Translation of 'Uber EKG-Veranderungen bei Hirntumorkranken'Article, an early article on brain-heart interaction

During my research on interoception-exteroception integration, I reviewed the article "Measures and Models of Brain-Heart Interactions" by D. Candia-Rivera and colleagues. Within this work, another article titled "Uber EKG-Veranderungen bei Hirntumorkranken" was mentioned, highlighting early studies on brain-heart interactions. This article was originally published in German, and I've translated it using GPT. Therefore, the translation might contain some inaccuracies.

Translation of this important study on the brain-heart interaction domain:

On ECG Changes in Brain Tumor Patients

R . ASCHENBRENNER und G. BODECHTEL.

Medizinischen Universitätsklinik, Deutschland & Neurologischen Universitätsklinik Hamburg-Eppendorf, Deutschland

Even if, until a few years ago, there were still skeptics who considered the theory of vegetative regulatory disorders merely as a set of buzzwords, recent research findings have clearly shown that these are not just clever speculations, but real issues that concern us in clinical practice—that is, at the patient’s bedside. One need only briefly recall the nervous regulation of blood composition or the control of blood pressure. Admittedly, in some cases, the discussion went too far, with too much being attributed to the “mysterious depths of the third ventricle,” as Friedrich von Müller put it; and indeed, the extreme localization of one disturbance or another to sharply defined anatomical cell groups within the theory of vegetative regulation has done more harm than good. But that phase is behind us now.

Today we know that the entire peri- and paraventricular gray matter—from the lamina terminalis of the third ventricle to the calamus scriptorius of the rhomboid fossa—is responsible for vegetative regulation. It not only regulates overall metabolism, temperature balance, and sleep, but can also act on specific organs via the vagus and sympathetic nerves. For instance, it is well known that the smooth muscle of the gastrointestinal tract and its blood supply are influenced not only from the dorsal vagal nucleus, but also from higher brain regions such as the diencephalon. CUSHING reported years ago on observations of acutely developed gastric ulcers in patients with brain tumors, thereby reviving the old theory of the neurogenic origin of gastric ulcers—though without claiming that the majority of the very frequent gastric ulcers arise from neurogenic causes. It should also be noted in this context that, apart from the gastrointestinal tract, the bladder is also influenced by the central gray matter.

With regard to the influence of these centers on cardiac activity, our knowledge until recently was based almost exclusively on experimental findings. In animal experiments, researchers primarily investigated whether and under what conditions extrasystoles could be triggered by a central nervous stimulus (Brow, Long and Beattie, Dikshit, Schott, Scherf, among others). Other authors (Riccitelli, North, Marx, and Weinberg) also examined the effects of pharmacological agents introduced into the cerebrospinal fluid on cardiac activity and the ECG. In recent years, it has been convincingly demonstrated that stimulation of the vegetative centers at the floor of the third ventricle can trigger not only extrasystoles but a whole range of rhythm disturbances. For instance, Van Bogaert found in detailed studies on dogs that stimulation of sympathetic and parasympathetic centers in the hypothalamus can, depending on the nature and site of stimulation, lead to sinus tachycardia and bradycardia, AV rhythm, dissociation, prolongation of conduction times, and more—all of which can be recorded electrocardiographically. Sympathetic and parasympathetic effects often overlap and are frequently difficult to differentiate. The latter can exert effects via both the vagus nerve and the spinal parasympathetic pathways, since even after vagus nerve transection and administration of atropine, both extrasystoles and other rhythm disturbances can still be induced. Measures that also raise blood pressure can further complicate the situation through involvement of pressure receptors (Dikshit, Schott).

Apart from the long-known “pressure pulse” observed in brain disorders, these relationships have until now received little attention in clinical practice. Although, as early as 1933, Neubürger pointed out pathological changes in the myocardium of young epileptics and brain tumor patients—changes attributed to disturbances in coronary blood flow—only this year have Lücke and Korth reported clinical observations. However, in each of their two cases, the arrhythmias occurred in patients over 50 years old, and the Korth patients also had significant underlying heart disease.

Over the past two years, we have systematically examined around 50 brain tumor patients using electrocardiography. In order to highlight the central origin of the ECG changes we observed as clearly and conclusively as possible, this report focuses only on juveniles between the ages of 5 and 15 and one adult aged 24. These cases involve individuals in whom vascular diseases—typically the most common cause of myocardial changes—could be ruled out. Based on the entire clinical picture, there can be no doubt about the central (i.e., brain-based) origin of their heart disturbances. However, whether the stimulus affecting the vegetative centers of the ventricular walls is due to hydrocephalus internus, significant intracranial pressure fluctuations, direct or indirect compression, or cerebral edema cannot always be determined with certainty in each individual case.

Regarding the mechanism of the EKG changes shown below, we can only say something definite in part. Concerning the explanation for the appearance of extrasystoles, we would like to align ourselves entirely with the ideas of Koeth. The other rhythm disturbances, according to the findings of Van Bogaert, are also quite understandable. More difficult, however, is answering the question of how the EKG changes involving the ST segment and the terminal T-wave deflection come about—changes which in our young patients must be interpreted as signs of “myocardial damage.” Insofar as they—as we were able to demonstrate—developed directly following prolonged, cerebrally induced tachycardias, one may reasonably assume so-called “coronary insufficiency” as the cause. Some of the muscle fiber changes triggered by this, according to our electrocardiographic findings (as was already suspected by Neubürger), are reversible. Whether, in the absence of such tachycardias, a narrowing of the coronary arteries due to central vagal influence is involved—which could also cause a mismatch between cardiac nutrition and performance—cannot be determined with certainty.

In any case, it was striking that we saw pronounced vagal bradycardia in our brain tumor patients only very rarely—especially not when clear EKG changes were present. Other authors have also pointed out that vagal influence may vary in its chronotropic, inotropic, and coronary effects, even though this was rejected by Hering. Nevertheless, we believe that the subendocardial hemorrhages often found by pathologists in brain tumor patients (which some, such as Kirsch, have directly referred to as “vagal hemorrhages”) can also be viewed as the anatomical basis of such EKG changes.

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Case 1: The first case seems especially interesting because, in addition to the brain tumor, a heart defect in the form of mitral valve disease was clinically suspected—although, as we can say in advance, no evidence of this was found during autopsy.

The 14-year-old girl had suffered from scarlet fever and diphtheria at age 7 but felt completely healthy afterward, with no heart complaints. At the age of 13, over the course of a year, she gradually developed a severe cerebral syndrome with profound vision loss, exophthalmos, ocular muscle paralysis, a tendency to fall backward, and pain radiating from the neck into the right arm. Since the girl had complained of heart issues from the onset of her illness, the general practitioner initially suspected a cardiac problem. Indeed, we also found a systolic murmur at the apex, an accentuated second pulmonary tone, and irregular heart activity suggestive of extrasystoles.

However, the appearance of papilledema soon pointed toward the correct diagnosis. The patient was admitted under the diagnosis of a posterior fossa tumor (possibly cerebellar vermis) for surgery (Dr. Voss), but the tumor could not be located during the procedure. Following the operation, she developed severe cerebral marasmus with increasing general deterioration and recurring cerebral fevers. Two days before death, due to marked circulatory impairment (cyanosis, irregular and weak pulse), an EKG was recorded, and two segments are shown in Figure 1.

Figure 1a shows a frequent sinus rhythm with flat terminal T-waves in leads I and II and a depressed ST segment in leads II and III. In lead I, two ventricular extrasystoles are visible. Figure 1b, lead II, displays a regular ventricular bigeminy. The QRS complexes of the paired beats differ in shape and are so widely coupled that the (non-conducted) P-wave is just visible before the second beat. In lead III, each extrasystole follows two sinus beats.

At autopsy, an apricot-sized tumor with a central cyst was found in the left thalamus. The heart, however, showed no pathological changes.

Epicrisis: There is all the more reason to believe in the central nervous origin of the extrasystoles observed in this case, as it concerns—unlike the cases reported by Lücke and North—a young female patient who also received digitalis. The extrasystoles apparently developed early in the course of the cerebral disease and became very frequent toward the end. They led to a significant impairment of circulation, and the signs of myocardial damage seen in the ECG may well be interpreted as a result of coronary insufficiency caused by prolonged tachyarrhythmia.

The previous episodes of scarlet fever and diphtheria appear—according to the patient’s history—to have passed without damaging the heart. At most, they may be viewed as a predisposing factor for the central triggering of the extrasystoles. Clinically, this case is a particularly striking example of how cerebrally induced disturbances of cardiac function can dominate the clinical picture even in a young and otherwise heart-healthy patient.

Figure 1a and 1b. ECG of a 14-year-old female patient with a tumor in the left thalamus, 2 days before death (ante exitum). Clinically: severe circulatory insufficiency.

Case 2: The 10-year-old girl had previously always been healthy, although the family had a strong history of tuberculosis. Following a fall on the back of the head, she developed severe headaches with vomiting, which led to her admission to the local pediatric clinic. Neurologically, only a slight increase in reflexes was found. Additionally, the patient could not converge her eyes, and the pupillary light reaction was somewhat sluggish. An outpatient examination at the neurology clinic revealed, aside from the convergence weakness, only a questionable right-sided Babinski sign. Since there was no papilledema, an encephalography was performed. Cerebrospinal fluid pressure was slightly elevated; otherwise, the air contrast study was entirely normal and revealed a pronounced internal hydrocephalus with insufficient visualization of the third ventricle.

Only the next day did pronounced drowsiness appear; around midday, the child suddenly became comatose, previously easily elicitable reflexes disappeared, sugar and acetone were found in the urine, and the face was abnormally pale. The child recovered upon administration of Coramin and glucose. Ophthalmoscopic examination now revealed clear papilledema. The following day, the child initially appeared normal. That evening, however, a sudden severe extensor spasm occurred, indicating decerebrate rigidity, along with deep, gurgling respiration. With a blood pressure of 120/0 and a pulse of 82, the temperature rose from 36.9 °C to 40.0 °C within half an hour, and the pulse reached 220. Shortly thereafter, death ensued.

Unfortunately, we only have an ECG from the morning of the day of death, before the onset of decerebrate rigidity (Fig. 2). It shows (upper tracing, lead II) three sinus beats at first, then the PP interval becomes so long that an AV rhythm takes over. The fourth P wave, which is no longer conducted, is just visible before the first AV beat. In the lower tracing, only the AV node conducts. The R waves of the AV beats are clearly higher than those of the sinus beats. This represents a competition between AV and sinus rhythm; the RR interval of the AV beats is clearly shorter than the final PP interval.

Autopsy: The autopsy revealed a tumor the size of a thumb tip that completely filled the third ventricle and, by obstructing the foramina of Monro, had led to an internal hydrocephalus of the lateral ventricles. In the heart, fresh subendocardial hemorrhages were found in the left outflow tract, as well as moderate enlargement of the right ventricle. The pituitary gland was completely flattened as a result of the third ventricle’s expansion.

Epicrisis: This case can be seen as a striking clinical parallel to the animal experimental studies by Van Bogaert, in which stimulation of the vegetative centers in the floor of the third ventricle also resulted in nodal rhythm. Another explanation is hardly plausible in this completely heart-healthy 10-year-old child. The fresh subendocardial hemorrhages found at autopsy in the left outflow tract clearly developed terminally as a result of the cerebral-induced extreme tachycardia.

Figure 2. 10-year-old girl with tumor of the third ventricle and internal hydrocephalus. ECG before onset of decerebrate rigidity: competition between sinus and AV rhythm.

Case 3:The 10-year-old boy was referred to us from an external hospital with the diagnosis of brain tumor for surgery. Symptoms had been present for about 1–2 years. He had previously always been healthy. The parents first noticed a marked development of the genitalia and pubic hair. Headaches appeared, followed by vomiting for 3–4 weeks. The boy frequently made unusual twisting movements of the fingers on his left hand (athetotic movements). Neurologically, a bilateral papilledema (5 diopters) with hemorrhages was found, along with marked tenderness over the left frontal bone and the already noted precocious puberty. X-ray showed partial destruction of the sella. The diagnosis was a tumor of the third ventricle.

An ECG recorded 5 days before surgery showed only minor changes (Fig. 3a). The operation (local anesthesia + Evipan, performed by Dr. Voss) revealed a tumor near the optic chiasm that originated from the sphenoid bone and not the third ventricle. Histological examination identified it as a juvenile dural endothelioma. It was largely removed. After surgery, the pulse rose to 165, the temperature to 39.2 °C; the patient showed marked drowsiness and occasional restlessness.

An ECG recorded the next day showed significant sinus tachycardia with a rate of 200 bpm, along with clear changes in the T-wave deflection and ST segment in leads II and III (Fig. 3b). The patient recovered relatively quickly from surgery; two days later, the ECG abnormalities had largely regressed (Fig. 3c), and later disappeared completely (Fig. 3d).

A very similar postoperative course (also under local anesthesia) was observed in a 13-year-old girl who had a tumor (neuroepithelioma) removed from the right centroparietal region due to left-sided hemiparesis with Jacksonian seizures (surgeon: Dr. Voss). Here, too, the ECG showed clear signs of myocardial damage with significant sinus tachycardia postoperatively, which, however, regressed only minimally even over a prolonged observation period.

Epicrisis:

Following brain operations, stimulation of hypothalamic sympathetic centers can lead even in completely heart-healthy children to persistent, severe tachycardia, resulting in myocardial perfusion disorders with clear changes in T-wave deflection and ST segment on the ECG. Depending on the extent of coronary insufficiency and any resulting myocardial necrosis, these ECG changes may regress to a greater or lesser extent.

Figure 3. ECGs of a 10-year-old boy with a dural endothelioma originating from the sphenoid bone, a = 5 days before surgery; b = on the day after surgery; c = 2 days later; d = 3 months later.

Case 4: The 15-year-old boy, previously always healthy but from a family with a strong history of tuberculosis, became ill six months before hospital admission with episodes of severe headaches accompanied by vomiting. He also noticed a sense of dizziness and was unable to maintain balance. Neurologically, there were ocular muscle pareses and cranial nerve symptoms affecting cranial nerves V and VII, coordination disturbances, and bilateral papilledema with extensive hemorrhages. An old chorioretinal lesion in the right eye prompted us, in light of the family’s tuberculosis history, to initially suspect a cerebellar tuberculoma.

Visual acuity, which was already significantly reduced at admission, deteriorated rapidly to complete blindness. In addition, the boy became severely emaciated and extremely frail. His pulse was persistently unstable; upon sitting upright, he would alternate between flushed and pale. The first ECG, taken 8 days after admission, already showed signs of myocardial damage: the T-waves were very flat or nearly isoelectric in all leads, and the ST segment was clearly depressed (Fig. 4a).

Due to his poor general condition, the boy was not operated on, although during a carefully performed suboccipital puncture, not cerebrospinal fluid but cystic content was aspirated. This finding led us to abandon the initial diagnosis of a cerebellar tuberculoma. In the following weeks, signs of increased intracranial pressure became more pronounced, yet only one episode of marked sinus bradycardia was observed despite frequent ECG monitoring (Fig. 4b). The signs of myocardial damage persisted until death; his pulse consistently showed large fluctuations (100–140 bpm). Under a rise in cerebral fever, the patient died three months after admission.

Autopsy:The autopsy revealed a partly cystic astrocytoma, primarily located in the cerebellar vermis, with severe internal hydrocephalus affecting all ventricles, slight dilation of the right heart chamber, and patchy hyperemia in the left ventricular outflow tract.

Epicrisis:In a previously completely healthy adolescent with a brain tumor, symptoms of intracranial pressure, and severe internal hydrocephalus, signs of myocardial damage were already detected in the ECG six months after the onset of illness. These remained consistently pronounced until death despite frequent monitoring. A significant sinus bradycardia was observed only once.

Whether these ECG changes were due to so-called “vagal hemorrhages” in the heart muscle or to perfusion disturbances caused by transient tachycardic episodes cannot be definitively determined. As seen in earlier animal experiments, stimulation of the hypothalamic vegetative centers can produce overlapping sympathetic and parasympathetic effects on the heart, which are often difficult to distinguish.

Figure 4a and b. ECGs of a 15-year-old boy with a cerebellar tumor and severe internal hydrocephalus.

Case 5:The 24-year-old patient was referred to us from another hospital with the diagnosis “suspected tumor of the posterior cranial fossa.” Fourteen days prior to admission, he suddenly became ill with severe headaches and nausea following prolonged sun exposure. He walked unsteadily and staggered like someone intoxicated. Cerebrospinal fluid showed slightly elevated protein and cell count; cultures were sterile.

Neurologically, there was bilateral papilledema with streaky hemorrhages, mild cranial nerve symptoms involving cranial nerves VII and XII, and a tendency to fall backward and to the right. Ventriculography revealed a symmetrical internal hydrocephalus with poor visualization of the aqueduct and the fourth ventricle, leading to a diagnosis of arachnoiditis or a posterior fossa tumor.

Surgical exploration of the posterior fossa (Dr. Voss) revealed nodular adhesions in the region of the left cerebellar hemisphere, which were identified histologically as chronic meningeal tuberculosis. After surgery, the patient’s clinical condition improved markedly, and he was discharged nearly symptom-free three months later.

The first ECG, taken 3 weeks before surgery, showed very flat T-waves in all three leads and a slightly depressed ST segment in lead II – signs of myocardial damage. Given the absence of fever and a normal sedimentation rate, a tuberculous-toxic origin seems unlikely.

Already 7 days after the operation (which provided substantial relief of intracranial pressure, especially from the hydrocephalus), the ECG showed marked improvement. Two months later, a nearly normal ECG was recorded (Fig. 5a–c).

Epicrisis:This too is a case of a young patient with symptoms of increased intracranial pressure and ECG signs of myocardial damage, for which the same mechanisms proposed in the previous case must be considered. A toxic myocardial injury – which is quite rare in tuberculosis patients – appears very unlikely here.

It is notable that, in this patient as well, no significant sinus bradycardia was observed. Following surgical decompression, there was a gradual and complete normalization of the electrocardiogram.

Figure 5. a = before, b = 7 days after, c = 2 months after surgical decompression in chronic meningeal tuberculosis.

Case 6:A very similar situation was observed in a 5-year-old boy who did not suffer from a brain tumor but from post-vaccinal encephalomyelitis. This condition was associated with high fever, a significantly accelerated pulse, and elevated temperature. The ECG, taken 4 days after admission while the boy was in a critical condition, showed sinus tachycardia with clear signs of myocardial damage (Fig. 6a). Two days later, after a marked clinical improvement and a drop in temperature, a lumbar puncture was performed. The ECG recorded shortly thereafter revealed a completely normal result (Fig. 6b).

Epicrisis:As in the previous case, a striking improvement in the ECG was observed following rapid resolution of cerebral irritative symptoms—this time within 48 hours. This makes it highly unlikely that the signs of myocardial damage in the ECG were solely due to toxic effects. However, this rapid improvement cannot be attributed solely to the lumbar puncture, as in other cases with clearly elevated intracranial pressure we have usually seen only minor ECG changes following puncture. Apparently, the spontaneous regression of the inflammatory symptoms alone was already sufficient to reduce the irritation of the vegetative centers. As already mentioned earlier, the mechanism of this central influence on the T-wave and ST segment in the ECG can for now only be speculated upon.

Figure 6. ECGs of a 5-year-old boy with post-vaccinal encephalomyelitis. a = at the peak of the illness; b = 2 days later following a lumbar puncture.

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Summary:

In juvenile brain tumor patients, ECG changes are described that include extrasystolic and other rhythm disturbances as well as alterations in the T-wave and ST segment. Based on both the experimental findings of other authors and our own clinical observations—partly confirmed by autopsy—we believe there is no doubt that these ECG changes are of central origin. Stimulation of the paramedian periventricular gray matter can lead to rhythm disturbances and myocardial perfusion deficits, both through the long cardiac nerves and via descending pathways including the spinal parasympathetic system. From a clinical standpoint, it is essential to recognize that in otherwise heart-healthy brain tumor patients, such centrally induced disturbances of cardiac activity can dominate the clinical picture.

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Literatur:

• Van Bogaert, Arch. Mal. Cœur 29, 15 (1936)

• Brow, Long u. Beattie, J. Amer. Med. Assoc. 95, 715 (1930)

• Cushing, Surg. etc. 55, 1 (1932)

• Dikshit, J. of Physiol. 81, 382 (1934)

• Hering, Verb. Dtsch. Ges. Kreislaufforsch. 6, 13 (1933)

• North, Dtsch. Med. Wschr. 1938 (im Druck)

• Korth, Marx u. Weinberg, Arch. f. Exper. Path. 185, 42 (1937)

• Lucke, Dtsch. Arch. Klin. Med. 180, 45 (1937)

• Neuburger, Klin. Wschr. 1933, 1355

• Riccitelli, Sperimentale 89, 348 (1935)

• Scherf, Z. Exper. Med. 65, 198 (1929)

• Schott, Pflügers Arch. 234, 51 (1934)