Neurovascular Compression at the Ventrolateral Medulla in Autosomal Dominant Hypertension and Brachydactyly
Background and Purpose Autosomal dominant hypertension with brachydactyly features severe hypertension that causes stroke usually before the age of 50 years. We recently characterized the hypertension as featuring normal renin, aldosterone, and catecholamine responses and mapped the gene responsible to chromosome 12p. Since angiography in an affected subject had earlier shown tortuous vessels, we performed magnetic resonance tomography (MRT) angiography to look for possible neurovascular anomalies (NVA), which have been previously associated with hypertension. NVA can be caused by a looping posterior inferior cerebellar or vertebral artery. Experimental and clinical evidence suggests that NVA may cause hypertension by a compression of the ventrolateral medulla.
Methods We performed MRT in 15 hypertensive affected (aged 14 to 57 years) and 12 normotensive nonaffected (aged 12 to 59 years) family members. We then tested for linkage between the hypertension-brachydactyly phenotypes and the presence of NVA.
Results All 15 affected persons had MRT evidence for NVA. All had left-sided posterior inferior cerebellar artery or vertebral artery loops, while 6 had bilateral NVA. None of the nonaffected family members had NVA. The phenotypes were linked with an LOD score of 9.2 given a penetrance of 99%.
Conclusions Autosomal dominant hypertension and brachydactyly regularly feature NVA, which is frequently bilateral. The early age at which NVA was identified suggests that the condition is primary. We suggest that NVA may be involved in the pathogenesis of this form of hypertension and perhaps essential hypertension as well. Further studies are necessary to address the question of causation.
Bilginturan et al1 first described the syndrome of severe autosomal dominant hypertension and brachydactyly in 1973. The brachydactyly and hypertension cosegregate 100%. In this syndrome the hypertension resembles essential hypertension, and the most common cause of death in affected individuals is stroke before the age of 50 years. We have reexamined this family and mapped the gene responsible for autosomal dominant hypertension and brachydactyly to chromosome 12p.2 Unpublished angiographic observations by Bilginturan in a single patient revealed elongated and ectatic intracranial vessels.
Vascular anomalies causing neurovascular compression are known to elicit hyperactive cranial nerve dysfunction syndromes, such as trigeminal neuralgia.3 Intraoperative observations4 5 anatomic studies,6 and MRT7 have demonstrated a posterior fossa NVA in patients with essential hypertension. This anomaly is believed to represent neurovascular compression of the VLM and the root entry zone of cranial nerves IX and X. The NVA, which is generally left sided in essential hypertension, consists of a looping vessel, which attaches to the root entry zone of a cranial nerve. The NVA may result in a hyperactive dysfunction of the respective underlying structures.5 In essential hypertension, NVA is predominantly caused by a PICA loop.6 Because of the initial observations of Bilginturan et al and our earlier findings,6 we performed MRT in 27 family members. We tested the hypothesis that autosomal dominant hypertension with brachydactyly features NVA. To assess the strength of the association between NVA and autosomal dominant hypertension with brachydactyly, we performed a linkage analysis involving the cosegregating markers identified earlier.
Subjects and Methods
We performed MRT in 27 members of the family with autosomal dominant hypertension and brachydactyly (15 affected and 12 nonaffected members). We recruited family members on the basis of their ability to participate. We performed the studies in the summer, when some family members were unable to participate because of their employment. All family members who were able cooperated in the studies. All participants have been described in our earlier report.2 For this study we obtained casual sphygmomanometric blood pressure measurements with the subjects in the sitting position. The study was approved by the ethics committee of Humboldt University, and informed written consent was obtained.
MRT was performed with a General Electric Vectra 0.5-T system in a head coil. We performed subtentorial axial and coronal T2-weighted studies (echo time, 45 and 90 milliseconds; repetition time, 2.5 milliseconds). The slices were oblique axial and at 90° to a line tangential to the dorsal surface of the brain stem, which is nearly parallel to the course of cranial nerves IX and X. The slice thickness was 3 mm, with an interslice gap of 1 mm. The gaps were covered in a second measurement. The coronal slices were also oblique and parallel to the surface of the posterior surface of the brain stem. Axial and coronal MR angiography with reconstructions (maximum intensity protection) were performed to detect the course of the vessels in the posterior fossa.7 Analysis of neurovascular relations at the VLM was based on the quality of the studies, imaging of the cranial nerves and vascular structures, detection of contacts between vessels and neural structures consistent with NVA, and the possibility of reconstructing the course of the vessels and demonstrating typical loops. A positive finding was defined as a visible vascular loop in the T2-weighted image or in the MRT angiogram with its convexity impinging on the VLM at the level of the root entry zone of cranial nerves IX and X.6 Normotensive and hypertensive persons were randomized and entered into the study for MRT examinations to avoid a group-dependent influence on later assessment by the observers. The scan was identified by an MRT number that the subjects received on entry. The studies were interpreted independently by two experienced observers who were unaware of the subjects’ diagnoses and blood pressures. The scans were assessed after all MRT examinations were completed.
We used the ABI PRISM Genotyping System to localize the gene for autosomal dominant hypertension and brachydactyly on chromosome 12p in a region defined by the markers D12S364 and D12S87.2 For the NVA linkage analysis, we used the LINKAGE package version 5.1.8 For the two trait (hypertension-brachydactyly versus NVA) loci, we used a model of nearly complete penetrance (0.99), a disease allele frequency of 0.001, and absence of mutation.
Fig 1⇓ shows representative hand photographs of affected (left) and nonaffected (right) persons. The brachydactyly is a type E brachydactyly, which in childhood features cone-shaped epiphyses.9 Affected persons are on average 10 cm shorter than nonaffected individuals; however, they are not obese and are neither physically nor mentally impaired in any way. Further details on the phenotype are published elsewhere.10
The family tree is shown in Fig 2⇓. The Table⇓ shows clinical data of the subjects included in the study. The subjects are numbered according to the pedigree. All 15 subjects with brachydactyly and hypertension had MRT evidence of NVA at the left VLM. Six affected subjects had bilateral NVA. All 12 nonaffected subjects had unremarkable MRT angiograms without NVA at the VLM. NVA on the left was caused by a PICA loop in 13 cases. Both vertebral artery loops and a combined compression by the PICA and vertebral artery were observed in one instance. Subject V.5 had large ectatic and elongated vertebral and basilar arteries, which had a tortuous course and which led to brain stem torsion and NVA at the left VLM. This patient had earlier developed a frontal lobe ischemic stroke. At the time of examination he had minimal neurological deficits. Subject IV.10 also had a brain stem torsion, as well as a PICA loop. This patient had suffered multiple lacunar brain infarcts, which left him with a right hemiparesis, right-sided facial weakness, and expressive aphasia. Subjects V.5, IV.10, and IV.25 are currently under antihypertensive treatment.
Fig 3⇓ shows a normal MRT result in a nonaffected person. No vascular structures impinge on the VLM. Fig 4⇓ shows a typical NVA in the axial and coronal slices from subject 7. Fig 4A⇓ shows axial T2 slices, and Fig 4C⇓ shows coronal T2 with a looping PICA attached to the VLM on the left. The MRT angiogram reconstructions in axial (Fig 4C⇓) and coronal (Fig 4D⇓) views demonstrate the course of the looping artery with its convexity pointing toward the VLM.
We used a two-by-two contingency table of the blood pressure/loop combinations for statistical analysis. The “NVA/hypertension” combination differed from the “no loop/no hypertension” combination by Fisher’s exact test. Our linkage analysis involving the phenotypes hypertension-brachydactyly and NVA revealed an LOD score of 9.2 at a recombination fraction of zero.
We found that loops cosegregated with hypertension and brachydactyly 100% in this group of 27 subjects. The prevalence of the loops was not affected by age or sex. The left-sided NVA impinging on the VLM corresponds to our previous observations in patients with essential hypertension.7 There was a high prevalence of bilateral NVA in our current subjects. The report of Jannetta et al,4 the anatomic studies,5 and the comparative MRT study we performed earlier7 all showed the loops to be left sided. The role of loop lateralization, if any, is unclear. No correlation with any hemispheric dominance has been observed. As we expected, the two phenotypes we tested were linked with a high degree of probability. These results suggest that NVA is an additional phenotype of this syndrome. The LOD value is a measure of the strength of the association between NVA and autosomal dominant hypertension with brachydactyly.
We do not know whether the loops contribute to or cause hypertension in affected subjects. Furthermore, although the term neurovascular compression is commonly applied, we are not certain that the loops are actually eliciting compression on neuronal tissue, since we did not perform direct measurements. However, we believe that a cause and effect relationship is possible. The loops appeared to precede the development of severe hypertension, since we identified them in children. Although we cannot absolutely exclude the possibility that the loops are secondary to the hypertension, this finding suggests that they are not. We previously showed that the renin-angiotensin-aldosterone axis and plasma catecholamines in affected subjects respond normally to volume expansion and contraction.10 Such responses do not rule out a role for the sympathetic nervous system in mediating the hypertension. Neurogenic causes of sustained hypertension have been previously described. One example is baroreflex failure, which is characterized by otherwise unexplained severe labile hypertension.11 We have not performed detailed baroreflex testing in our subjects. However, we have not observed that their blood pressures are labile with 24-hour ambulatory monitoring.
Jannetta et al4 observed the blood pressures of 51 hypertensive patients who underwent surgery for trigeminal neuralgia or hemifacial spasm. Blood pressure values normalized in 36 of 42 patients after microvascular decompression of the left VLM. Jannetta et al12 subsequently performed animal investigations in baboons, which had a small balloon implanted into the region of the VLM. This balloon was connected by a catheter to a second balloon in the thoracic aorta. The aortic balloon caused the balloon impinging on the VLM to pulsate. The pulsatile impulse was conducted over days in the baboons and was associated with an increase in blood pressure sufficient to induce an increase in heart size.11
Dittmar13 first demonstrated the importance of structural integrity of the medulla oblongata for cardiovascular functions in 1873. Cushing14 studied the effect of intracranial pressure elevation mediated by the brain stem on blood pressure and heart rate. Cushing observed contraction of the splanchnic vessels and also noted that vagotomy augmented the response. He concluded that a sympathetic stimulus was responsible for the increase in peripheral resistance. Brain stem mechanisms contributing to hypertension, which may be involved in neurovascular compression, have been reviewed in detail elsewhere.15 16 17 Stimulation of the adrenaline-containing C1 neurons of the VLM induces the greatest possible pressor response from the central nervous system. Efferents from these C1 neurons reach the sympathetic neurons in the intermediolateral column of the thoracic medulla. There are reciprocal connections between C1 neurons and the nucleus tractus solitarii, which is the first central area processing afferents from the heart and circulation.14
Affected individuals in our family with hypertension and brachydactyly have severe hypertension that obviously warrants treatment. Subjects IV.10 and IV.25 in this report are currently being treated with a combination of medications, which successfully controls their blood pressures. Other affected subjects are currently participating in a randomized, controlled, crossover, double-blind trial to determine which medications are most effective. They will subsequently be treated with the most effective medications. If we are able to convincingly show that NVA is responsible for hypertension in our subjects, operative decompression may be a helpful therapeutic option. Such operations are safe and successful in treating trigeminal neuralgia.18 Interestingly, none of our subjects have been afflicted with trigeminal neuralgia or hemifacial spasm.
In summary, we describe the presence of PICA loops in affected family members with autosomal dominant hypertension with brachydactyly, which maps to chromosome 12p. Thus, NVA appears to be an integral feature of this syndrome. We suggest that the neurovascular compression of the VLM by NVA could be responsible for hypertension in this family. We suggest that NVA in essential hypertension may also be influenced by genetic variance and that additional studies to investigate this hypothesis are warranted.
Selected Abbreviations and Acronyms
|LOD||=||logarithm of odds|
|MRT||=||magnetic resonance tomography|
|PICA||=||posterior inferior cerebellar artery|
This study was supported by a grant-in-aid from the Bundesministerium für Bildung und Forschung and the United States Air Force, as well as by a grant from Astra Hässle Pharmaceuticals. This work fulfills in part requirements for a Doctor of Medicine degree (O.T).
- Received April 3, 1997.
- Revision received May 12, 1997.
- Accepted May 15, 1997.
- Copyright © 1997 by American Heart Association
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