The Peripheral Nervous System and Changes in Blood Pressure: Lights and Darkness

Olivopontocerebellar atrophy was discovered in 1900. In 1960, Shy and Dragger described “a neurological disorder associated with orthostatic hypotension”; subsequently, nigrostriatal and cerebellar nigrostriatal degenerations were also described. Today, all these pathologies make up the multiple systemic atrophies (MSAs), which are divided into 2 types: parkinsonian (MSA-P) and cerebellar (MSA-C). The main histological features of MSA encompass 4 types with different severities: S-immunoreactive substance inclusions within oligodendrocytes, also known as Papp–Lantos bodies (the presence of which is required for definitive histopathological diagnosis). Less frequent are the neuronal cytoplasmic, nuclear glial, and neuronal nuclear inclusions. The resulting neurodegeneration affects multiple systems, involving not only the striatonigral system and the olivopontocerebellar pathway, but also autonomous nuclei of the brain stem, spinal cord, and even the peripheral nervous system,1–4 which is what causes visceral manifestations such as vascular and genitourinary pathologies. The main characteristic of the vascular effects is a high variability of blood pressure (BP) that alternates between markedly high and symptomatic low levels. On the other hand, there is a subgroup of essential hypertensive patients who have high variability and the absence of drops in BP at night. This type of hypertension is mainly related to stress and occurs in nervous people. It responds well to beta-blockers and obliges to rule out secondary hypertension and fundamentally pheochromocytoma, sleep apnea–hypopnea syndrome, and dysautonomia.5 A 47-year-old patient, an athlete in his youth, without history of cardiovascular disease or toxic habits, was referred to the cardiology department for syncopal episodes triggered by getting up, standing, or making efforts. He denied other symptoms. The cardiological assessment included an echocardiography showing concentric left ventricular remodeling (left ventricular mass index 83.16 g/m2), relative wall thickness (0.47) with normal left atrium size (diameter 35 mm × height 38 mm), and mitral inflow suggestive of a grade I diastolic dysfunction. A coronary angiography reported the normality of coronary arteries with left dominance. An electrophysiological study performed at different institutions showed extrinsic sinus dysfunction, and continuous cardiac rhythm evaluation through a Holter device from 2013 to 2017 did not detect arrhythmic events. Finally, a tilt test was performed, showing a vasodepressor response intensified with severe hypotension after receiving sublingual nitroglycerin. The combined results of these studies led to the diagnosis of neuromediated syncope. In July 2014, a registry of ambulatory blood pressure monitoring (ABPM) was also performed. The Space labs 90207R (Box 97013, Redmond, WA 98073-9713, United States) was used and BP was automatically measured every 20 minutes. The cuff size was 24–32 cm (average adult), and the patient was given a diary to record any incidents. In that diary, the patient would also register the time he went to sleep and when he woke up. The period between 08:00 and 23:59 hours was considered daytime and from 00:00 to 08:00 hours was considered nighttime. The ABPM showed normal values: 110/72 mm Hg; however, BP did not decrease at nighttime (108/71 mm Hg during the day and 111/73 mm Hg at nighttime) and high variability was also detected (SD of the mean of 19.41 mm Hg for systolic and 14.81 mm Hg for diastolic, range of variation: 157–71 mm Hg for systolic and 110–42 for diastolic BP). The heart rate (mean ± SD) was 86 ± 8.7 bpm with a range of variation of 110–70 bpm. This means that normotensive but with a riser nocturnal pattern and high variability of BP. All biochemical parameters including glucose, HbA1c, creatinine, sodium, potassium, hemoglobin, and albumin–creatinine ratio were within the normal range; there was no evidence of end-organ damage. Months later, he was referred to the urologist for urinary urgency and erectile dysfunction. After starting treatment with a phosphodiesterase-5 inhibitor (Tadalafil®), he presented an episode of priapism that required hospital admission and urological evaluation. It was decided to suspend the medication, and there were no further episodes of priapism. Two years later, he was referred to the neurology department for the difficulty in swallowing, trembling hands, difficulty writing, and disturbing dreams. The treatment was started with Levodopa without response (this is typical of MSA and unlike Parkinson’s disease). An 123Iodine-labelled N-(3-fluoropropyl) -2β-carbomethoxy-3β-(4-iodophenyl) nortropane (123I-FP-CIT) single photon emission computerized tomography (SPECT) showed signs of nigrostriatal degeneration leading to the likely diagnosis of type P MSA. Due to the highly variable BP levels, the neurology department referred him to our Vascular Risk Unit. During his first visit, he reported frequent dizziness coinciding with hypotension while standing. On physical examination, his body mass index was normal, he presented a BP of 160/100 mm Hg on recumbent position, and 110/80 mm Hg after 3 minutes standing. The heart rate was, respectively, 65 and 59 bpm. A 24-hour ABPM was requested in 2016 (Figure 1), while the patient was under treatment with fludrocortisone for orthostatic hypotension. Mean BP was 138/94 mm Hg and, as shown in Figure 1, there was a riser pattern of nighttime BP with very high variability. It was also striking that during the period from 15.00 to 16.00 hours, the average of the readings was 160/110.5 mm Hg. This was attributed to napping in a decubitus position during that timeframe. We advised him not to take a nap in decubitus without success, as we will see 1 year later. Registry of ABPM under treatment with fludrocortisone. The ordinate axis represents blood pressure and the abscissa axis the time from the beginning to the end of the record (10.59–10.18 hours). Abbreviation: ABPM, ambulatory blood pressure monitoring. The patient was sent to the sleep unit, where after a nighttime, polygraph was diagnosed with sleep apnea–hypopnea syndrome and treated with continuous positive airway pressure. However, this treatment was suspended 4 months later due to a lack of adherence. In order to discard the causes of secondary hypertension, 24-hour urinary catecholamines and urinary-free cortisol determination were performed and reported within normal range: metanephrines 0.4 nmol/mg Cr [0–0.9], normetanephrines 0.8 nmol/mg Cr [0–2.00], vanilmandelic acid 10.0 nmol/mg Cr [0–45.2], homovanillic acid 17.0 nmol/mg Cr [0–56.5], 5-OH-indolacetic acid 11.0 nmol/mg Cr [0–34], and urinary-free cortisol 48 µg/24 hours (normal range 12–103 µg/24 hours). An abdominal ultrasound with Doppler examination of renal arteries, plus a renin and aldosterone measurement after 2 hours standing and 4 weeks without fludrocortisone nor other antihypertensive drugs, was also measured, all of them with negative results. Due to the high vascular risk associated with high elevated nocturnal BP, the treatment with fludrocortisone was suspended, and the patient was started on 25 mg captopril before bed. One year after continuous positive airway pressure and fludrocortisone suspension and having started nighttime captopril, a new 24-hour ABPM was performed (Figure 2 and Table 1). There was a decrease in BP (126/86 mm Hg) and a slight improvement in variability. The BP profile continued as riser, especially for diastolic BP. 24-Hour blood pressure mean, extreme values during daytime and nighttime and variability of the mean (SD) Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure. 24-Hour blood pressure mean, extreme values during daytime and nighttime and variability of the mean (SD) Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure. ABPM registry 1 year later, after removing fludrocortisone, CPAP (lack of compliance) and having added captopril before going to bed. The ordinate axis represents blood pressure and the abscissa axis the time from the beginning to the end of the record (10.13–09.14 hours). Abbreviations: ABPM, ambulatory blood pressure monitoring; CPAP, continuous positive airway pressure. Patients with MSA are frequently diagnosed lately or misdiagnosed with Parkinson’s disease. The inhomogeneous clinical presentation of the disease and years of confusing nomenclature contributed to the lack of awareness among physicians. We present a patient who was studied by 5 different medical specialists for the same pathology. This illustrates the diagnostic difficulty of such pathology and the multiple visceral affectations that accompany it. Finally, as far as we know, there are no descriptions when crossing the terms MSA and secondary hypertension in MEDLINE, with one exception6 nor is it usual to refer to the MSA in secondary BP reviews and texts.5 In our patient, the mean ABPM changed from 110/72 to 138/94 mm Hg in only 2 years. However, in our opinion, the clinical observations and the pathophysiology known in the MSA would support considering this entity as a type of secondary hypertension. This case raises the question of whether it is appropriate to refer patients with high BP variability, ABPM rises pattern and symptomatic hypotension in relation to postural changes for a comprehensive neurological study. Biomarkers have clinical relevance for noninvasive early detection or diagnosis in several pathologies, however, no reliable biomarkers are currently available for diagnosis and prognosis in MSA. Recently, studies assessed several biomarkers in the cerebrospinal fluid such as neurofilament light-chain protein (NFL), FMS-like tyrosine kinase ligand (FLT-3), and α-syn. Homocysteine, C-reactive protein, and uric acid levels were also measured in peripheral blood, all of them with controversial results. Recently, Cong et al. report in a meta-analysis 3 biomarkers (α-syn, NFL, and t-tau) that significantly differed in the cerebrospinal fluid of MSA patients with low heterogeneity levels which increase the diagnosis value.7 Supine hypertension complicates the treatment of BP alterations in patients with MSA. Therefore, it has been proposed that it can be treated with overnight administration of antihypertensive drugs8 instead of mineralocorticoid agonists such as fludrocortisone. There are 2 new approaches that act directly on the autonomous system. One is the sympathetic denervation of the renal arteries. This procedure was designed to treat resistant hypertension, but recent data from a systematic review have failed to demonstrate undoubtful efficacy in this indication.9 Up to date, there are no reports about its use in MSA. Another even more promising approach would be carotid sinus stimulation. The carotid sinus is sensitive to pressure changes at this level and it is the major baroreceptor site in humans; it contains numerous baroreceptors that function as a “sampling area” for many homeostatic mechanisms for maintaining BP. Its stimulation has been proposed for the treatment of hypertension. Recently, the subcutaneous implant Barostim® (CVRx, Minneapolis, MN, United States) has been shown to decrease BP.10,11 Preliminary data have shown favorable cost-effectiveness in the treatment of resistant hypertension12,13 and the more recent 2018 guidelines for the management and control of hypertension (European Society of Hypertension/European Society of Cardiology) consider it a possible future therapy for resistant hypertension.14 From the pathophysiological standpoint, carotid sinus stimulation appears more attractive since changes in carotid sinus baroreception status in relation to posture could contribute to the observed rapid changes of BP in these situations. Another potential advantage of this system is that it can be deactivated by placing a magnet on the skin, unlike renal denervation which is definitive. However, and unfortunately, it has never been studied in any dysautonomic alteration related to BP; therefore, its effects in MSA remain unknown. MSA is an underdiagnosed disease that could be deemed as a secondary cause of hypertension. The question remains on whether all patients with a high BP variability and a riser pattern in ABPM should be referred for neurological assessment. Future studies could help elucidate early biomarkers that might help improve our ability to diagnose this condition and how to treat it more effectively by either pharmacotherapy, renal denervation, or Barostim implantation or a combination of these. The authors declared no conflict of interest.