Can constipation precede the diagnosis of Parkinson’s disease by years?

Although the association of constipation and Parkinson’s disease (PD) is well known, less appreciated is that constipation may be among the earliest symptoms of PD, affecting 50% of patients for up to 20 years before the onset of motor symptoms.1  

A 2016 systematic review and meta-analysis found that patients with constipation were at significantly higher risk of developing subsequent PD (O.R. 2.27, 95% CI 2.1-2.46).2 Even, when analysis was restricted to studies assessing constipation more than 10 years prior to PD, the risk was equally elevated. In an interesting longitudinal study in which information on the frequency of bowel movements was collected from men aged 51-75 y, a strong association between < 1 bowel movement daily and subsequent diagnosis of PD was reported (average followup 12 y).3

Given the potential multicentric nature of neurodegenerative process in PD, these findings are perhaps not too surprising. Inflammation and other pathological processes in PD may involve not only the brain but also the intestine, leading to uncoordinated bowel-related muscle involvement and transit disorder, respectively.1 Indeed, Lewy bodies and α-synucleine immunoreactive inclusion bodies have been observed in the intramural ganglia of the GI tract of PD patients.4

Final fun pearl: Did you know that caffeine may reduce the risk of PD?5

 

References

  1. Chen Y, Yu M, Liu X, et al. Clinical characteristics and peripheral T cell subsets in Parkinson’s disease patients with constipation. Int J Clin Exp Pathol 2015;8:2495-2504. https://www.ncbi.nlm.nih.gov/pubmed/26045755
  2. Adams-Carr KL, Bestwick JP, Shribman S, et al. Constipation preceding Parkinson’s disease: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2016;87:710-6. https://www.ncbi.nlm.nih.gov/pubmed/26345189
  3. Abbott RD, Petrovitch H, White LR, et al. Frequency of bowel movements and the future risk of Parkinson’s disease. Neurology 2001;14:57:456-62. https://www.ncbi.nlm.nih.gov/pubmed/11502913
  4. Jost WH. Gastrointestinal dysfunction in Parkinson’s disease. J Neurol Sci 2010;289;69-73. https://www.ncbi.nlm.nih.gov/pubmed/19717168
  5. Costa J, Lunet N, Santos C, et al. Caffeine exposure and the risk of Parkinson’s disease: a systematic review and meta-analysis of observational studies. J Alzheimers Dis 2010;20 (Suppl 1):S221-38. https://www.ncbi.nlm.nih.gov/pubmed/20182023
Can constipation precede the diagnosis of Parkinson’s disease by years?

How should I manage hypertension in my patient with neurogenic orthostatic hypotension?

The frequent concurrence of supine hypertension (SH) and neurogenic orthostatic hypotension (nOH)1 makes treatment of SH in these patients particularly challenging.

To begin with, your threshold for treatment of SH in patients with neurogenic orthostatic hypotension (nOH) may need to be higher than that commonly recommended by national guidelines for treatment of essential hypertension to avoid exacerbation of nOH.  Although SH in nOH patients is often arbitrarily defined as a systolic BP ≥150 mmHg or diastolic BP≥90 mmHg, a supine systolic BP of up to 160 mmHg may not warrant treatment, particularly if the symptoms of nOH have improved.2

A 2017 consensus panel recommends treatment of SH in the setting of nOH if systolic BP exceeds the range of 160-180 mmHg or diastolic BP exceeds 90-100 mmHg.  “Permissive” approach to SH in this setting may be reasonable, particularly in those with the largest drops in BP upon standing ( >80 mmHg drop). 2

Regardless, all patients with nOH and SH should be advised to avoid supine posture during the day and elevate the head of the bed as tolerated during the night.

If necessary, significant SH may be treated with short acting agents, including2:

  • Captopril 25 mg qhs
  • Clonidine 0.2 mg with evening meal
  • Hydralazine 10-25 mg qhs
  • Losartan 50 mg qhs
  • Nitroglyerine patch 0.1 mg/h patch qhs (remove patch in am)

Long acting antihypertensive agents and diuretics should be avoided given their inherent risk of significant exacerbation of nOH.

 

References

  1. Goldstein DS, Pechnick S, Holmes C, et al. Association between supine hypertension and orthostatic hypotension in autonomic failure. Hypertension 2003; 42:136-142. https://www.ncbi.nlm.nih.gov/pubmed/12835329
  2. Gibbons CH, Schmidt P, Biaggioni I, et al. The recommendations of a concensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension. J Neurol 2017;264:1567-82. https://www.ncbi.nlm.nih.gov/pubmed/28050656
How should I manage hypertension in my patient with neurogenic orthostatic hypotension?

My patient with low back pain was just diagnosed with a lumbar spinal epidural abscess. Should I order an MRI of the rest of the spine?

First, look closely for any signs or symptoms which may suggest cord involvement due to spinal epidural abscess (SEA) at other levels of the spine (in this case cervical or thoracic) which would necessitate an urgent MRI. Be particularly on the lookout for new pain (particularly radicular) or paresthesias involving the abdomen, chest or upper extremities (with or without weakness)1.

Otherwise, whether an MRI of the entire spine should be routinely obtained after a diagnosis of SEA in the absence of any suggestive signs or symptoms is less clear, in part related to lack of properly designed studies.1-4

Nevertheless, a retrospective study involving 233 patients with SEA may shed some light on the subject. Based on 22 cases of noncontiguous SEA (9.4% of total), the following independent risk factors were identified3:

  • Delay in presentation (≥1 week of symptoms)
  • Concomitant area of infection outside the spine and paraspinal region
  • ESR > 95 mm/h at presentation

Probability of non-contiguous SEA based on the number of risk factors was as follows:

  • 3 risk factors: 73%
  • 2 risk factors: 13%
  • 1 risk factor: 2%
  • Zero risk factor: 0%

Despite several shortcomings and the need to confirm its findings2,3, this study helps raise awareness of the potential for concurrent but asymptomatic SEA elsewhere in the spine whenever SEA is diagnosed.

 

References

  1. Bond A, Manian FA. Spinal epidural abscess: a review with special emphasis on earlier diagnosis. BioMed Res International 2016;Volume 2016, Article ID 1614328. https://www.hindawi.com/journals/bmri/2016/1614328/
  2. Schoenfeld AJ, Hayward RA. Predicting modeling for epidural abscess: what we can, can’t, and should do about it. Spine J 2015;15:102-104. http://www.sciencedirect.com/science/article/pii/S152994301401554X
  3. Ju KL, Kim SD, Melikian R, et al. Predicting patients with concurrent noncontiguous spinal epidural abscess lesions. Spine J 2015;15:95-101. https://www.ncbi.nlm.nih.gov/pubmed/24953159
  4. Pfister HW, vonRosen F, Yousry T. MRI detection of epidural spinal abscesses at noncontiguous sites. J Neurol 1996;243:315-7. https://www.ncbi.nlm.nih.gov/pubmed/8965103
My patient with low back pain was just diagnosed with a lumbar spinal epidural abscess. Should I order an MRI of the rest of the spine?

What pharmacological options should I consider when treating neurogenic orthostatic hypotension in my elderly patient with supine hypertension?

Treating symptomatic neurogenic orthostatic hypotension (nOH) in patients with supine hypertension can be challenging.

Before adding new agents, consider discontinuation or dose reduction of medications that can potentially aggravate orthostatic symptoms (eg, diuretics, vasodilators, negative chronotropic agents, including beta blockers).

Midodrine (an α1-adrenoreceptor agonist) and droxidopa (a norepinephrine pro-drug) are the only 2 FDA-approved drugs for the treatment of OH.

  • Midodrine is typically dosed between 2.5 mg-15 mg 1-3x/d during waking hours (prior to getting out of bed, before lunch, mid-afternoon).
  • Droxidopa is dosed from 100-600 mg 3x/day during waking hours (eg, 8 AM, noon, 4PM).
  • To reduce the risk of supine hypertension, these agents are not recommended to be taken within 5 h of bedtime, and should be used with caution in patients with congestive heart failure and chronic renal failure.

Fludrocortisone and pyridostigmine are used off-label for treatment of nOH.

  • Fludrocortisone (typical dose 0.1-0.2 mg/day) expands intravascular blood volume by increasing renal sodium and water reabsorption, with an attendant risk of exacerbating supine hypertension, hypokalemia, and edema.
  • Pyridostigmine (typical dose 30-60 mg 1-3x/day) is an acetylcholinesterase inhibitor that potentiates neurotransmission in the sympathetic ganglia and has the advantage of not worsening supine hypertension. Side effects include abdominal cramps, diarrhea, excessive sweating and urinary incontinence.

In practice,  1 or more of these agents are often used along with non-pharmacological measures.

Go to a related pearl at https://pearls4peers.com/2017/09/18/which-non-pharmacological-approaches-may-help-symptoms-of-orthostatic-hypotension-in-my-patient-with-autonomic-insufficiency/.

 

Reference

Gibbons CH, Schmidt P, Biaggioni I, et al. The recommendations of a concensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension. J Neurol 2017;264:1567-82.https://www.ncbi.nlm.nih.gov/pubmed/28050656

 

What pharmacological options should I consider when treating neurogenic orthostatic hypotension in my elderly patient with supine hypertension?

Which non-pharmacological approaches may help symptoms of orthostatic hypotension in my patient with autonomic insufficiency?

A number of simple measures to help reduce the symptoms of neurogenic orthostatic hypotension (nOH) in susceptible patients have been recommended.1

  • Blood volume repletion (a minimum of 64 oz or 2L of water intake daily), depending on cardiac status. In addition, rapid consumption (within 5 min) of 16 oz or 500 ml of water can raise blood pressure by 30 mmHg for about an hour. It’s worth noting that liquids other than water (eg, water plus salt) do not provide the same BP response, likely due to water-induced hypo-osmolar reflex in the portal circulation.2,3
  • Increase salt intake if possible (eg, add 1-2 teaspoons or 2.3-4.6 g of salt per day), as many patients with nOH have an inadequate salt intake.
  • Improve physical conditioning that is not gravitationally challenging (eg, stationary recumbent bicyle, rowing machine).
  • Avoid increased core body temperature (eg hot tubs, prolonged hot showers).
  • Head-up position while sleeping through use of a wedge under the mattress or blocks under the head of the bed so that the head is 6-9 inches (15-23 cm) higher than the feet. This is to minimize nocturnal supine hypertension which can cause pressure diuresis and volume depletion.
  • Compressive garments, preferably either an abdominal binder or thigh high stockings when erect; knee high stocking are not likely to be effective.
  • Smaller, more frequent,  meals not high in carbohydrates in patients with postprandial hypotension.
  • Dietary supplementation with B12 or iron, if deficient.

 

References

  1. Gibbons CH, Schmidt P, Biaggioni I, et al. The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension. J Neurol 2017;264:1567-1582. https://www.ncbi.nlm.nih.gov/pubmed/28050656
  2. Jordan J, Shannon JR, Black BK, et al. The pressor response to water drinking in humans: a sympathetic reflex? Circulation 101:504-9. http://circ.ahajournals.org/content/101/5/504.long
  3. Raj SR, Biaggioni I, Black BK, et al. Sodium paradoxically reduces the gastropressor response in patients with orthostatic hypotension. Hypertension 2007;48:329-334. https://www.ncbi.nlm.nih.gov/pubmed/16785332
Which non-pharmacological approaches may help symptoms of orthostatic hypotension in my patient with autonomic insufficiency?

My elderly patient is scheduled to undergo elective surgery? Is there an objective “stress test for the brain” that may predict postoperative delirium?

Possibly, in the near future! Although the pathophysiology of postoperative delirium (POD) is not fully understood, a recently proposed conceptual model of delirium may provide a basis for preoperative neurophysiologic testing1.

According to this model, delirium is a “consequence of the breakdown in brain network dynamics” precipitated by insults or stressors (eg, surgery) in persons with low brain resilience ie, low connectivity between brain regions and/or deficient neuroplasticity (the ability of brain to reorganize itself by forming new neural connections).  

As expected,  patients with strong baseline connectivity and optimal neuroplasticity would not be expected to have POD, whereas those with weakened connectivity (eg baseline cognitive dysfunction) and/or suboptimal neuroplasticity (eg due to aging) may be at higher risk. Transcranial magnetic stimulation (TMS)  is considered a powerful tool that measures the connectivity and plasticity of the brain through induced perturbation.  When applied in repetitive trains, TMS produces changes in cortical excitability that can be measured using electromyography and EEG,  and is thought to have the ability to assess neuroplasticity 2. If proven effective in predicting POD, it could revolutionize preoperative risk assessment in the elderly! Stay tuned!

 

Reference

  1. Shafi MM, Santarnecchi E, Fong TG, et al. Advancing the neurophysiological understanding of delirium. J Am Geriatr Soc 2017. DOI:10.1111/jgs.14748.
  2. Pascual-Leone A, Freitas C, Oberman L, et al. Characterizing brain cortical plasticity and network dynamics across the age-span in health and disease with TMS-EEG and TMS-fMRI. Brain Topogr 2011, 24:302-15.
My elderly patient is scheduled to undergo elective surgery? Is there an objective “stress test for the brain” that may predict postoperative delirium?

When should I suspect spinal epidural abscess in my 55 year old patient with severe back pain?

 It cannot be overemphasized that up 50% of patients with spinal epidural abscess (SEA) have no known risk factors,  one-half may have no fever,  and 20-40% lack leukocytosis1. In fact, the “classic triad” of back pain, fever, and neurological deficits is found only in the minority of patients!  No wonder that up to 75% of patients SEA are misdiagnosed on their initial healthcare encounter1!

Potential “red flags” for infectious causes of low back pain include age >50 y, night pain, unremitting pain even when supine, duration > 6 weeks, fever, chills, night sweats, weight loss, conditions associated with Staphylococcus aureus bacteremia (eg intravenous drug use), incontinence, saddle anesthesia, and severe or rapidly progressive neurologic deficits1,2.  

ESR and C-reactive protein (CRP) are almost uniformly elevated in SEA1 and can serve as a good starting point in excluding this condition when in doubt.   In patients ≥50 y of age with low back pain, obtaining ESR routinely has been suggested for detection of systemic disease (eg cancer, infection)3.  Similarly, in a recent algorithm of severe back pain, routine measurements of ESR and CRP, even in the absence of any neurological findings, has been recommended1; elevation of either may necessitate consideration of MRI.

References:

  1. Bond, A, Manian FA. Spinal epidural abscess: a review with special emphasis on earlier diagnosis. BioMed Res International 2016; https://www.hindawi.com/journals/bmri/2016/1614328/http://dx.doi.org/10.1155/2016/1614328  
  2. Della-Giustina. Acute low back pain: recognizing the “red flags” in the workup. Consultant 2013;53:436-440. http://www.consultant360.com/article/acute-low-back-pain-recognizing-%E2%80%9Cred-flags%E2%80%9D-workup
  3. Jarvik JG, Deyo RA. Diagnostic evaluation of low back pain with emphasis on imaging. Ann Intern Med 2002;137:586-597. http://annals.org/aim/article/715687/diagnostic-evaluation-low-back-pain-emphasis-imaging

 

Disclosure: The author of this post (FAM) also coauthored reference 1.

When should I suspect spinal epidural abscess in my 55 year old patient with severe back pain?