Dysautonomia: A Forgotten Condition - Part 1

Abstract

Dysautonomia covers a range of clinical conditions with different characteristics and prognoses. They are classified as Reflex Syndromes, Postural Orthostatic Tachycardia Syndrome (POTS), Chronic Fatigue Syndrome, Neurogenic Orthostatic Hypotension (nOH) and Carotid Sinus Hypersensitivity Syndrome. Reflex (vasovagal) syndromes will not be discussed in this article. Reflex (vasovagal) syndromes are mostly benign and usually occur in patients without an intrinsic autonomic nervous system (ANS) or heart disease. Therefore, they are usually studied separately. Cardiovascular Autonomic Neuropathy (CAN) is the term most currently used to define dysautonomia with impairment of the sympathetic and/or parasympathetic cardiovascular autonomic nervous system. It can be idiopathic, such as multisystemic atrophy or pure autonomic failure, or secondary to systemic pathologies such as diabetes mellitus, neurodegenerative diseases, Parkinson's disease, dementia syndromes, chronic renal failure, amyloidosis and it may also occur in the elderly. The presence of Cardiovascular Autonomic Neuropathy (CAN) implies greater severity and worse prognosis in various clinical situations. Detection of Orthostatic Hypotension (OH) is a late sign and means greater severity in the context of dysautonomia, defined as Neurogenic Orthostatic Hypotension (nOH). It must be differentiated from hypotension due to hypovolemia or medications, called non-neurogenic orthostatic hypotension (nnOH). OH can result from benign causes, such as acute, chronic hypovolemia or use of various drugs. However, these drugs may only reveal subclinical pictures of Dysautonomia. All drugs of patients with dysautonomic conditions should be reevaluated. Precise diagnosis of CAN and the investigation of the involvement of other organs or systems is extremely important in the clinical suspicion of pandysautonomia. In diabetics, in addition to age and time of disease, other factors are associated with a higher incidence of CAN, such poor glycemic control, hypertension, dyslipidemia and obesity. Among diabetic patients, 38-44% can develop Dysautonomia, with prognostic implications and higher cardiovascular mortality. In the initial stages of DM, autonomic dysfunction involves the parasympathetic system, then the sympathetic system and, later on, it presents as orthostatic hypotension. Valsalva, Respiratory and Orthostatic tests (30:15) are the gold standard methods for the diagnosis of CAN. They can be associated with RR Variability tests in the time domain, and mainly in the frequency domain, to increase the sensitivity (protocol of the 7 tests). These tests can detect initial or subclinical abnormalities and assess severity and prognosis. The Tilt Test should not be the test of choice for investigating CAN at an early stage, as it detects cases at more advanced stages. Tilt response with a dysautonomic pattern (gradual drop in blood pressure without increasing heart rate) may suggest CAN. Treatment of patients at moderate to advanced stages of dysautonomia is quite complex and often refractory, requiring specialized and multidisciplinary evaluation. There is no cure for most types of Dysautonomia at a late stage. NOH patients can progress with supine hypertension in more than 50% of the cases, representing a major therapeutic challenge. The immediate risk and consequences of OH should take precedence over the later risks of supine hypertension and values greater than 160/90 mmHg are tolerable. Sleeping with the head elevated (20-30 cm), not getting up at night, taking short-acting antihypertensive drugs for more severe cases, such as losartan, captopril, clonidine or nitrate patches, may be necessary and effective in some cases. Preventive measures such as postural care; good hydration; higher salt intake; use of compression stockings and abdominal straps; portioned meals; supervised physical activity, mainly sitting, lying down or exercising in the water are important treatment steps. Various drugs can be used for symptomatic nOH, especially fludrocortisone, midodrine and droxidopa, the latter not available in Brazil. The risk of exacerbation or triggering supine hypertension should be considered. Chronic Fatigue Syndrome represents a form of Dysautonomia and has been renamed as a systemic disease of exercise intolerance, with new diagnostic criteria: 1 - Unexplained fatigue, leading to occupational disability for more than 6 months; 2 - Feeling ill after exercising; 3 - Non-restorative sleep; 4 - One of the following findings: cognitive impairment or orthostatic intolerance. Several pathologies today have evolved with chronic fatigue, being called chronic diseases associated with chronic fatigue. Postural orthostatic tachycardia syndrome (POTS), another form of presentation of dysautonomic syndromes, is characterized by sustained elevation of heart rate (HR) ≥30 bpm (≥40 bpm if <20 years) or HR ≥120 bpm, in the first 10 minutes in an orthostatic position or during the tilt test, without classical orthostatic hypotension associated. A slight decrease in blood pressure may occur. Symptoms appear or get worse in an orthostatic position, with dizziness, weakness, pre-syncope, palpitations, and other systemic symptoms being common.

Figura 1. Inervação do coração e dos vasos sanguíneos pelo SNA simpático e parassimpático. Os neurônios parassimpáticos estão representados em vermelho e os neurônios simpáticos, em verde. Nodo SA — nodo sinoatrial; nodo AV — nodo atrioventricular. Para facilitar a visualização, foi representado um único segmento medular esquemático e as imagens não estão representadas na mesma escala gráfica.

Figura 2. Causas de disautonomia.

Figura 3. Fluxograma para Avaliação e Seguimento das disautonomias ou neuropatias autonômicas cardiovasculares (NAC)

1. Ocorre de forma idiopática como na atrofia multissistêmica ou na falência autonômica pura, ou em patologias como diabetes mellitus, doenças neurodegenerativas, Doença de Parkinson, síndromes demenciais, insuficiência renal crônica, amiloidose, algumas doenças neoplásicas e nos idosos.

2. Eletrocardiograma para avaliar frequência cardíaca e intervalo QT.

3. Testes neurológicos como eletromiografia, ressonância cerebral, testes cardiológicos como Holter 24 h, avaliação de isquemia.

   Testes laboratoriais como hemograma completo, função renal, cortisol, ACTH, perfil glicêmico, catecolaminas plasmáticas colhidas deitado e logo após ortostase, marcadores neoplásicos e de doenças autoimunes, dentre outros (vide seção específica).

4. Conforme recomendação das diretrizes internacionais no diabético1,2,7.

5. SGLT2 — Medicamentos para diabetes – inibidores da enzima cotransportadora de sódio-glicose, sendo usados para tratamento da diabetes.

6. Pacientes com extrassístoles muito frequentes, fibrilação atrial, marca-passo cardíaco ou disfunção cognitiva avançada não conseguem ser avaliados por essa metodologia. Considerar que vários fármacos devem ser suspensos para o exame e os valores das medidas devem ser correlacionados com valores de normalidade para a idade e o sexo.

Figura 4. Teste de inclinação com medidas hemodinâmicas, onde os valores do volume sistólico, débito cardíaco e resistência vascular periférica (RVP) foram corrigidos para a superfície corporal, obtendo-se o índice sistólico (IS), índice cardíaco (IC) e índice de RVP (IRVP). 4A. Paciente com diagnóstico clínico de fadiga crônica. Logo após inclinação, observa-se redução exagerada do IS (>30%), compensada inicialmente por elevação esperada do IRVP e da FC. Após 15 minutos de inclinação, observa-se maior redução do IS, associada com redução do IRVP, ao invés de maior elevação compensatória esperada do IRVP, de modo que a compensação para manter a PA estável se faz às custas de maior elevação da FC, que passa a apresentar um aumento exagerado (>30 bpm), do que observado em posição supina. Essa alteração ocorre mais tardiamente (após 10 minutos do início do exame), não preenchendo os critérios para SPOT. 4B. Paciente com diagnóstico de SPOT. Observa-se, durante a inclinação, redução do IS não compensada pela elevação do IRVP. Há redução ao invés de elevação no IRVP ao assumir a posição ortostática. Desse modo, a pressão arterial média (PA) se mantém estável, às custas de elevação exagerada da frequência cardíaca (FC) em >30 bpm ocorrendo nos primeiros 10 minutos de inclinação, associado com sintomas, preenchendo, portanto, critérios para SPOT. A diferença entre as duas entidades pode ser, em alguns casos, apenas temporal.

Figura 5. Teste de inclinação com medidas hemodinâmicas, onde volume sistólico, débito cardíaco e resistência vascular periférica (RVP) foram corrigidos para a superfície corporal, obtendo-se índice sistólico (IS), índice cardíaco (IC) e índice de RVP (IRVP). PA: pressão arterial. 5A. Paciente com intolerância ortostática. Não ocorre a elevação esperada do IRVP, que apresenta redução progressiva compensada por elevação progressiva da FC até o final da inclinação, com redução discreta da PA. Os sintomas ocorrem na vigência de déficit na elevação da RVP em posição ortostática. 5B. Paciente com hipotensão ortostática tardia. Neste, também se observa ausência de redução do IS e redução progressiva do IRVP durante inclinação. Após 10 minutos de inclinação, quando ocorre maior redução do IRVP, que não é acompanhada de elevação adicional da FC, observa-se hipotensão ortostática, com sintomas. Nota-se que após 20 minutos ocorre recuperação espontânea do IRVP e da PA, com alívio dos sintomas.

Figura 6. Algoritmo de tratamento para portadores de SPOT.

Figure 1. Schematic representation of heart and blood vessels innervation by the sympathetic and parasympathetic ANS. Parasympathetic neurons are represented in red and sympathetic neurons are represented in green. SA node — sinoatrial node; AV node — atrioventricular node. For better viewing, a single schematic spinal segment was represented and the images are not represented on the same graphic scale.

Figure 2. Causes of dysautonomia.

Figure 3. Flowchart of Evaluation and Follow-up of Dysautonomia or Cardiovascular Autonomic Neuropathy (CAN)

1. It occurs idiopathically, as in multiple system atrophy or pure autonomic failure, or in pathologies such as diabetes mellitus, neurodegenerative diseases, Parkinson's disease, dementia syndromes, chronic renal failure, amyloidosis, some neoplastic diseases and in the elderly.

2. Electrocardiogram to assess heart rate and QT interval.

3. Neurological tests such as electromyography, brain resonance imaging, cardiological tests such as 24-h Holter, ischemia evaluation.

4. Laboratory tests including complete blood count, renal function, cortisol, ACTH, glycemic profile, plasma catecholamines collected lying down and immediately after orthostasis, neoplastic and autoimmune disease markers, and others (see specific section).

5. As recommended by international guidelines on diabetics.^,,

6. SGLT2 — Diabetes medications — sodium-glucose co-transporter inhibitors used to treat diabetes

7. Patients with very frequent extrasystoles, atrial fibrillation, cardiac pacemaker and advanced cognitive dysfunction cannot be evaluated using this methodology. Consider that several drugs must be suspended for the examination and the values of the measurements must be correlated with normal values for age and sex.

Figure 4. Tilt test with hemodynamic measurements, where systolic volume, cardiac output and peripheral vascular resistance (PVR) were corrected for body surface, resulting in systolic index (SI), cardiac index (CI) and PVR index (PVRI). 4A. Patient with clinical diagnosis of chronic fatigue. Right after tilting, there is an exaggerated reduction in SI (>30%), initially compensated by the expected increase in PVRI and HR. After 15 minutes of tilting, there is a greater SI reduction associated with a PVRI reduction, instead of the greater compensatory increase expected of the PVRI. Therefore, the compensation to keep the BP stable occurs at the expense of a greater HR increase, which then presents excessive increase (>30 bpm), than in the supine position. This change occurs later (10 minutes after the beginning of the test), not fulfilling the criteria for POTS. 4B. Patient diagnosed with POTS. During the tilt test, an SI reduction is not compensated by a PVRI increase. PVRI decreases, rather than increases, in orthostatic position. Therefore, mean blood pressure (BP) remains stable due to an excessive increase in heart rate (HR) by >30 bpm, occurring in the first 10 minutes of tilting, associated with symptoms, thus fulfilling the POTS criteria. The difference between the two conditions can be, in some cases, only time-related.

Figure 5. Tilt test with hemodynamic measures, where systolic volume, cardiac output and peripheral vascular resistance (PVR) were corrected for body surface, resulting in systolic index (SI), cardiac index (CI) and PVR index (PVRI). BP — blood pressure 5A. Patient with orthostatic intolerance. There is no expected PVRI increase. Instead, it presents a progressive reduction compensated by a progressive increase in HR, until the end of tilting, with a slight reduction in BP. The symptoms occur in the presence of a deficit in PVR increase in an orthostatic position. 5B. Patient with late orthostatic hypotension. In this case, there no SI reduction and there is a progressive PVRI reduction during the tilt test. After 10 minutes of tilting, when there is a greater PVRI reduction, which is not accompanied by any additional HR increase, orthostatic hypotension is observed, with symptoms. After 20 minutes, spontaneous recovery of PVRI and BP occurs, with relief of symptoms.

Figure 6. Treatment algorithm for patients with POTS.