that pre-emptive bladder emptying greatly reduces but does not eliminate the nocturnal panic attacks entirely. The psychiatrist refers JD to a Urologist. He is assessed and treated with tamsulosin - an alpha blocker that relaxes smooth muscle fibers in the bladder neck and prostate. Taking the medication results in a significant improvement but not a normalization of bladder emptying. JD is back to voiding once a night. He has no nocturnal panic attacks or dreams where he is fearful or exerting himself.

The background and case illustrate a few points. Now that micturation is no longer a black box in the brain, the affected structures and the types of symptoms that can be generated need to be considered. It is an easy mistake to treat what seems like a panic attack like a panic attack - especially when previous physicians have not been impressed enough to work up or treat the problem. Nocturnal panic attacks in a 68 year old man with no previous psychiatric history suggests that there are possible medical causes for these symptoms and in this case it was bladder outlet obstruction. The closest syndrome to account for the findings in this case is cystocerebral syndrome - typically delirium in elderly men with acute urinary retention where no other cause can be identified (3-9). Decompressing the bladder typically results in resolution of the acute confusion. That has led several of the authors to postulate that an adrenergic rather than anticholinergic mechanism is involved. I don't not have access to all of these papers and cannot tell if the authors documented some of the problems noted in the case described here (tachycardia, palpitations, VPCs, anxiety and panic) but they are all presumptive hyperadrenergic mechanisms. 

Whether sleep disturbance, panic attacks, and eventual delirium can all occur in the same men with bladder outlet obstruction is not known at this point. That progression of symptoms seems to make sense but it is not well documented and may just be another syndrome waiting for better characterization.  One of the main differences may be the post void residual volume.  In the case presented here that was about 200-300 ml.  In the literature on cystocerebral syndrome there is usually urinary retention and a much larger volume - often 1 liter or more.  

Until then BPH and the associated lower urinary tract symptoms (LUTS) are markers that psychiatrists and sleep medicine specialists need to pay close attention to - especially if it comes with insomnia, panic attacks and palpitations. 

George Dawson, MD, DFAPA

References:

1: Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition. Nat Rev Neurosci. 2008 Jun;9(6):453-66. doi: 10.1038/nrn2401. Review. PubMed PMID: 18490916.

2: Griffiths DJ, Fowler CJ. The micturition switch and its forebrain influences. Acta Physiol (Oxf). 2013 Jan;207(1):93-109. doi: 10.1111/apha.12019. Epub 2012 Nov 16. Review. PubMed PMID: 23164237.

3: Shirvani N, Jimenez XF. Cystocerebral Syndrome: A Case Report and Review of Literature and Mechanisms. J Am Geriatr Soc. 2015 Dec;63(12):2645-2647. doi: 10.1111/jgs.13851. PubMed PMID: 26691712.

4: Washco V, Engel L, Smith DL, McCarron R. Distended bladder presenting with altered mental status and venous obstruction. Ochsner J. 2015 Spring;15(1):70-3. PubMed PMID: 25829883; PubMed Central PMCID: PMC4365850. 

5: Saga K, Kuriyama A, Kawata T, Kimura K. Neurogenic bladder presenting with cystocerebral syndrome. Intern Med. 2013;52(12):1443-4. PubMed PMID: 23774572. 

6: Young P, Lasa JS, Finn BC, Quezel M, Bruetman JE. [Cystocerebral syndrome]. Rev Med Chil. 2008 Nov;136(11):1495-6. Spanish. PubMed PMID: 19301784. 

7: Waardenburg IE. Delirium caused by urinary retention in elderly people: a case report and literature review on the "cystocerebral syndrome". J Am Geriatr Soc. 2008 Dec;56(12):2371-2. doi: 10.1111/j.1532-5415.2008.02035.x. Review. PubMed PMID: 19093953. 

8: Blè A, Zuliani G, Quarenghi C, Gallerani M, Fellin R. Cystocerebral syndrome: a case report and literature review. Aging (Milano). 2001 Aug;13(4):339-42. Review. PubMed PMID: 11695503. 

9: Liem PH, Carter WJ. Cystocerebral syndrome: a possible explanation. Arch Intern Med. 1991 Sep;151(9):1884, 1886. PubMed PMID: 1888260. 8: Blackburn T, Dunn M. Cystocerebral syndrome. Acute urinary retention presenting as confusion in elderly patients. Arch Intern Med. 1990 Dec;150(12):2577-8. PubMed PMID: 2244775.

10: Glen W Barrisford GW, Graeme MS, Steele S. Acute urinary retention.  O'Leary MP, Hockberger, RS Editors. UpToDate. Waltham MA: UpToDate Inc.  http://www.uptodate.com (Accessed on March 30, 2018.)


Graphic Credits

Both neuroanatomy and urology graphics in this post are from reference 1 and posted here:

Reprinted by permission from Nature/Springer: Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition. Nat Rev Neurosci. 2008 Jun;9(6):453-66. doi: 10.1038/nrn2401. Review. PubMed PMID: 18490916. License number  4319020942759

The graphic of the empty sample cup is from Shutterstock per their standard licensing agreement.

Waiting List Mortality? - An Example of Nocturnal Panic Attacks

Any PubMed search on waiting list mortality will produce a long list of articles on mortality that occurs on transplantation waiting lists and all of the associated ethical and logistic problems.  I could not locate any work done on waiting lists to get in to see psychiatrists, primary care physicians, or specialists.  To an extent, waiting list mortality is expected and some of the risk factors (increasing age, significant chronic medical illnesses, high  risk medications) is undoubtedly predictive.  But what about the person who calls in and describes a clear cut problem that is misclassified and the error is potentially life threatening.  I have picked up a few of these problems in psychiatric clinics where the ultimate emergency diagnosis was unrelated to the reason for the appointment.  Seeing a patient who is white as a ghost, complaining of coffee ground emesis, and determining the hemoglobin to be 7 is one of many examples.  Anxiety was the reason for that appointment.  I have found a number of acutely anemic patients due to blood loss with complaints about anxiety, shortness of breath, and panic attacks  who really needed blood transfusions.

I have a more concrete recent example that is much more common in psychiatric practice, especially if a significant number of patients with alcohol and benzodiazepine problems are being seen.  That is the problem of nocturnal anxiety with panic attacks.  To make it a little more interesting, let's say our hypothetical patient is 55 years old, has a history of paroxysmal atrial fibrillation (2 brief episodes), does not take an anticoagulant, and takes flecainide to prevent atrial fibrillation and metroprolol to prevent palpitations.  He has obstructive sleep apnea and is on APAP.  His AHI is 3.5 or less on any given night.  He has never has an electrophysiological study. Stress test and echocardiogram were both negative.  He has had to taper the metoprolol over a period of about 5 years from 25 mg BID to 3.125 mg daily due to lower and lower BP.  Suddenly the patient is noticing palpitations at night.  They seem to occur at the end of REM type dreams and do not seem to correlate with the emotional content of the dream.  The awakenings with palpitations typically occur at 4AM.  He has not had a panic attacks in 35 years.  He does not drink or use benzodiazepines.  To terminate the palpitations he gets up and drinks a large glass of water or walks around and they resolve in about 10 - 20 seconds.  He gets a small single lead ECG device that reads one aberrant beat as "occasional PVC".

He gets in to see his primary care MD in a couple of days.  His exam is normal and he is in sinus rhythm.  No aberrant heart beats are noted by his internist.  Electrolytes and magnesium level are normal.  He goes home that night and the palpitations continue.  He calls his sleep medicine physicians who tells him to start with his Cardiologist.  He calls the Cardiologist who concludes that "these are beats that originate in the lower chambers of the heart and there is nothing to be concerned about." Despite the acute change in symptoms that is waking him up on a nightly basis - no further testing, examination. or diagnosis is offered.  Frustrated - he calls a referral center and schedules a sleep study in about 2 1/2 months.

Is there something else that could have happened in this case? If you happen to be this man's psychiatrist - like I am in many of these cases of sleep related symptoms what is the differential diagnosis and what else can be done.  A reasonable differential diagnosis of these palpitations might consider the following list of conditions.

 

Night time palpitations – differential diagnosis:
1.	Sleep  terrors
2.	Nightmares
3.	Nocturnal panic attacks
4.	Alcohol or sedative hypnotic withdrawal
5.	Stimulant or hallucinogen intoxication
6.	Cardiac arrhythmia Tachyarrhythmias Ventricular arrhythmias Supraventricular arrhythmias Conduction delay arrhythmias

In considering the list. there are some useful clinical features.  Sleep terrors are rare in adults.  They typically occur in the first half of the night.  The patient suddenly arouses from sleep.  They may  scream.  They have intense sympathetic output including diaphoresis, flushing, tachycardia, tachypnea,and mydriasis.  They may appear to be disoriented.  Nightmares are typically dreams with negative emotional content that occur with awakening from non-REM sleep.  Sympathetic arousal is not as prominent.  Nocturnal panic attacks (NP) can occur in people with daytime panic attacks (DP) or as a separate entity.  People with combined DP/NP had more symptom severity. Palpitations are a feature of panic attacks.  In a recent study (2) the authors also rule out associated disorders  like substance use problems and obstructive sleep apnea by exclusion and testing.  The pure NP group were predominately male, had a childhood history of sleep terrors, and were more likely to have respiratory symptoms (choking sensations) despite a lower overall symptom severity score than the DP/NP group suggesting a more common mechanism with night terrors.  Because of the similarity between nocturnal panic attacks, sleep terrors, dream anxiety attacks and nocturnal seizures some authors encourage "extreme caution" in making the diagnosis (3).

The alcohol and substance intoxication and withdrawal states may be less obvious outside of treatment setting specializing in these disorders.  Patients with these problems may not disclose the full extent of use.  In the proper context, discontinuation of both cannabis and hallucinogens like LSD occurs due to increasing anxiety and panic attacks.  Alcohol and sedative hypnotic withdrawal can cause prominent sympathetic symptoms including night sweats, tachycardia, and panic attacks.  Those symptoms typically resolve with treatment of the underlying withdrawal syndrome.  In some cases the anxiety and panic attacks persist and require additional treatment.

Pure cardiac symptoms associated with sleep can be confusing.  The patient is aroused and may notice the arrhythmia.  The question becomes is the arrhythmia secondary to anxiety and sympathetic arousal or is the anxiety secondary to the chest sensation?  In the case of a patient with known sleep apnea and atrial fibrillation here are several possible causes including breakthrough atrial fibrillation at the time of the awakening.  In this case there was a crude monopolar tracing that showed a ventricular premature beat (VPB).  VPBs are commonly associated with anxiety, but is it enough to count on the patient capturing the event by getting up out of bed and holding an inexpensive device to his chest?  Patient with sleep disordered breathing are at increased risk from nocturnal death (midnight to 6AM) and one of the mechanisms may be arrhythmia from the cardiac effects of sleep disordered breathing. 

The patient in this case is very much alive and functioning at a high level.  He still has the nocturnal palpitations but is less anxious about them because they are now intermittent and always seem to resolve in a short period of time. If he thinks about it for nay length of time the question that comes up is: "Why now?"  He hopes that the referral center will have the answer to that question.

  I don't have any outcome or ready solutions to this problem. In many ways it highlights a potential quality problem in the high tech American healthcare system.  Here we have a patient who is fairly compulsive about his own health care.  He has a primary care physician who he saw and contacted both his specialists.  When there was no answer, he contacted a referral center and set up an appointment 2 1/2 months out into the future.  What will happen while he is on that waiting list is a probability statement with a series of unknown probabilities.  What is disappointing from my perspective as a physician trained in the 1980s is that at some point - the rigorous intellectual approach to patients problems has fallen by the wayside in favor of rationing.  We are no longer in pursuit of a diagnosis that might make a difference.  We are satisfied with saying "I checked off all of the boxes and I didn't see anything".  It's a 21st century variation of the old joke: "The operation was a success but unfortunately the patient died."

I am very interested in what the cost of this approach is in terms of human life and additional comorbidity.  I think that what happens to people on these waiting lists (compared to controls) is where the emphasis should be place and not on how fast patients should be discharged and not readmitted to hospitals.  Despite all of the press about unnecessary tests and the risks associated with those tests, the commonest errors I see that result in patient injury is missing the obvious diagnosis and not doing the appropriate tests.     

There is something wrong with a health care system when a psychiatrist cares more about these problems than the physicians running the system.               


George Dawson, MD, DFAPA


References:

1:  Selim BJ, Koo BB, Qin L, et al. The Association between Nocturnal Cardiac Arrhythmias and Sleep-Disordered Breathing: The DREAM Study. Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine. 2016;12(6):829-837. doi:10.5664/jcsm.5880.

2: Nakamura M, Sugiura T, Nishida S, Komada Y, Inoue Y. Is nocturnal panic adistinct disease category? Comparison of clinical characteristics among patients with primary nocturnal panic, daytime panic, and coexistence of nocturnal and daytime panic. J Clin Sleep Med. 2013 May 15;9(5):461-7. doi: 10.5664/jcsm.2666. PubMed PMID: 23674937.

3: Shouse M, Mahowald MW.  Epilepsy, sleep, and sleep disorders.  in: Kryger MH, Roth T, Dement WC. Principles and Practice of Sleep Medicine. 5th ed. St. Louis, Missouri. Elsevier Sanders, 2011: 1048-1063.