A brief history

Autonomic Neuropathy is well established as a “crystal ball” for morbidity and mortality risks in patients diagnosed with Diabetes . Unfortunately, Autonomic Neuropathy is poorly understood and perceived to be untreatable . Yet significant morbidity and mortality risks may now be attributable to autonomic imbalance between the Parasympathetic and Sympathetic (P&S) nervous systems and their regulation of cardiovascular and respiratory function , indeed the function of all organs and virtually every cell in the human body. Heart rate alone , nor heart rate variability (HRV) alone , provides reliable diagnostic criteria for Autonomic Neuropathy. Diabetes, with its many factors and symptoms [e.g., high blood sugar, low insulin, obesity, overproduction of inflammatory cytokines, sleep apnea, high blood pressure (BP), oxidative stress, etc.], leads to, and exacerbates, P&S imbalance .

In Diabetes, these factors and symptoms are mostly mediated by the Sympathetic nervous system, causing or contributing to Sympathetic Excess (SE). This SE is typically the beginning of P&S imbalance in most patients diagnosed with Diabetes. SE will cause a Parasympathetic Excess (PE), as the still healthy P&S nervous systems attempt to reestablish proper balance. Eventually, prolonged SE prolongs PE, and leads to an accelerated aging of the Parasympathetic nervous system, which is the beginning of Autonomic Dysfunction and its progression to Autonomic Neuropathy. Granted, earlier and more aggressive treatment has become the norm for Diabetes, based on published standards, diagnosis and intervention is usually not early enough and oftentimes therapy is too much. Since the typical measures of Diabetes are Sympathetic in nature, and the drive is to normalize the symptoms of SE, many times the Sympathetics are unintentionally overmedicated, exacerbating the PE and further accelerating the onset of Autonomic Neuropathy. More information is needed to improve outcomes.

It has long been well established that restoring proper autonomic balance reduces morbidity and mortality, thereby improving outcomes . To do so, independent, simultaneous measurements of P&S activity is needed. Unfortunately, virtually all autonomic measures are measures of only total autonomic activity (which is a measure of the combined P&S effect), and the activity of the two autonomic branches is based on assumption and approximation or criteria that require prolonged suffering before a diagnosis (and therefore treatment) may be considered. For example, it has been stated that Orthostatic Hypotension (OH) is the most debilitating symptom of Autonomic Neuropathy . The clinical definition of OH is a 20/10 mmHg decrease in BP upon assuming an upright posture (i.e., sitting or standing up). A normal change in BP upon standing is a 10% increase in BP (e.g., approximately an 11/7 mmHg increase , assuming a normal average resting BP). Therefore a weak increase is already abnormal, and a lack of change in BP upon standing is already significantly abnormal. Yet we are forced to make our patients wait (and suffer) until the abnormal BP change becomes a threefold ^a

a Normal is a 10 mmHg increase in systolic BP, and the criterion for OH is a 20 mmHg decrease in systolic BP. The net is a 30 mmHg decrease. Comparing the abnormal decrease (30) to the normal increase (10), the result is a threefold abnormal change, and that is just the threshold for a clinical diagnosis.

b Waiting for the clinical OH criteria may accelerate the onset of Heart Failure. The decrease in BP upon standing may also cause poor cardiac perfusion and reduced Diastolic pressure. The resulting poor brain perfusion often leads to Sympathetic stimulation that increases Systolic pressure. If left undetected, the Systolic-Diastolic difference (Pulse Pressure) may eventually grow to Hypertension and Heart Failure (two common comorbidities associated with Diabetes). In these cases, when the Hypertension and Heart Failure are treated with Sympatholytics, the Sympatholytics may further exacerbate the condition.

Autonomic neuropathy references the progression from healthy to end stage. The end stage is known as Cardiovascular Autonomic Neuropathy (CAN, see Fig. 10.1 ). This terminology is unfortunate in that “neuropathy” is often misleading. The perception of “neuropathy” is “dead nerves.” The teaching is that dead nerves are not treatable. Therefore the logic is that Autonomic Neuropathy is not treatable. This is compounded by the fact that the function of the two individual Autonomic branches, the P&S nervous systems, has been difficult to measure independently and simultaneously, without assumption and approximation. The result is that Autonomic Neuropathy is largely unknown. However, recently, patients have been seeking solutions to long-standing conditions and have driven an increased awareness.

The progression of P&S Dysfunction. The Parasympathetic or Vagal measure is RFa (the Respiratory Frequency area in bpm ² ) and the Sympathetic measure is LFa (the Low Frequency area in bpm ² ). The normal range for both is 0.5–10.0 bpm ² . The ratio of the two (LFa/RFa, known as Sympathovagal Balance or SB) has a normal range of 0.4–3.0. The normal region (depicted in gray) is the best we get when we are born. Regardless of health condition, the P&S nervous systems decline with age. Disease and disorder accelerate the decline. The slowest decline is to stay within the normal limits of Balance. At the origin, with no energy left in either branch, life ceases. The stages of P&S Dysfunction start in the periphery when patients appear normal at rest. The second stage is Diabetic Autonomic Neuropathy (DAN, or Advanced Autonomic Dysfunction, or AAD, if not Diabetic). DAN indicates higher morbidity risk. The third stage is Cardiovascular Autonomic Neuropathy (CAN). CAN indicates mortality risk. There are two possible states of CAN: structural and functional. If CAN is structural, then only responses around the point A1 are possible with treatment, and while structural CAN is irreversible, treatment to normalize SB minimizes or normalizes the mortality risk of CAN. If CAN is functional, then both the responses around points A1 and A2 are possible with treatment, and functional CAN may be temporarily reversible. Treating functional by also normalizing SB minimizes mortality risk. P&S , Parasympathetic and Sympathetic.

Regardless of the terminology, and contrary to the common misperception, Autonomic Neuropathy is treatable, even in the end stage ; P&S balance is the key. To help with the misperception, where appropriate, we will use “Autonomic Dysfunction” or more specifically “P&S Dysfunction” as the “new name” for “Autonomic Neuropathy.” Hopefully, this will also help with earlier detection. The earlier P&S Dysfunction is detected, the greater the number of available therapy options, including supplements and lifestyle modifications as well as pharmaceutical therapies. While it is easier to correct early-stage P&S Dysfunction compared with advanced-stage autonomic neuropathic damage, now that we are able to measure P&S Dysfunction in all stages, all stages are treatable .

Autonomic function

The main function of the Autonomic Nervous System (ANS) is to maintain homeostasis, regardless of the conditions. The P&S dynamically adjust their output to maintain homeostasis and apparent normalcy even in the face of degraded P&S function or degraded end-organ function. The P&S nervous systems control and coordinate organ function. Organ dysfunction generates symptoms (typically not P&S dysfunction). The P&S nervous systems control and coordinate normal organ function even when they are in abnormal states. ^c

c For example, assume proper organ control requires a P&S activity of 4. Given normal conditions, with proper P&S balance, that would be a P-activity of 2 and an S-activity of 2 (2+2=4). All is normal and there are no symptoms. However, if S-activity becomes excessive (i.e., SE) and rises to a 3, and P-activity degrades to a 1, normal organ function is still maintained because P&S activity is still a 4 (3+1=4), and there are yet to be any symptoms. An ultimate possibility is when SE rises to a 4, and P-activity degrades to a 0. Normal organ function is still maintained because P&S activity is still a 4 (4+0=4), and there are still no symptoms until the ultimate symptom, Sudden Cardiac Death, because there is no longer sufficient P-activity to prevent a Sympathetically mediated Ventricular Tachyrhythm from progressing. Since we know that Diabetes leads to P&S Dysfunction, then we should monitor P&S activity more frequently and right from the beginning, even when asymptomatic, to detect the earliest P&S dysfunction and treat to reestablish and maintain P&S balance.

By way of an example, consider the thermostat on the wall of your house. Assume that you have no knowledge of, and cannot access or hear, the separate heating and cooling systems of your house. Further, assume that you like your house temperature to be 70°F (like heart rate at 70 bpm), and that is what your thermostat is set to. As long as the thermostat reads “70,” everyone is happy. Now assume it is a hot, humid, August day in a southern US city, the cooling system is working well, but a $5 heater switch fails, and the heater comes on full. What happens to the temperature in the house as read on the thermostat? … Nothing! … The cooling system is working well, so it “amps-up” and compensates, not only for the ambient temperature, but also for the dysfunctional heating system, and 70 is still the reading. If temperature was heart rate, the heart rate does not change even though both autonomic branches are overactive. This is more information and potentially earlier detection.

The question becomes, how long will the dysfunctional situation last until there is a catastrophic failure (costing $5000 or more) in one or both of the cooling and heating systems? Meanwhile, you are totally unaware (like your heart rate is still normal, 70) until the catastrophic failure (like a heart attack), when it is too late. Monitoring the P&S nervous system independently and simultaneously will detect when the $5 switch fails. Unfortunately, most noninvasive, autonomic measures only measure total autonomic function. They only measure the resulting temperature as read on the thermostat, and the underlying abnormality is missed until it is late in the progression. From monitoring the individual branches, therapy recommendations (as described herein) help keep the systems functioning normally (healthy) and a proper balance between the cooling (Parasympathetic) and heating (Sympathetic) systems maintained, to help keep the “$5 switches” functioning normally, helping to maintain both health and wellness. The technique known as P&S Monitoring monitors the switches (and more) as well as the thermostat.

Autonomic dysfunction and morbidity and mortality risk

Again, CAN is end-stage P&S Dysfunction (see Fig. 10.1 ). CAN leads to the catastrophic failure in the above model. It is approximated by a severe lack of HRV, which is by definition a severe lack of resting Parasympathetic activity. ^d

d CAN is defined as the Parasympathetic measure (RFa, or Respiratory Frequency area) < 0.1 bpm ² . This indicates that there is insufficient Parasympathetic activity to prevent, for example, a Sympathetically mediated Ventricular Tachyrhythm from progressing. In other words, the mortality risk is high as in the Framingham Heart criteria.

With P&S Monitoring, early-stage Dysfunction (the $5 switch failure in the thermostat model) may now be detected early and clinically followed, before the onset of CAN (the $5000 failure in the thermostat model). When P&S balance is restored, by normalizing the ratio of resting S-activity to resting P-activity (known as Sympathovagal Balance, or SB=S/P), the progression of P&S Dysfunction is slowed or stayed. As you know, aging is dictated by an individual’s history, lifestyle, and genetic make-up. The normal aging process (without the acceleration due to chronic disease or disorder) causes autonomic decline, ultimately leading to CAN. This normal aging process is the target rate of autonomic decline. This is one reason why even “healthy” older people have greater morbidity and mortality risk than younger people. CAN is inevitable for all and each individual is different.

Even after the onset of CAN, normalizing SB (see Fig. 10.1 ) slows the progression of P&S Dysfunction by limiting the morbidity and mortality risk, optimizing QoL, and promoting normal longevity for the individual. Establishing and maintaining normal SB, appropriate for the individual, also reduces secondary symptoms, which reduces medication load, prevents hospitalizations and re-hospitalizations, and thereby lowers healthcare costs .

CAN is associated with high risk of sudden cardiac death and other Major Adverse Cardiovascular End-points (MACE). In patients with Diabetes, Diabetic Autonomic Neuropathy (DAN) indicates an increased risk of CAN and is diagnosed based on the early symptoms of neuropathy and P&S Dysfunction (see Fig. 10.1 ). DAN involves lightheadedness (or dizziness, arguably the worst of the symptoms), as well as nervous system dysfunction, vascular dysfunction, gastrointestinal (GI) upset, BP dysfunction, vision decline (faster than presbyopia), Anhydrosis, dry and cold skin, sex dysfunction, renal dysfunction, mental and cognitive dysfunction, and cardiovascular disease . Much of the sensory and motor dysfunctions (including wound healing difficulties and amputation issues) are a function of poor autonomic nerve control of the vasculature. This causes vascular dysfunction, leading to poor tissue perfusion, predisposing the patient to acquiring wounds and not having the sensation of the wound’s existence (sensory nerves need blood also), facilitating infection (due to the poor perfusion and again without sensation) and often ending in amputation. Clinical symptoms generally do not appear until long after the onset of Diabetes. However, subclinical P&S Dysfunction may occur within a year of diagnosis in type 2 Diabetes and within two years in type 1 Diabetes . In general, a diagnosis of DAN is made only after eliminating other causes of neuropathy.

CAN is defined as very low, resting Parasympathetic activity (see Fig. 10.1 ). CAN indicates that the Parasympathetics maybe too weak to prevent a Sympathetically mediated Ventricular Tachyrhythm from progressing. Thus CAN with high, resting Sympathetic activity relative to Parasympathetic activity is a mortality as well as a morbidity risk indicator (e.g., silent MI, respiratory failure, and sudden death) . The mortality risk for DAN has been estimated to be 44% within 2.5 years of diagnosing symptomatic autonomic neuropathy . Meta -analysis data for the pooled prevalence rate risk for silent myocardial ischemia was 1.96, with 95% confidence interval of 1.53–2.51 ( P <.001; n =1468 total subjects). Thus a consistent association between autonomic neuropathy and the presence of silent myocardial ischemia was shown .

There are two forms of CAN: functional and structural (see Fig. 10.1 ). Functional CAN patients often find (temporary) relief of CAN once a proper P&S balance is restored for them, the individual patient. Structural CAN is not reversible. Both carry mortality risks. CAN risk is the same as for post-MI and post-coronary artery bypass graft (CABG) patients, as documented in the Framingham Heart Study , as well as for other MACE (including stroke) patients. CAN has been found to carry a 50% increase in the 2-year mortality rate .

CAN is typically normal for post-MI, post-CABG, chronically ill, and geriatric patients. CAN is a normal part of the aging process on the ANS. Again, CAN simply indicates mortality risk. In other words, it is a sign of age, and people with CAN, who tend to be older, have a greater risk of dying than people without CAN, who tend to be younger and healthier. However, regardless of age, CAN with abnormal P&S balance (SB) is not normal. CAN with high SB is high risk and is associated with other risk factors , including (1) low ejection fraction ; (2) poor cardiac output ; (3) arrhythmias ; (4) cardiomyopathies , including chronic heart failure ; (5) poor circulation , including poor cardiac circulation (Angina or CAD) ; (6) greater mortality ; and (7) greater morbidity , including silent MI and early cardiac death . CAN with low P&S balance is associated with “Broken Heart Syndrome” , depression, and depression-anxiety syndromes. Often, CAN leads to the need for cardiac intervention or an implanted cardiac device. CAN affects longevity.

Natural history of autonomic decline

Normal autonomic decline

As mentioned above, autonomic decline is a fact of life (see Fig. 10.2 ). Humans are born with as active a P&S nervous system as they will have. Ultimately, at the end of life, there is no activity in the P or S nervous systems. The normal aging process causes a gradual decline over time. Fig. 10.2 displays the normal Parasympathetic (broken, blue curve) and normal Sympathetic (broken, red curve) changes over time from 346 known healthy volunteers from ages 3 to 96years (58% female). None of these subjects are diagnosed with chronic disease and all demonstrate normal responses to the clinical P&S assessment study. P&S activity is presented on the ordinate (in bpm ² ) and age (in years) is presented on the abscissa. The broken, black line at the 1.0 level is the normalized threshold for DAN or Advanced Autonomic Dysfunction (AAD, if not diabetic), based on Framingham Heart Study findings. These curves offer several insights to normal autonomic decline. At both ends of the age range, Parasympathetic activity is normally higher than Sympathetic activity (SB ^g

g SB=(resting Sympathetic activity)/(resting Parasympathetic activity), Normal range: 0.4<SB<3.0; Preferred normal for geriatric and chronically ill: 0.4<SB<1.0; Preferred normal for younger patients: 1.0<SB<3.0.

is in the low-normal range: 0.4<SB<1.0). In the early years, this reflects the Parasympathetic involvement in development. In the later years, the low-normal SB reflects the added Parasympathetic activity that has been shown to protect the organs, reduce morbidity and mortality, and improve outcomes . This has become the recommended P&S balance for geriatric patients. In the middle years, the balance is approximately 1.0 (the curves overlie each other) or a little above 1.0. This may reflect the need of young adults to have the additional energy for child-rearing.

An age-matched comparison between normal subjects and patients with Diabetes. See text for details.