Author: John F. Kerrigan, MD, Director, Hypothalamic Hamartoma Program, Phoenix Children's Hospital
My last column I focused primarily on the diagnosis of HH with the use of our current brain imaging tools, most importantly, magnetic resonance imaging (MRI). Using the technology currently available, radiologists should be able to give patients and doctors a definitive yes or no answer as to whether an HH is present. An MRI of the brain with careful examination of the hypothalamus is indicated (should be done) for any patient with gelastic (laughing) seizures, and for any young child with precocious (early) signs of puberty.
I would like to focus this column on the relationship between the anatomy of the HH lesion and the symptoms that it causes. Symptoms related to HH tend to occur in two primary areas. The first are HH lesions that cause central precocious puberty, which is abnormally early onset of the usual developmental program that results in normal puberty, resulting from a “central” (or brain-related) reason. HH is a common cause of central precocious puberty, particularly in very young children (less than 6 or 7 years of age) but certainly not the only cause.
The other major symptom area is epilepsy, usually with gelastic seizures as the first type of seizure experienced by the patient, but developing other types of seizures as the child gets older. For HH patients with epilepsy, associated (or “co-morbid”) neurological problems are often present, including delayed development, actual loss of milestones or skills, and behavioral problems such as rage attacks. These co-morbid features may begin or worsen when the seizures worsen.
Approximately 40% of HH patients with epilepsy also have precocious puberty, so the two symptoms can occur together.
We now have a better understanding of why an HH lesion may cause one type of symptom or the other, or why a patient may have both. This is a story that is much easier to tell with the use of some representative figures, which follow.
Let us look at Figure 1, which represents normal imaging in a patient without an HH. This is an MRI in the sagittal plane (the patient’s nose is to the left edge of the image, the top of the head is to the top edge of the image, and the back of the head is to the right edge of the image). In the first panel (Figure 1A), the asterisk (*) marks the third ventricle and hypothalamus and the dotted line marks the floor of the third ventricle. HH lesions are always attached at some location along this line, although there is a lot of variation between individual patients.
Let us first look at the important structures that are near the anterior (more forward, or closer to the nose) region, as shown in Figure 1B. Immediately above the thin arrow is the pituitary gland (which includes the grey signal of the anterior pituitary, and behind it, the bright or white signal of the posterior pituitary gland). It is the posterior pituitary that is actually part of the brain, with a stalk or connection that descends from the hypothalamus. The region of the hypothalamus that connects to the pituitary is shown by the short thick arrow. These regions are very important with regard to hormonal function (the hypothalamus sends the signals that cause the pituitary gland to go into action). This includes the mechanisms that control puberty.
Now let us look at Figure 1C, which highlights one of the structures in the posterior hypothalamus, known as the mammillary body. The mammillary body is indicated in Figure 1C with the arrow. The mammillary bodies are part of an important circuit that enables learning and memory (along with the temporal lobes and other structures) and are also part of pathways that are very important as parts of epilepsy circuits for some patients with seizures.
Some readers may be already guessing what I am about to say. Recent research has provided further evidence (one might now use the word “proven”) that HH lesions that attach anteriorly (that is, in the region of the structures highlighted in Figure 1B) result in precocious puberty. An HH lesion that attaches anteriorly, resulting in precocious puberty (and not resulting in epilepsy) is shown in Figure 2, where the HH lesion is marked by an asterisk.
On the other hand, HH lesions that attach posteriorly, near the region of the mammillary body, are associated with epilepsy, and do not cause precocious puberty. Such an HH lesion is shown in Figure 3, also marked by an asterisk. Note that in Figure 3, the normal mammillary body is the darker structure below the HH.
HH lesions that are particularly large, and therefore attach both anteriorly and posteriorly to the hypothalamus, are capable of causing both precocious puberty and epilepsy. An example of a large HH lesion of this nature is shown in Figure 4 (once again, marked by an asterisk). The arrow points to the close proximity between the pituitary stalk and the HH in this patient.
Two recent research papers address the issue of HH attachment and symptoms. The first (Reference 1 below) resulted from a collaboration between my laboratory at Barrow and the Reproductive Endocrinology Laboratory of Dr. Stephanie Seminara at Massachusetts General Hospital. In brief, when examining the expression levels of various chemical compounds related to puberty in surgically-resected HH tissue, we compared a group of patients with epilepsy and a history of precocious puberty with a group that had epilepsy but no precocious puberty. We found no differences in expression levels between the two groups (all patients had evidence for the presence of the main chemical messenger of puberty). However, the patients did differ when we looked at their imaging, as all patients with precocious puberty had attachment to the anterior region of the hypothalamus, and almost all of the patients without precocious puberty did not.
The second paper (Reference 2 below) resulted from a collaboration between Barrow and Dr. Josef Parvizi at Stanford University Medical Center, in which we looked at the relationship between symptoms and anatomy in the other direction. We found that all HH patients with epilepsy had attachment in the posterior hypothalamus, in the region of the mammillary bodies.
Location, location, location…
1) Chan YM, Fenoglio KA, Paraschos S, Muhammad L, Troester MM, Ng YT, Johnsonbaugh RE, Coons SW, Prenger EC, Kerrigan JF, Seminara SB. Precocious puberty associated with hypothalamic hamartomas correlates with anatomic features but not with expression of GnRH, TGFα, or KISS1. Horm Res Paediatr 2010;73:312-319.
2) Parvizi J, Le S, Foster B, Bourgeois B, Riviello JJ, Prenger E, Saper C, Kerrigan JF. Gelastic epilepsy and hypothalamic hamartomas: neuroanatomical analysis of brain lesions in 100 patients. Brain 2011;134:2960-2968