The central nervous system is the control center for energy regulation. Initially, case studies suggested the association between hypothalamic injury or tumor and obesity (1). Animal studies confirmed this association with specific lesions in the hypothalamic nuclei, producing unique hypothalamic obesity syndromes (2). The discovery of leptin (3) confirmed the pivotal role of the hypothalamus in energy regulation. The hypothalamus serves as a central relay receiving input from peripheral energy stores and cerebral cortex, regulating feeding behavior, insulin secretion, and autonomic and sympathetic activity.
Damage to the hypothalamus and central nervous system can disrupt this finely tuned system and result in obesity.
State of the Problem
In animal studies, rats that undergo bilateral lesions of the ventromedial hypothalamus (VMH) develop a syndrome of hyperphagia, hyperinsulinemia, and weight gain called “hypothalamic obesity.” Obesity due to hypothalamic injury is often associated with other hypothalamic endocrinopathies and is characterized by insulin hypersecretion (4). In a study of children who underwent treatment for primary brain tumors, intermediate- and high-dose radiation to the hypothalamus was a significant factor in body mass index (BMI) increase (4). Rate of BMI increase was not associated with extent of surgery, ventriculoperitoneal shunting, long-term steroid treatment, or chemotherapy. Patients with associated endocrinopathies had greater increases in BMI than those who did not (4).
There are at least two distinct hypothalamic syndromes whose manifestations differ depending on which hypothalamic nuclei are affected. Injury to the paraventricular nucleus causes hyperphagia, which is the primary cause of obesity, and when overeating is prevented, obesity does not develop (2).
Injury to the ventral medial nucleus (VMN), in contrast, causes increased activity of the vagal efferent system with greater insulin secretion and reduced thermogenesis. The ventral medial nucleus is also the site of growth hormone–releasing hormone (GHRH) release, and destruction of this nucleus is also associated with decreased growth hormone secretion (2). If lesions are large enough, additional endocrine abnormalities can be seen, including disruption of reproductive function and adrenal and thyroid dysfunction.
In the 1940s, lesions in the VMH were identified as leading to obesity (5). VMH lesions can affect adipocyte function. In rats, VMH lesions resulted in a biphasic response. In the initial stages, insulin level, insulin receptor number, and insulin-stimulated glucose transport and glucose oxidation were increased, contributing to greater lipogenesis. Thereafter, insulin binding and glucose transport decreased to control levels, but insulin-stimulated glucose oxidation remained reduced (6). Decreased glucose tolerance after VMH lesions has been reported in animals and humans (1,7). Hypothalamic lesions of the VMH in mice resulted in marked increases in ob gene product (leptin) secretion (8). Leptin, ghrelin, and insulin affect neuropeptide Y in the arcuate nucleus, allowing signal transduction from peripheral afferent energy signals to affect efferent sympathetic and vagal nerve modulation of appetite and energy balance (9). The exact mechanism of this is unclear; it is thought that increased vagal tone with stimulation of beta cells and hyperinsulinemia may be the cause of weight gain (10). Bilateral vagotomy can reverse obesity in this case (11).
Leptin may be involved in the hyperphagia seen in children with suprasellar injury. Significantly elevated levels of leptin relative to BMI were found in a study of children with suprasellar injury in contrast to those with intrasellar injury and controls. It was hypothesized that a decrease in hypothalamic leptin receptors due to injury resulted in increased neuropeptide Y and reduced corticotropin-releasing hormone, causing hyperphagia (12). In contrast, in a study of obese children with and without hypothalamic obesity, no difference was found between fasting total ghrelin levels, fasting insulin levels, or leptin levels (13). There is some evidence that animals with hypothalamic obesity have a reduction in spontaneous activity (14) as well as lowered rates of lipolysis when exercised (15).
Hypothalamic obesity has been defined as obesity resulting from an injury to the hypothalamus by tumor, surgery, or radiation. Symptoms that have been reported in patients with hypothalamic obesity due to tumors include the following (16):
Hypothalamic obesity has been associated with trauma (16). Inflammatory diseases such as sarcoidosis, tuberculosis, arachnoiditis, and encephalitis have also been linked to the development of hypothalamic obesity (16).
Solid tumors involving the hypothalamus are causes of hypothalamic obesity as well, with craniopharyngioma being the most common (16). Craniopharyngiomas arise from cells that lie between the pars anterior and the pars distalis and are composed of the remnants of Rathke's pouch. The frequency of obesity associated with craniopharyngioma has been reported from 0% to 40% (16). Children with brain tumors are at high risk for development of obesity after treatment (17). Risk factors include type of tumor (craniopharyngioma), hypothalamic location, extent of surgery, hypothalamic irradiation exceeding 51 Gy, and presence of hypothalamic endocrinopathies. Young age at diagnosis is also a risk factor (17).
Obesity is also a “late effect” in children with cancer.
Up to 47% of young adults with childhood acute lymphoblastic leukemia (ALL) had, at their final height, BMI measurements exceeding the 85th percentile (18). Overweight or obesity as a late effect of ALL has been linked to cranial irradiation (4); it may be increased in those survivors considered growth hormone deficient (18).
A paraneoplastic syndrome involving hypothalamic dysfunction associated with neuroblastoma has been reported (19). Paraneoplastic neurologic disorders develop in association with a neoplasm without direct invasion by tumor and are believed to be autoimmune disorders. Idiopathic hypothalamic dysfunctions linked with neural crest tumors include obesity, central hypoventilation, hypersomnia, hyperphagia, behavior change, abnormal thermoregulation, decreased sensitivity to pain, and hypernatremia. Other manifestations have included hyperprolactinemia, seizures, scoliosis, precocious puberty, and growth hormone deficiency (19).
Weight gain after hypothalamic injury can be rapid and hard to control (20,21). In a study of children who had sustained central nervous system injury as a result of tumor, surgery, or irradiation and had evidence of hypothalamic injury, an average weight gain of 6 kg per 6 months was noted (10). When children were treated with octreotide, a long-acting somatostatin analog that attenuates insulin release, the average weight loss was 4.8 kg per 6 months (10). In one series of children treated for craniopharyngioma, 53% were obese and 23% were overweight, and both these groups had greater abdominal obesity and dyslipidemia [higher triglycerides, lower high-density lipoprotein (HDL)] than controls (22). Hyperphagia is not unusual in this population after surgery, despite pituitary hormone replacement (23).
Impact on Weight Management
Development of severe obesity affects both quality of life and long-term morbidity in these patients (24). Strategies for diet, exercise, and close follow-up for obesity are warranted.
DS is a 10-year-old African American boy who has recently undergone treatment for craniopharyngioma. He comes to your office for follow-up and for a school physical. His current weight is 150 lb (>95th percentile) and his height is 5 ft (95th percentile); the BMI is 29.3 (>95th percentile). His blood pressure is 119/68 mm Hg. He is taking desmopressin (DDAVP) and thyroid medication prescribed by the endocrinologist. He is excited about returning to school and wants to play basketball this coming season.
Review of systems reveals that he is snoring, with some daytime somnolence and napping after school; his mother is not sure if he has apnea. His mother notes that before his diagnosis, he was normal weight and very active; she notes that he “can't stay away from food” and seems to always want larger portions and second helpings. You see that he has gained 40 lb in the 6 months since his surgery. The family history is positive for diabetes in two grandparents and hypertension in aunts and uncles. On physical examination, DS is a cheerful young man but does become somewhat sad when he talks about how his stamina for physical activity has decreased. He has normal findings on physical examination except for increased central obesity and scars from his craniotomy. He has not yet entered puberty.
You review his diet and activity history and note that his predominant beverage is regular soda. He has no outdoor time and is having about 6 to 8 hours of screen time (mostly television) per day. His mother is concerned about the health effects of his obesity added to the major effects of his tumor, which have resulted in difficulties with learning and memory. DS is mostly concerned about his ability to play sports.
After going over causes of obesity, including his increased risk from his tumor and treatment as well as from his family history, you present some possible changes. DS and his mother think they could eliminate the soda, changing to diet soda because DS does not like to drink water. Planning to see DS again in 1 month, you start with this change and request laboratory test results from his most recent endocrine appointment. You also have his mother call to schedule a sleep study for DS.
One Month Later
One month later DS comes to your office reporting that he has cut back to almost no regular sodas. He has gained 3 lb. His physical examination is essentially unchanged except for a 2-in. decrease in his waist measurement. He is disappointed, but you emphasize that this rate of weight gain is half of what he had been gaining. You have reviewed his laboratory studies, which show that he has elevated insulin but normal glucose, indicating insulin resistance; he also has a triglyceride level of 212 mg/dL, with a normal cholesterol and slightly decreased HDL of 33 mg/dL. His liver enzymes are normal. He had his sleep study the week before; the study revealed that he has sleep apnea, and you review the results with DS and his mother and arrange an appointment to initiate bilevel airway pressure (BiPAP). You praise him for the changes he has made, and the three of you discuss decreasing portion sizes and substituting lower calorie snacks for those he has been eating. Television watching is a major trigger for DS's eating, and you ask him to try limiting his television time. DS gets upset and feels he cannot reduce his television watching at all. You then explore other activities DS might enjoy, such as going to the YMCA or Boys and Girls Club; he responds more positively, and his mother agrees to look into these activities. You schedule the next visit in 1 month and ask the mother to call if any problems or difficulties arise.
About 2 weeks later, you get a call from DS's mother; she says that DS has been complaining of right knee pain and she has noticed him limping once or twice. You ask her to come to the office right away. When DS comes in, you see that he is limping; you send him immediately for x-ray studies, which come back positive for slipped capital femoral epiphysis (SCFE). DS and his mother go right to the hospital, and he is admitted for pinning of his right hip.
You see DS 1 month after surgery, and he is in the process of following up with his physical therapy (PT). His weight is up 4 lb, and he is discouraged both because of the weight and the current limitations to physical activity. He agrees to come to your office weekly for a weight check after his PT appointment, and you schedule an appointment for him with a nutritionist. DS seems somewhat depressed; you ask about this, and he admits he has been feeling pretty sad; there is no suicidal ideation. You ask if he would like to talk about his situation and feelings with a counselor and he agrees, so you schedule an appointment.
You continue to follow up DS monthly as you help him and his family work through his medical issues and continue to focus on family-based lifestyle change for his weight.
State of the Problem
Pseudotumor cerebri can be a complication of obesity that, if untreated, can result in visual impairment or blindness. In a survey of the general population in Louisiana and Iowa in the 1980s, the incidence of pseudotumor was 0.9 per 100,000 people. The prevalence rose to 19 per 100,000 in the population of adult women who were 20% or more over their ideal body weight (25). A Canadian study estimated the incidence of pseudotumor in children by age and gender. In boys age 2 to 11, the incidence was 0.4 per 100,000 child-years of exposure; in girls age 2 to 11, it was 1.1. Girls also had a higher estimated incidence than boys in the adolescent period, with the incidence in girls being 2.2 per 100,000 child-years of exposure and in boys being 0.8. (26).
Several mechanisms have been proposed for the increased incidence of pseudotumor cerebri in obese patients. In a group of female patients undergoing bariatric surgery for pseudotumor cerebri, intracranial pressure, urinary bladder pressure, transesophageal
and pleural pressures, and central venous and pulmonary artery pressures were all elevated compared with normal values and control patients. This supports a hypothesis that obese patients with pseudotumor cerebri have increased intra-abdominal pressure, which may lead to higher pleural and cardiac filling pressures, impeding venous return from the brain, which may cause intracranial venous pressure elevations leading to pseudotumor cerebri (27).
FIG. 12.1. Papilledema. (From
Bickley LS, Szilagyi PG. Bates' guide to physical examination and history taking, 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2002.
Papilledema has been associated with obstructive sleep apnea. The mechanism is thought to be episodic nocturnal hypoxemia and hypercarbia causing cerebral vasodilatation that results in increased intracranial pressure (28). In a group of obese women with intracranial hypertension, inflammatory markers and opening CSF pressure were increased and the subarachnoidal space was decreased on magnetic resonance imaging (MRI) when compared with control patients (29).
In adult women, polycystic ovarian syndrome (PCOS) and coagulation disorders, often augmented by exogenous estrogens or pregnancy, are associated with pseudotumor cerebri (30).
Pseudotumor cerebri is a diagnosis of exclusion. Other causes of increased intracranial hypertension must be ruled out before this diagnosis can be made (Table 12.1) (31,32,33,34).
Lumbar puncture should be performed only after ensuring that there is no intracranial lesion or mass. The diagnosis of pseudotumor is defined by the modified Dandy criteria (Table 12.2) (35).
Patients with pseudotumor cerebri may present with headache, vomiting, blurred vision, and/or diplopia. Loss of peripheral visual fields and reduction in visual acuity may be present (36). Transient obscuration of vision (TOV) may occur and is described as transient blurring or complete loss of vision in one or both eyes for a few seconds, often occurring when the patient bends over or rolls the eyes (37). Patients may also see spots, shadows, or other disturbances in their field of vision (38). Cranial nerve deficits may also be present at presentation and can include bilateral or unilateral sixth nerve palsy, acute esotropia with full abduction, skew deviation, and seventh cranial nerve palsy (39).
TABLE 12.1. Causes of increased intracranial hypertension
TABLE 12.2. Modified Dandy criteria
In some cases, neck, shoulder, and back pain has also been reported (40). Although papilledema is part of the pathologic picture, it may not occur on presentation with the other symptoms.
Obesity has been reported in 29.6% of children with pseudotumor cerebri (41). In a case-controlled series of adolescents and adults, obesity and recent weight gain were the only factors found significantly more often in patients than in controls (42).
Various drugs have been associated with increased risk for pseudotumor cerebri (Table 12.3) (37,43,44), including growth hormone, nalidixic acid, ciprofloxacin, and tetracycline. Steroid withdrawal after long-term administration has also been reported as a cause (37,39), as well as vitamin A and isotretinoin therapy (45,46). Some patients experience a prolonged course of headache and visual disturbance and may have permanent visual defects (47).
Primary headaches may be more common in the obese population. Obese adults in a bariatric surgical series had a higher incidence of migraine and tension headaches when compared with normal weight controls. Migraine is the predominant headache, with a high incidence of headaches that were considered incapacitating (48). In a population study, BMI was associated with frequency but not incidence of migraine headaches, with a fivefold increase in headaches in the obese versus the normal weight group. Severity also increased, with doubling of pain in the morbidly obese compared with normal weight adults as well as increases in photophobia and phonophobia (49).
TABLE 12.3. Medications associated with the development of pseudotumor cerebri
Treatment of pseudotumor cerebri is with acetazolamide (50), and weight loss leads to remission of symptoms (51). In severe cases, a lumboperitoneal shunt may be needed until pharmacologic treatment and weight loss become effective. Weight loss will correct pseudotumor cerebri, and in some cases pseudotumor cerebri has been an indication for bariatric surgery (52).
Lumboperitoneal shunting may be needed to treat pseudotumor cerebri if medical management is not effective and intracranial pressure remains elevated (53,54).
Optic nerve sheath fenestration is a treatment used to relieve papilledema and optic nerve damage. It has been shown to stabilize or improve vision in adults, especially those with chronic disc edema and severe or progressive vision loss (55).
LT is a 16-year-old sophomore in high school who comes to your office for a football physical. LT's weight is 275 lb and he is 5 ft 8 in. tall. His BMI is 41.8; his blood pressure is 122/76 mm Hg. His mother is with him and says he has gained about 30 lb this past year and the football coach is planning to start him on the varsity defense. LT has no allergies and is not taking any medication. LT's family history is positive for gallbladder disease in a maternal grandmother and hypertension in the paternal grandfather, and the mother notes that the father's whole family is “big,” with several aunts and uncles weighing more than 350 lb. She and LT are not at all concerned about his size.
On review of systems, LT notes that he has “some headaches;” he snores at night and sleeps on two or three pillows. You begin the physical examination and immediately note that LT has bilateral papilledema. There are no localizing neurologic signs. The rest of the physical examination yields findings within normal limits except for his obesity. You perform a visual field check by confrontation, and it seems that there may be some peripheral field loss of vision.
You have your staff call the neurologist at the hospital, who agrees to see LT right away. You explain the papilledema to LT and his mother, emphasizing that you are very concerned about the findings.
LT goes to the neurologist, who orders an MRI. You check in with LT's mother, who says the MRI is normal and the neurologist is going to perform a spinal tap; you reassure her that this is an important diagnostic test. Later that afternoon, you make rounds at the hospital and check in with LT and the neurologist, who reports that LT has pseudotumor cerebri and has been started on acetazolamide (Diamox). You arrange to see LT in your office in about 1 week.
A week later, LT and his mother return to your office. His headaches have disappeared; he is still taking acetazolamide. You begin by discussing pseudotumor cerebri and the relationship to his weight; you also express concern about possible sleep apnea from his initial history. LT and his mother are worried; they agree to a sleep
study and want to address his weight gain. You arrange for a sleep study and go over LT's diet and activity. It turns out that LT routinely skips breakfast, eats a school lunch and buys extra chips and two juices, and usually stops at the corner store after school for a snack. His snack consists of a soda and hot dog, and he eats dinner with his family, usually taking two helpings. He snacks at night while on the computer, usually leftovers, and drinks one to two regular sodas before going to bed. You go over several options for working on lowering his weight; these include changing from regular to diet soda, substituting lower calorie food for snacks, and beginning to eat breakfast. LT and his mother say that they can choose different snack food, but the soda will be a challenge. You ask if they have ever tried diet soda, and LT says he has not. You ask him to try some varieties of diet drinks and see what he thinks. You give LT and mom a list of low-calorie snack food to have in the house and some ideas for breakfast. You arrange to see LT in 1 month.
One Month Later
One month later, LT returns. His weight is down 4 lb and he has had his sleep study, which was positive for sleep apnea. You arrange to start him on bilevel airway pressure (BiPAP) and ask him how he lost weight. LT says he has been drinking only one regular soda per day and has “lightened up” on his snacks. Mom has also been reducing the amount of food she cooks for dinner, so there is less for second helpings and no leftovers. He has seen the neurologist, is no longer taking acetazolamide, and is not having any headaches. You encourage him to think about joining a conditioning program at the YMCA and arrange to see him again in 1 month.
One month later, LT has lost another 4 lb. He has been working out at the YMCA and enjoying it. He is not as hungry as before and is happier with a single portion at dinner. He is, however, having trouble wearing his BiPAP, although he can notice the improvement in his energy level when he does. You discuss his bedtime routine and suggest some relaxation techniques to see if this will help the BiPAP use. You schedule a follow-up visit for 1 month.
The visit 1 month later starts with LT telling you that he is wearing his BiPAP at night and feels better. His mother notes that he is less irritable and seems to be doing better in school. He is going to the YMCA three or four times per week and has begun a weight-training program there. His weight is down another 5 lb. You arrange a 6-week follow-up.