A Woman with Hyponatremia.


What are some of the clinical and laboratory findings associated with primary adrenal insufficiency?

Hyponatremia can occur in all forms of adrenal insufficiency, although it tends to occur most prominently in primary adrenal insufficiency (Addison’s disease). Primary adrenal insufficiency is caused by impairment of the adrenal glands, whereas secondary adrenal insufficiency is the result of corticotropin deficiency caused by either pituitary or hypothalamic disease. A Case Record of the Massachusetts General Hospital explains.

Clinical Pearl

  • What is the most common cause of primary adrenal insufficiency in high-income countries?

Primary adrenal insufficiency is a rare entity, and in high-income countries, autoimmune adrenalitis is the most common cause.

Clinical Pearl

  • Do patients with adrenal insufficiency have a normal life expectancy?

Patients with adrenal insufficiency have a mortality rate that is 2 or 3 times the normal rate, and they have an increased incidence of certain cancers. Morbidity is considerable. Patients often have absences from school or work, frequent hospitalizations, and alterations in work life, social life, family life, and physical activity.

Morning Report Questions

Q: What are some of the clinical and laboratory findings associated with primary adrenal insufficiency?
A: The signs and symptoms are nonspecific and include fatigue, dizziness, gastrointestinal illness, salt craving, and hyperpigmentation. Hyperpigmentation is almost always present in chronic primary adrenal insufficiency. There are also some case reports of chronic primary adrenal insufficiency in which hyperpigmentation is absent, most likely because there are adequate resting levels of plasma cortisol, which would prevent increased corticotropin secretion and subsequent melanocyte stimulation. Among patients with adrenal insufficiency, hyperkalemia occurs only in those with the primary form, owing to the aldosterone deficiency. Hyperkalemia occurs in only 50 to 60% of patients with primary adrenal insufficiency, perhaps because of aldosterone-independent regulatory mechanisms in the distal nephron that maintain eukalemia. A fraction of patients with adrenal insufficiency have a peripheral eosinophilia.

Figure 1. Laboratory Abnormalities in Primary Adrenal Insufficiency.

 

Q: How sensitive is the 21-hydroxylase antibody test for autoimmune adrenal insufficiency?
A: A 21-hydroxylase antibody test is approximately 60 to 75% sensitive, so a positive test would indicate an autoimmune cause, but a negative test does not rule it out. Other antibodies have been identified in patients with autoimmune primary adrenal insufficiency, such as antibodies against the steroid 17α-hydroxylase and side-chain cleavage enzymes. These tests are not widely available and are not specific.

Source:nejm.org

Miniature brain and skull found inside 16-year-old girl’s ovary.


Appendix surgery
A very unusual teratoma was discovered during appendix surgery

A tumour containing a miniature brain has been found growing on the ovary of a 16-year-old girl in Japan.

The 10-centimetre-wide tumour was discovered when the girl had surgery to remove her appendix. When doctors cut the tumour out, they found clumps of greasy, matted hair inside, and a 3-centimetre-wide brain-like structure covered by a thin plate of skull bone.

Closer analysis revealed that it was a smaller version of a cerebellum – which usually sits underneath the brain’s two hemispheres. A mass on one side resembled a brain stem – the structure that normally joins to the spinal cord.

 Monsters within

About one-fifth of ovarian tumours contain foreign tissue, including hair, teeth, cartilage, fat and muscle. These tumours, which are normally benign, are named teratomas after the Greek word “teras”, meaning monster.

Although the cause of ovarian teratomas is unknown, one theory is that they arise when immature egg cells turn rogue, producing different body parts.

Brain cells are often found in ovarian teratomas, but it is extremely unusual for them to organise themselves into proper brain-like structures, says Masayuki Shintaku at the Shiga Medical Centre for Adults in Japan, who studied the tumour.

Angelique Riepsamen at the University of New South Wales in Australia, agrees. “Neural elements similar to that of the central nervous system are frequently reported in ovarian teratomas, but structures resembling the adult brain are rare.”

The miniature brain even developed in such a way that electric impulses could transmit between neurons, just like in a normal brain, says Shintaku.

Brain confusion

The girl didn’t experience any symptoms, neurological or otherwise. However, there have been a handful of reports worldwide of women with ovarian teratomas who have developed personality changes, paranoid thoughts, confusion, agitation, seizures or memory loss.

Some of these neurological symptoms can arise when the immune system recognises brain cells in the ovary as foreign and launches an attack, because cells in the woman’s real brain can end up being attacked as well, leading to inflammation.

These symptoms can usually be stopped by removing the tumour.

The 16-year-old girl has had the tumour removed without any complications and she has recovered well.

Medical detectives raced to save a man from a rare, ‘universally lethal’ disease



Erich Burger, of Baltimore, is recovering at home from a rare and often fatal disease.

The problems started after Erich Burger returned from an unforgettable safari in Botswana and Zambia last month.

The Baltimore software engineer got sick the day after he got home. He headed to a community hospital after about a week of fever and chills, thinking he might have malaria given his recent travel to Africa.

Clinicians took a detailed travel history, admitted him to the intensive care unit as his blood pressure plummeted and ordered blood tests. A sharp-eyed hematology technician discovered when she looked in her microscope that he was suffering from a disease so rare in the United States that it has been seen only 40 times in the past 50 years. The disease is one of the few “universally lethal” infections: It always kills unless it is treated, and it kills quickly.

It is often what went wrong that dictates the course of stories about exotic diseases or the challenge of diagnosis. But in this case, the opposite was true: At every step, Burger encountered health-care workers who did the right thing at the right time, with little precedent for their decisions, while everyone raced the clock.

 

Burger, 48, spent about four weeks this fall in Botswana and Zambia with his wife, Bernadette, his brother, Dorsey, a wildlife biologist, and friend, Patrick Sosnowski. It was a reunion of a safari trip they had taken together two decades earlier. They roamed game parks without guides, driving 30 to 60 miles a day in rented Toyota Land Cruisers, spotting wildlife that included lions, elephants, hyenas, even a python.

Burger and his wife returned to Baltimore on Nov. 19. When he developed fever, aches and chills the next day, he thought he had picked up a minor bug — and that the long flights were catching up with him. He got progressively worse and had to skip Thanksgiving at a relative’s house.

On Monday, Nov. 28, Burger went to his primary care doctor. Initial blood tests showed some troubling indicators, such as elevated readings of liver enzymes. The doctor suggested over-the-counter medication to control the fever. But by Dec. 1, Burger had nausea and was having bad night sweats and difficulty getting out of bed. His wife drove him to the emergency room at Greater Baltimore Medical Center in Towson, Md., the hospital where his doctor is affiliated.

Burger could barely stand. His blood pressure had fallen to 70 over 52 millimeters of mercury; a typical reading is 120 over 80. For several hours, Burger received intravenous fluids to stabilize his blood pressure before being admitted to the intensive care unit.

“He was very sick. Once that top number is much below 100, it’s often associated with a patient who is in shock,” said David Vitberg, the ICU doctor at GBMC who oversaw Burger’s care.

The ER team took his travel history, including the specific countries he had visited. Like Burger, doctors thought malaria was the most likely suspect, even though he had taken anti-malarial medication. The ICU team started Burger on medication to treat malaria and sent his blood to the lab for a positive diagnosis.

A panic alert

The order for a blood parasite test was at the top of Gail Wilson’s to-do list when she arrived for work at 7 a.m. Friday, Dec. 2. She has worked for 22 years as a medical technologist, the last two at GBMC. She knew the procedure would take several hours. The blood smears — one thin and one thick — needed to dry for three hours first before a stain could be applied that would highlight any parasites.

Looking at his blood cells under a microscope, she realized he didn’t have malaria. Instead, she found a rare and lethal parasite most clinicians have only seen in textbooks. Wilson had to look really hard because “there were just a few on my slide and could have easily been missed,” she said. But there they were, some purplish-blue parasites that looked “like a wavy kind of ribbon with a dot in the middle,” she said. Wilson recognized the distinctive shape from competency exams she is required to take every year.

“When I first saw it, I was like, ‘Oh, no,’ ” recalled Wilson. “I knew it was serious and that the patient could die.”

After conferring with colleagues and supervisors, she notified Burger’s nurse that the blood parasite screen was positive for trypanosome parasites. The notification was a panic alert reserved for lab tests that show extreme or unusual results. Wilson realized that Burger had African trypanosomiasis, or sleeping sickness — a deadly disease spread by the tsetse fly.

It was 10:55 a.m.

Among infections, African trypanosomiasis is in a special category.

“Unlike almost any other infection, this is a death sentence if it’s not treated,” said Theresa Shapiro, a clinical pharmacology professor at Johns Hopkins University School of Medicine, who has spent much of her career studying the disease. Along with HIV and rabies, sleeping sickness is one of the few “universally lethal” diseases: they are always fatal without treatment.

The disease has two forms, both transmitted by the tsetse fly, which lives only in rural Africa. The parasites for both forms look identical.

West African trypanosomiasis accounts for virtually all reported cases of sleeping sickness, according to the World Health Organization. A person can be infected for months or years without major signs or symptoms of the disease.

Initial symptoms include fever, headache, and muscle and joint aches. But left untreated, the disease progresses to the central nervous system after one to two years, leading to personality changes, daytime sleepiness and progressive confusion, according to the CDC. Death usually occurs in about three years.

East African trypanosomiasis is more rare but kills within months. Nearly all cases are reported in parts of eastern and southeastern Africa, including Uganda, Tanzania, Malawi and Zambia. People at greatest risk are tourists, hunters and others working in or visiting game parks, where hoofed animals are the main reservoirs for the parasite that causes the disease and tsetse flies are common.

Fighting Neglect: Sleeping Sickness

Sleeping sickness is a fatal and much neglected disease that plagues parts of Africa. Sleeping sickness is a fatal and much neglected disease that plagues parts of Africa.

Over the past century, the disease has caused several epidemics in Africa, and those hardest hit live in the most remote parts of the continent. In the United States, most cases of sleeping sickness have been in travelers such as Burger, on safari in East Africa.

Within seconds of Wilson’s panic alert, the information popped up in Burger’s electronic medical record. Vitberg and the rest of Burger’s medical team happened to be in his room during their daily rounds.

“I think I said, ‘Holy cow, I’ve never seen that before,’ ” Vitberg recalled. He knew that making a diagnosis of African trypanosomiasis in the United States was “probably a once-in-a-medical career experience.” He wanted to make absolutely sure. On the laptop, he immediately pulled up an online medical reference, an industry standard known as UpToDate, and rifled through the sections on the disease.

He asked Burger whether he remembered being bitten by tsetse flies, “and he was immediately able to tell me he was bitten when he was in Africa,” Vitberg recalled.

Burger suspects he was bitten by tsetse flies while walking through game parks. “They’re sizable and they hurt and they tend to land on you and they stay,” Burger said. Once, he had a dozen flies on his back. It was too hot to wear anything but shorts and T-shirts, he said. Insect repellent is not particularly effective against tsetse flies, which can bite through lightweight clothing.

Immediately, the diagnosis shifted from a consideration to near 100 percent confidence.

What was worse, Burger’s medical team knew he must have the fast-acting East African form of the disease because of his travel history and because he got sick so quickly after infection.

But no one knew which stage of the disease he had, and the treatments are different — and dangerous.

Within minutes, the hospital’s infectious disease doctor, Alina Sanda, started making calls, including to the CDC’s 24-hour parasitic diseases hotline, to ask for help. The drugs to treat the disease are extremely toxic, and only the CDC has a supply. Sanda, with seven years as an infectious disease doctor, had only learned about sleeping sickness in theory.

“I never took care of a patient with it, so that made me anxious and worried,” she said.

Unable to reach someone at the CDC right away — she left a message on a recording — Sanda contacted an infectious disease colleague at Hopkins for help. Robin McKenzie, an infectious disease specialist, had never treated African trypanosomiasis, either. But she was able to reach an epidemiologist at CDC’s parasitic diseases branch.

It was just before 2 p.m.

‘The stakes are very high’

At the CDC, epidemiologist Eugene Liu spoke with both infectious disease experts, consulted with another CDC expert and began putting the wheels in motion for the agency to get the medicine and transport it to Baltimore. His background is also infectious disease, but he had also never cared for a patient with African trypanosomiasis.

“It is very rare, even for the CDC,” he said.

GBMC sent electronic images of the blood smear to Atlanta, and the CDC lab confirmed it showed the lethal parasites.

But now a critical question loomed.

Which medicines to send? The medications differ depending on the form of the disease and how far the infection has spread. Suramin, discovered in 1920, is used to treat patients with the East African form if the parasites are only in blood. But if the parasites have reached the central nervous system, a much more toxic medication is the only treatment. Called melarsoprol, it is basically arsenic.

“Between five and 10 percent of people die from the treatment because it’s so toxic,” said Shapiro, the Hopkins sleeping sickness expert. Untreated, the patients always die. “So the stakes are very high,” she said.

The CDC, which maintains a stockpile of therapeutics to treat rare, serious or life-threatening diseases, decided to send both medicines, just in case. By then, the agency’s regular drug service was closed. Liu had to get the medicines from an emergency supply at the Parasitic Diseases Branch.

He wrapped 10 ampuls of the melarsoprol and five vials of suramin in bubble wrap and put them in a package marked with a red-and-white “emergency medical supply” label. The agency’s Emergency Operations Center arranged for the medicine to be flown on a Delta Air Lines flight leaving Atlanta at 10 p.m. for Baltimore-Washington International Airport. Liu waited outside the agency’s security gate for the courier. There would be no charge for the medicine or the emergency transportation.

The only way to tell whether Burger had parasites in his central nervous system was by performing a spinal tap to collect the clear fluid that circulates in the space surrounding the spine and brain. But there was concern about when to do the spinal tap. If the infection had not yet spread to the central nervous system, injecting a needle into Burger’s back could make things worse.

“Often when you do a spinal tap, as you push the needle through the skin and muscle, you drag in red blood cells from those tissues,” Vitberg said. That could introduce parasites from the blood into the spinal column.

By then, it became clear that Hopkins, an academic medical center with more resources and expertise, would be better equipped to treat Burger than GBMC, a community hospital. Burger arrived by ambulance at Hopkins on Friday evening. The medicines from the CDC arrived a few hours later, at 1:30 a.m. Saturday, Dec. 3.

Burger got his first dose of suramin on Saturday, an intravenous treatment that lasted four hours. That allowed the drug to reduce the level of parasites in his blood so doctors could do a spinal tap the next day to check for parasites or evidence of infection in his spinal fluid.

The results showed no parasites and no sign of infection. “That was a big relief for me,” Burger said.

Within days, he was feeling better. On Dec. 8, he was discharged, one week after he showed up in the emergency room.

He still needs one more treatment, on Friday. And doctors must monitor him closely because the drug can be toxic to the kidneys and liver. He has developed an itchy rash on his arms, legs and chest.

But he feels lucky and grateful to the CDC and the personnel at both hospitals, especially to technician Wilson who first spotted the parasite. She, more than anyone, saved his life. He’s thinking of framing the electronic image of the parasite from her blood test, but he may hold off. He still needs to have a spinal tap every six months for the next two years to make sure the parasites aren’t lurking in his nervous system. And he doesn’t want to press his luck.

And yet, he would not hesitate to travel to Africa again.

“Really, my answer has always been, of course I’ll go back to Africa,” said Burger, who has made several trips, starting when he was 15. “I don’t want to go through life too frightened of the risks to actually live and enjoy. I’m not going to stop traveling because a fly bit me.”

Beyond High BP — Thorough Evaluation


A 17-year-old female presented to the Hypertension and Vascular Evaluation (HAVE) Programfor high blood pressure (BP) during multiple office visits in the setting of morbid obesity and type 2 diabetes mellitus. Family history was significant for high blood pressure and high cholesterol. On exam, her weight was 176.9 kg (99th percentile) and her BMI was 60.92 kg/m2 (99.7th perentile). She had acanthosis nigricans with an otherwise unremarkable cardiac exam. We assessed for target-organ abnormalities associated with hypertension on the same day of the visit. Her cardiac status was evaluated by echocardiogram, which demonstrated an elevated LV mass index of 82 g/m2 (>95th perentile). The health of her arteries was evaluated by measuring the pulse wave velocity (PWV) in the aorta, which was elevated to 7.5 m/s. Her carotid artery intima-media thickness (cIMT) was increased to 0.72 mm. An ambulatory blood pressure monitor (ABPM) demonstrated sustained systolic hypertension on antihypertensive medication.

Discussion

Over the last 5 decades, there has been a steady rise in obesity in children. In conjunction with this epidemiologic shift, prevalence of other cardiovascular co-morbidities, including systemic hypertension, has also increased. These risk factors track into adulthood. Therefore, early recognition and treatment of hypertension in childhood has the potential to reduce adverse cardiovascular events later in life.

Blood pressure should be measured annually in patients > 3 years of age and in those at risk for secondary hypertension < 3 years of age. Multiple high BP readings, along with certain medical conditions (see below), may warrant referral to the HAVE Program, a joint clinical program between the Cardiac Center and the Division of Nephrology. At the initial visit, a comprehensive history and physical exam is performed for clues to the cause of hypertension. A work-up for a secondary cause of hypertension may include a renal ultrasound, urinalysis, and blood work to assess for renal and endocrine causes and an echocardiogram to assess for aortic arch obstruction. Placement of 24-hour ABPM further assesses for hypertension outside the healthcare setting.

Medical conditions that put children at risk for hypertension*

  • Chronic kidney disease
  • Renal artery stenosis
  • Coarctation of the aorta
  • Solid organ transplant (eg, heart, kidney)
  • Obesity Diabetes, type 1 and type 2
  • Lipid disorders (eg, homozygous FH)
  • Kawasaki disease (with or without coronary artery involvement)
  • Chronic inflammatory disease (eg, vasculitis, Lupus)
  • Sickle cell disease
  • Cancer treatment survivors

* Cardiovascular risk reduction in high-risk pediatric patients. Circulation. 2006;12;114(24):2710-2738.

We also assess cardiovascular impact of chronically elevated BP using simple, non-invasive tests. These results aid in assessing overall risk, tailoring treatment strategies, making recommendations for activity levels, and in counseling patients and families. On echocardiogram, left ventricular hypertrophy and increased left ventricular mass index (LVMI) are associated with hypertension and contribute to the adverse cardiovascular profile in these patients. In addition, evidence suggests that fatty streaks are present in the intimal layer of arteries as early as 3 years of age and can progress to atherosclerotic plaque in adolescence—a process further stimulated by the presence of risk factors such as hypertension. One marker of subclinical atherosclerotic disease easily measured by ultrasound is cIMT (see Figure 1). Hypertension also alters the structure of the arteries and increasing the vascular load to the heart. Pulse wave velocity (PWV) in the aorta measured by Doppler technology evaluates one component of vascular structure: arterial stiffness. An increased cIMT and elevated aortic PWV are noted in children with cardiovascular risk factors and can improve with interventions.

CIMTFigure 1

To round out our comprehensive evaluation, we counsel on healthy diet and exercise. In addition to caring for patients with primary hypertension, we have diagnosed hypertension and guided treatment in patients with high-risk conditions, such as solid organ transplant, rheumatologic disease, and coarctation of the aorta. Our team recognizes the critical role that primary care providers play in the treatment of hypertension. Communication and collaboration with the patient’s primary team remains an important part of our care for each patient.

Despite optimizing BP medications, our patient continued to have hypertension and was unable to lose weight. She underwent a sleeve gastrectomy. At a recent HAVE Program visit, her BMI decreased to 47 kg/m2, her BP was normal, echocardiography demonstrated a normal LVMI of 46 g/m2, and vascular profile included a normal PWV at 6.2 m/s and decreased cIMT to 0.68 mm. We decreased her anti-hypertensive medications. We relayed encouraging results to the patient and her care team, which suggest that markers of cardiovascular risk were slowly improving with efforts to address her co-morbidities. Hopefully, this information will motivate our patient to pursue further weight loss, adhere to her medication regimen, and continue to develop a healthy lifestyle.

Autonomous thyroid nodule detected by molecular testing with next-generation sequencing


A 35-year-old woman with a medical history significant for anxiety and recurrent episodes of silent or subacute lymphocytic thyroiditis was evaluated in a tertiary care endocrine clinic for symptoms of palpitations.

She was initially evaluated for subclinical hyperthyroidism in February 2013 with a thyroid-stimulating hormone level that ranged from 0.04 mIU/L to 0.14 mIU/L and normal free thyroxine and total triiodothyronine levels that spontaneously evolved through mild hypothyroidism with a TSH of 7.17 mIU/L before normalizing to a TSH of 1.93 mIU/L. Thyroid peroxidase antibody was less than 1 IU/mL (normal < 5 IU/mL) and thyroid-stimulating immunoglobulin titers were negative.

Stephanie L. Lee

 

Poorani Goundan

The patient reported that her thyroid was never tender. She was diagnosed with painless subacute lymphocytic thyroiditis. At the time of her initial evaluation, she was noted to have a 1.2 cm x 0.8 cm x 1.3 cm (sagittal x anterioposterior x transverse) heterogeneous isoechoic nodule with indistinct margins. Two years later, she had a repeat episode of tachycardia with TSH of 0.04 mIU/L. She returned to the endocrine clinic as a repeat thyroid ultrasound demonstrated growth of the nodule to 2 cm x 1 cm x 1.8 cm (Figure 1).

Imaging, molecular testing

A fine-needle aspiration biopsy showed a Hürthle cell lesion of undetermined significance with a Bethesda III classification. Cells from one of the fine-needle aspiration passes were sent for molecular testing (next-generation sequencing panel for thyroid cancer, ThyroSeq v.2), which revealed a TSH-receptor mutation (M453T) identified at a low level (with allelic frequency of 8%, which corresponds to heterozygous mutation present in 16% of the cells).

Somatic mutations of TSH-receptor gene are known to frequently occur in autonomously functioning thyroid nodules (AFTN). Mutations in this particular hotspot — codon 453 — have been reported primarily in benign thyroid nodules and frequently in AFTN.

Based on this finding, a radioactive-iodine scintigraphy scan was ordered that showed a single area of uptake corresponding with the left lobe nodule (Figure 2). Radioactive iodine uptake in the remainder of the thyroid was suppressed. A large field of view was obtained to exclude ectopic uptake along the thyroglossal duct path or the anterior mediastinum. The measured radioactive iodine uptake was lower than normal at 3.8% at 4 hours (expected, 5%-15%) and 4.7% at 24 hours (expected, 15%-30%). This nuclear scan with a low radioactive iodine uptake was thought to be compatible with a mixed picture of subacute thyroiditis causing the lack of radioactive iodine uptake in the gland surrounding a “hot” or AFTN.

Figure 1. Thyroid ultrasound. A single heterogeneous isoechoic nodule (yellow arrow) was found in the left upper lobe of the thyroid. The margins were indistinct, but the nodule is not infiltrative. Doppler analysis showed strong peripheral vascular flow (grade 2). No microcalcifications were seen. (A) Transverse image. (B) Transverse image with Doppler analysis. (C) Sagittal image. (D) Sagittal image with Doppler analysis.

Images reprinted with permission from: Stephanie L. Lee, MD, PhD, ECNU

TSH-receptor mutation

Figure 2. I-123 Thyroid scintigraphy. Anteroposterior images showing increased uptake in the left upper lobe autonomous functioning thyroid nodule (AFTN; yellow arrow). The radioactive iodine uptake was suppressed in the rest of the gland. 0.5 mCi I-123 was administered orally. AP images were obtained at 4 hours with large field of view imaging with a gamma camera. Radioactive iodine uptake was measured with a sodium-iodine probe over the thyroid bed at 4 and 24 hours. Sternal notch (SN; white arrow).

There is evidence of somatic mutations of the TSH receptor in toxic adenomas, and although the incidence of these mutations in the literature varies, it has been reported to be as high as 60% to 80%. The presence of TSH-receptor mutations has also been seen in areas of autonomy in patients with multinodular goiter and been associated with thyroid cancer. The M453T mutation is a replacement of methionine by threonine in amino acid number 453 located in exon 10 of the thyrotropin-receptor gene. The M453T gene mutation has been reported in various case reports and case series to be associated with autonomous toxic adenomas, autonomous nodules in multinodular goiter and congenital non-autoimmune hyperthyroidism, and it also has been seen in papillary thyroid cancer.

This activating mutation of the TSH receptor increases the TSH receptor-cAMP pathway without the binding of the TSH ligand. The sodium-iodide symporter (NIS) is an intrinsic plasma membrane protein that mediates active iodide transport into the thyroid gland. Normally, TSH activation of the TSH receptor increases NIS gene expression. High expression of the sodium-iodate transporter NIS(SLC5A5) gene in this sample provided additional evidence in support of AFTN caused by an activating mutation M453T of the TSH receptor.

Gene sequencing changes practice

Now, with the availability of molecular testing, a mutation found in this patient after fine-needle aspiration prompted a radioiodine scan when her TSH level would not have otherwise indicated performing the imaging at the time. The advantage of knowing this nodule is autonomous will allow future monitoring of hyperthyroidism and avoiding fine-needle aspiration if the nodules grows.

Medical Mysteries: A bad diagnosis



Dan Moreau and his wife, Dianne, lived with his dire diagnosis of an incurable brain disease until a psychiatrist discovered a different explanation for his problems.

The doctor’s words were measured and unequivocal, which made her message even more devastating. Dan Moreau and his wife, Dianne, sat in stunned silence as the prominent Baltimore neurologist explained that his angry outbursts, terrifying hallucinations and faltering balance were the result of Lewy body dementia, a relentlessly progressive, largely untreatable and ultimately fatal illness that resembles both Parkinson’s disease and Alzheimer’s.

Dianne Moreau, whose first husband had died at 55 of a rapidly fatal form of kidney cancer, was dumbfounded. “I thought, ‘Can lightning be striking twice?’ ” she recalled.

For Dan Moreau, then 62 and the author of six books, several on career development and personal finance, the March 2012 diagnosis was another stark reminder of his mortality. In 2009 he had undergone successful quintuple bypass surgery to correct a heart problem. But this illness, he knew, would not end in recovery. The neurologist told him he needed to stop driving immediately. After his initial shock wore off, Dan focused on traveling with his wife of six years and spending time with family and friends.

“I wanted to appreciate things before I went nuts,” he recalled.

For more than two years, the Annapolis couple prepared for Dan’s death. He planned his memorial service and practiced skills he thought he might need as his dementia progressed. A retired reading specialist, Dianne, then 60, immersed herself in research about his disease, joined a support group and toured Maryland institutions in search of the best place for her husband when she could no longer care for him.

[My mom, Robin Williams and Lewy body dementia.]

None of the many medical specialists they saw — a cardiologist, several neurologists, an endocrinologist, a urologist — questioned the diagnosis. But in June 2014, Dan consulted a geriatric psychiatrist for help managing his anger.

“I don’t know what you have,” Dan said the psychiatrist told him, “but it’s not dementia.”

The Moreaus were stunned and tried to tamp down their initial elation. Unraveling what was really wrong would take months of tests and a hypothesis that proved to be correct. Dan’s problems, they would discover, were easily treatable, not signs of an incurable brain disease. For both, the emotional impact of living under the specter of a fatal diagnosis has lingered. The truth, Dan said, “is still sinking in.”
Not himself
In early 2011, Dan began complaining that his “thinking wasn’t right.” He seemed unusually moody. “I had to walk on eggshells,” Dianne recalled. Recovered from his bypass surgery, he was taking a slew of drugs, including a beta blocker to reduce his blood pressure and slow his heart rate, and several to lower his cholesterol.

A CT scan of Dan’s brain found nothing unusual. But during a trip to France in June, Dan passed out while driving over a bridge. An old friend traveling with the couple grabbed the steering wheel, narrowly averting a disastrous accident. The friend later told Dianne he was shocked by how out of it Dan seemed during the trip.

For the next few months his fogginess and increasing irritability, directed mostly at Dianne, waxed and waned. Appointments with a neurologist in Annapolis failed to find anything specific. Dan complained of feeling unusually tired and said his legs felt “rubbery.”
Dianne grew increasingly alarmed. The year before her first husband died, he had reported feeling unwell, complaints that were dismissed by doctors until his diagnosis of cancer, eight weeks before his death. “I learned a very hard lesson of really researching and digging into things,” she said. She plunged into Dan’s case, but found that “none of it was making sense.”

In addition to the motor problems and anger, Dan was beset by dizziness, hallucinations and vivid nightmares. In February 2012, while Dianne was driving through a Baltimore tunnel, he became convinced it was collapsing around them. At other times he thought that his car was filled with tigers and that squirrels had invaded their bed. Sometimes he awoke in the middle of the night yelling, “What is happening?”

After tests revealed nothing, the neurologist sent him to the Baltimore specialist who diagnosed Lewy body dementia, or LBD. “She said very assuredly that Dan had a very early case,” Dianne recalled.

The disease is characterized by fluctuating but deteriorating cognitive function, vivid visual hallucinations and, in some cases, a tremor or abnormal gait. Comedian Robin Williams was diagnosed with it shortly before his suicide last year.

Dan sank into a deep depression. He viewed the cable TV series “Boss,” featuring Kelsey Grammer as a corrupt Chicago mayor coping with newly diagnosed LBD. “I watched the opening episode of that show dozens of times as Grammer’s character learns what he’s in for,” Dan recalled. “And I recommended it to my friends to help them understand the disease.”
Dianne, who had been told by the Baltimore neurologist that she might need to protect herself if Dan became violent or unmanageable, joined a support group. She grew close to two women whose husbands had LBD and learned patience, which, she said, “I needed every minute of every day.” Dan was given Aricept, the first of several dementia drugs he would take, none of which helped.

He also began passing frequent kidney stones — more than two dozen over the next two years. These hard mineral deposits are excruciating for many people; for Dan, however, they were only mildly painful. His urologist attributed them to his diet.

Getting worse
By the summer of 2012, Dan became verbally abusive, often accusing Dianne of being manipulative. “It was so unlike him,” she said. One night after Dan, in the grip of a hallucination or nightmare, pinned her to the mattress while trying to “protect” her, Dianne began sleeping in the guest room behind a locked door.

For the next year they struggledwith Dan’s condition, which was evident to close friends and relatives but not casual acquaintances. Dianne said that Dan seemed unusually aware of the impact of his behavior and remorseful about its effect on her, insight unusual for someone with dementia.

And he remained able to compensate for some deficiencies. A gourmet cook, he still prepared the couple’s meals even though it would take him four hours to make dinner and he needed to write down steps that previously had been automatic.

Dianne thought it strange that Dan was not deteriorating as fast as the husbands of women in her support group. She said that one doctor told her Dan “was so bright he was not declining at the rate a normal person would.”

In April 2014, Dan consulted a geriatric psychiatrist at Johns Hopkins for help managing his outbursts. The doctor ordered cognitive tests, and a brain scan was performed.

The results were a complete surprise. Not only did they reveal that Dan had a high level of cognitive function — inconsistent with a person who had had LBD for nearly three years — but a PET scan of his brain showed no evidence of any disease.

“I keep looking at this high calcium,” Dan remembers the psychiatrist saying. “Hasn’t anyone looked at this?”
The answer was: Not really.

It’s not clear when lab tests first revealed an elevated level of calcium in Dan’s blood, though it was noted by the neurologist who diagnosed him with dementia in 2012. Dianne said she had repeatedly asked various doctors whether Dan’s elevated calcium might be causing his symptoms but was told no. She remained skeptical; her research revealed that excess calcium, particularly in conjunction with elevated levels of parathyroid hormone, or PTH, can cause kidney stones as well as cognitive and behavioral problems.

Elevated calcium
Several doctors told her that Dan’s level of PTH, a protein produced by four tiny glands that regulate levels of calcium and phosphorous, was normal. And Dan’s calcium was only slightly elevated. A few weeks before seeing the psychiatrist, an Annapolis endocrinologist had refused Dianne’s request to order a scan of Dan’s parathyroid glands to check for a benign tumor called an adenoma, which can cause calcium and PTH levels to rise.

The psychiatrist referred Dan to Suzanne Jan De Beur, a Hopkins endocrinologist who specializes in calcium disorders.

“It was a giddy moment of disbelief,” Dan recalled. Dianne was cautious: “I felt that to protect myself, I couldn’t get too excited.”

During Dan’s initial appointment with her in October, Jan De Beur was struck by his unusual symptoms. “We don’t usually see hallucinations or angry outbursts” in patients with hypercalcemia, as elevated calcium is known, she said. And Dan’s was only 10.7 milligrams per deciliter; the upper range of normal is 10.2.

She wondered if more than one problem was causing Dan’s symptoms. First, she had to determine the reason for his elevated calcium. A scan revealed a pea-size parathyroid adenoma, which would account for the numerous kidney stones, fatigue and cognitive fuzziness.

In reviewing Dan’s long and growing list of medications, some of which he had been taking since his heart surgery, one stood out: a beta blocker called metoprolol. Jan De Beur had treated several patients who suffered from terrifying hallucinations while taking the drug; one man had tried to strangle his wife.

The problem is not new, Jan De Beur says, but remains under­recognized. As far back as 1985, doctors have reported hallucinations, vivid nightmares and behavioral disturbances in some patients who took metoprolol. Several patients, British researchers wrote, described animals in their bedrooms, just as Dan had.

At Jan De Beur’s suggestion, Dan’s cardiologist prescribed a different beta blocker. His hallucinations and nightmares disappeared. But it became increasingly clear that Dan would need surgery to remove the tumor as his levels of calcium and para­thyroid hormone rose.
In March 2015, Dan underwent a 45-minute operation. In the recovery room, he said, “it felt as though a bale of cotton had been pulled from my brain.” His mood swings and problems with thinking and motor coordination disappeared. His calcium and PTH levels quickly returned to normal, where they have remained.

Dianne’s support and persistence, he said, enabled him to get through two hellish years. Dianne credits the help provided by their internist Scott Eden.

To Jan De Beur, Dan’s experience underscores the potential pitfalls of a clinical diagnosis made largely on the basis of symptoms, not a concrete test that confirms or refutes a diagnosis. For Lewy body dementia and many other ailments, there is no such test. That’s why, she said, it’s important for doctors to ask, ‘Is there any other explanation for this?’ “In his case you had several things coming together that looked like something else. In the meantime, he had to live with a devastating diagnosis.”

The couple has struggled to come to terms with their ordeal. Dan has met several times with a psychologist. He said he was told by another doctor that the neurologist who made the Lewy body diagnosis has been informed of her error.

Dan has not contacted her. “I don’t know what I’d say to her,” he said. “I wonder what she’d say to me.”

Medical Mysteries: It seemed like a heart attack, but the tests said no.


As Pamela Meredith sank onto her living room sofa to watch an action movie with her visiting grandson, she felt unusually relieved that their busy day was over. The sultry heat of a Washington August, combined with the pace required to keep up with an active 12-year-old, had sapped her energy, which had flagged in recent weeks. As she put her feet up, Meredith was alarmed to see that her normally slim ankles were swollen, obscured by bands of puffy flesh.

The retired nurse practitioner gingerly pressed her finger into one ankle. The pressure left a visible dent in her skin, a telltale indication of a condition calledpitting edema, caused by an accumulation of fluid in body tissues.

As Meredith mentally scrolled back through the events of Aug. 1, 2013, for a possible cause, she suddenly worried that her worsening fatigue might portend something ominous. She had dismissed recent sporadic heart palpitations as a mere nuisance, the recurrence of a harmless condition that had first appeared in her 30s. But the combination of pitting edema, worsening fatigue and palpitations seemed to point in one direction: a heart attack.

A few hours later, tests at a Northern Virginia hospital quickly ruled out Meredith’s biggest fear. She had not had a heart attack. But her level of potassium, critically important in regulating blood flow and kidney function, was perilously low and her normally low blood pressure was dangerously high. Meredith was admitted to the intensive care unit, where doctors spent the next four days figuring out what had caused her problem — and how best to treat it.

The answer proved to be both simple and surprising, revealing a malady with which Meredith, the former editor of a nursing magazine, was unfamiliar.

“This is definitely an underrecognized problem,” said Hesham Omar, a hospital-based internist who was not involved in her case. “I think these cases get admitted and treated, but the cause is never figured out. Luckily, it’s not very common.”

The fatigue began in July soon after Meredith, then 70, returned from her family’s annual summer reunion in Atlantic, Iowa, an event that drew relatives from as far as Chile.

She began having difficulty completing her customary two-mile daily walk through her hilly Alexandria neighborhood, and noticed brief palpitations. They didn’t alarm her. In her 30s, she had experienced similar irregular heartbeats when she was stressed; testing at the time had ruled out a serious problem. “I’d always associated them with anxiety,” Meredith said. Although she did not feel anxious, “I’d just come back from a trip, and it was 100 degrees out.”

Her grandson was staying with her for a week, and they relaxed by watching movies in the evening as Meredith snacked on the Dutch salt licorice candy coins she had first tasted at the reunion.

On the afternoon of Aug. 1, Meredith had a physical therapy appointment designed to treat a shoulder problem. Two years earlier, she had been diagnosed with psoriatic arthritis, an autoimmune disorder that causes joint pain, swelling and stiffness in people with the scaly skin condition.

At the start of her PT appointment, a student took her blood pressure. The reading was unusually high: about 168/90; Meredith’s reading is usually about 100/60. Meredith said she assumed the elevated reading reflected the student’s inexperience.

“I asked her, ‘Are you sure your monitor’s working okay?’ ” she remembers inquiring.

A foolish move
Meredith recalled that blood pressure reading as she considered what to do about her swollen ankles. She chewed an aspirin tablet, something a person suspected of having a heart attack should do to prevent platelets from clumping and blocking an artery. Then she called her daughter, who lives nearby, and told her to pick up her son. “I knew I had to get to the hospital as soon as possible,” she said.

Then she did something she admits was dumb, partly to avoid upsetting her grandson.

Rather than calling 911, as she should have, Meredith got in her car and at 10 p.m. drove three miles to Inova Alexandria Hospital. She parked her car and walked across the darkened parking lot and into the emergency room. “If I had collapsed in the parking lot at that hour of the night, I might not have been found until daylight,” she said.
Inside the ER, she waited while another patient discussed a hand injury, then announced to the triage nurse in oddly stilted language, “I think I’m having a cardiac event.” Meredith was quickly whisked by wheelchair to an examining bay.

Several hours later, after tests ruled out a heart attack, she began to relax. “I was surprised — and delighted,” she said. She figured that a few intravenous bags of potassium would restore her count and that her blood pressure could be lowered with medications.

But Meredith’s doctors were concerned. Her systolic blood pressure, which measures pressure in the arteries when the heart beats, had risen to nearly 200 at one point, increasing her risk of a stroke. And her potassium level hovered around 2.6, a condition called hypo­kalemia, considered a medical emergency because it can trigger ventricular fibrillation, a wildly irregular heartbeat that can be fatal.

Doctors were perplexed by the cause of her sky-high blood pressure and hypo­kalemia. Hypokalemia has many causes, among them the use of diuretics (medicines used to treat high blood pressure); other causes include tumors, metabolic disorders, kidney disease and vomiting or diarrhea that leads to dehydration. Blood tests of Meredith’s levels of plasma renin, an enzyme that regulates blood pressure and kidney function, and aldosterone, a hormone produced in the adrenal gland, were abnormally low.

“People can die from low potassium,” said Irmindra S. Rana, a kidney specialist who was among the doctors who treated Meredith.

Meredith said she was repeatedly asked by her doctors and nurses whether she had taken diuretics or had suffered a recent bout of vomiting or diarrhea; the answer to those questions was no.

On the second or third day of her hospitalization, a second kidney specialist asked her a new question, one that commanded her attention.

“Have you eaten licorice lately?” he asked.

Meredith said, “I sat up in bed and said ‘Yes! What does that have to do with it?’ ”

Everything, it turned out.
An unexpected culprit
Meredith told her doctors she had not just eaten a few black licorice coins. A lifelong licorice lover, she enjoyed the candy coins so much that after the reunion she had ordered two two-pound bags. And in the space of about a week after she returned home, she had eaten one of those bags herself. “My practice with forbidden goodies,” she said, “is to eat them as fast as possible” so they’re not around to tempt her.

The type Meredith had eaten is called salt licorice and is popular in northern Europe. It contains glycyrrhizin, which causes the candy to taste sweet. The ingredient is made from licorice root, consumption of which can prompt the kidneys to release too much potassium, disrupting cardiac function and sometimes causing palpitations. Glycyrrhizin is not present in red licorice or in some licorice-flavored candy that uses a sweetener other than licorice root.

“We were looking for a unifying hypothesis” to explain her symptoms, said Rana, who made the diagnosis in conjunction with the other nephrologist and the hospital internist. In the absence of other findings, patients with very high blood pressure, fatigue and very low potassium and who have consumed large quantities of licorice are presumed to be suffering from licorice poisoning. And eating a two-pound bag of licoricein a short time is clearly enough to cause it.

“The key is to take a good history from patients,” said Rana, who said he has seen one other case of licorice toxicity in his career.

Shortly before Halloween 2011, the Food and Drug Administration cautioned consumers to avoid overconsumption of black licorice. The agency warned that people older than 40 who consume too much black licorice in a concentrated period could risk heart rhythm disturbances or muscle weakness. Sensitivity to glycyrrhizin varies and may be affected by genetic factors as well as sex and age.

The link between licorice and metabolic problems goes back decades, said Hesham Omar, an Iowa hospitalist who has written two papers on licorice poisoning.

Omar, who graduated from an Egyptian medical school, said that the problem is not uncommon among Muslims during Ramadan, when people are forbidden to eat or drink for 12 hours or more each day. Some consume enormous amounts of liquid licorice — sometimes in the form of tea — to blunt thirst, he said, only to wind up in the hospital. Patients who also take diuretics are particularly susceptible to accidental poisoning as are those who binge on licorice.
After four days in the ICU, Meredith was discharged from the hospital; by then, her potassium level had returned to normal. Her blood pressure declined slowly but steadily, though it remained elevated for several months, as is common in cases of excess licorice ingestion.

“I was dumbfounded by this,” Meredith said. “I certainly had never heard of it.”

She regrets driving herself to the emergency room. “If anyone in my family had done this, I would have hit them upside the head,” she said.

Meredith, who saw Rana several times after discharge to monitor her blood pressure and kidney function, has recovered completely with no ill effects, as do most patients. She has not touched licorice since, although the second large bag of Dutch candy coins remains in her kitchen cupboard.

“I’m not sure why,” she said. “Maybe as a reminder.”

 

He went from a playful little boy to ‘a zombie.’ Why wouldn’t the doctors listen?


As she grabbed her car keys and sprinted out of her office, Kimberly Almarode struggled to control the terror that surged through her body.

Her son’s preschool teacher had just called to say that Almarode’s 4-year-old son, Bentley, had fallen asleep in a classroom playhouse and teachers were having trouble rousing him.

“I just panicked,” recalled Almarode, 26, who lives in Stuarts Draft, Va., a town about 40 miles west of Charlottesville. She sped to the school to pick up Bentley, who lay on a cot in the nurse’s office. He opened his eyes when he saw her and said, “Mommy, I want to go to the doctor right now.”

During the previous two weeks, Almarode had grown increasingly worried about her previously healthy middle child. Bentley complained of frequent headaches that had worsened from bothersome to debilitating. “He went from a playful little boy to a zombie who couldn’t move off the floor,” she recalled.

[What caused a newborn twin’s badly swollen legs?]

But Almarode’s insistence that something serious was wrong with Bentley was dismissed by doctors who attributed his headaches, lethargy and episodic vomiting to a virus.
Three days after that March 2 call from the preschool, an optometrist had a distinctly different reaction. While examining Bentley for a possible vision problem, the eye doctor was so alarmed that he called the University of Virginia Medical Center to schedule an emergency brain scan and told Bentley’s father to take his son to Charlottesville immediately. What he saw, the optometrist told Curt Almarode, “was not normal in a child.”

“We expected to find a horrendous brain tumor,” recalled U-Va. neurosurgeon Kenneth Liu, who met the family soon after Bentley was admitted. The optometrist had detected a condition called papilledema, a swelling of the optic nerve caused by an accumulation of fluid that presses on the brain. Along with lethargy and vomiting, papilledema in a child is often a sign of pediatric brain cancer. Instead, Liu and his colleagues were surprised to discover a disorder unusual in children.
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Young adults are using online resources to drive their offline activism.
To treat it they used a new and potentially risky procedure, then waited anxiously to see if it would work. During a timeout in the operating room — a brief period during which the surgical team huddles to confirm important details before beginning an operation — Liu recalls feeling “scared [to death].”

“I remember very clearly saying, ‘This is not only a 4-year-old, [but] we’re doing things that have never been done, so let’s try not to screw it up,” the neurosurgeon said. “It was a fairly tense room.”

[A pain in his foot. Her swollen ankles. Her patches of dry skin. More medical mysteries]

Liu’s gamble paid off. Six weeks after his surgery, Bentley went back to school, and he was soon playing T-ball, wearing a helmet to protect his head.

‘We don’t overreact’
At first Almarode thought Bentley’s headaches might be an excuse to get out of doing something he didn’t want to do, such as putting his toys away, or a sign of routine illness. “We don’t overreact,” said Almarode, who with her husband also has a daughter, now 8, and a 3-year-old son. “If our kids get a boo-boo, we tell them to suck it up.” She gave Bentley an over-the-counter pain reliever and assumed he would get better.
But over the next week, he didn’t. His teacher called to say he was falling asleep in class. One night while the family was out to dinner, Bentley told his mother his head hurt terribly, then vomited all over the table.

A few nights later, she watched Bentley fall into a deep sleep, during which he began to shake and twitch uncontrollably. The next morning — Saturday, Feb. 28 — she took Bentley to the pediatrician who was covering for his regular doctor.

The pediatrician diagnosed Bentley with a virus. Almarode was skeptical and noted that he had no sign of a virus, such as a fever. She asked whether Bentley might be developing migraines, which she suffered from. The doctor seemed noncommittal but offered to put the child on Topomax, a potent anti-seizure drug used to prevent or treat migraines.

“I don’t think so,” Almarode remembers telling him. “I was on it, and it makes you feel like a zombie.” She told the doctor she wanted to discuss the medication with her husband first.

She took Bentley home and began watching him closely. The normally wiggly preschooler lay on the floor watching silently as his little brother played with his toys. That alone was a huge red flag. Bentley never let anyone — especially his brother — play with his toys.

By Monday morning he seemed a little better, so his parents took him to school. A few hours later, his teacher called.

Normal scan
At the emergency room where his mother took him straight from school, the doctor who checked him out didn’t seem concerned. He, too, told Almarode that Bentley had a virus. His recommendation: Take the little boy home and give him Tylenol and anti-nausea medicine. Almarode, who works as a scheduler in a radiology office, said she pushed for a CT scan of Bentley’s head, worried that he might have suffered an injury from a fall. When the scan came back — it was normal — she recalled that the doctor seemed peeved, particularly when she questioned how a virus could cause such symptoms.

“He told me nothing was wrong with him and advised me to take him to a pediatrician, which he was not,” she said. “He made me feel like an idiot and that I was overreacting.”

Once home, Almarode wondered if Bentley’s headaches might signal a problem with his vision. She made an appointment with an optometrist, who agreed to see Bentley three days later.

Almarode was at work when her husband called from the optometrist’s office. He tersely told her he was taking Bentley to Charlottesville. For the second time that week, Almarode grabbed her purse and ran out of her office. “I knew something was wrong,” she remembers telling her husband as she jumped into his car for the 45-minute drive. “I just needed someone to listen.”

One of the first tests U-Va. doctors performed was an MRI scan of Bentley’s brain. Liu said that instead of finding a large cancer, as they expected given his symptoms, the scan showed a Chiari malformation in which tissue from the cerebellum protrudes into the spinal canal.

But a Chiari shouldn’t cause high intracranial pressure, a life-threatening condition. A normal reading for a 4-year-old is about 10 mmHG, Liu said; Bentley’s pressure at times rose into the 50s. “Anything over 20 makes neurosurgeons really nervous,” he said.
After further testing, Liu suspected that the malformation was not the cause of Bentley’s problem but the result of it. His headaches, vomiting and stupor were caused by pseudotumor cerebri — essentially, a false brain tumor. “Patients behave like they have a brain tumor,” Liu said. “But the brain looks completely normal.”

Pseudotumor is most common in young obese women, but it sometimes occurs in children. If no underlying cause is found, as in Bentley’s case, the disorder is called idiopathic intracranial hypertension; it affects about 1 person in 100,000.

In many patients, Bentley among them, the problem results from narrowed or obstructed veins in the transverse sinuses, areas beneath the brain critical to the drainage of blood. In Bentley’s case said Liu, an assistant professor of neurosurgery, the Chiari appears to have developed as a result of the increased pressure on Bentley’s brain. Without treatment, he was at risk of a brain bleed or permanent blindness.

There are three ways to treat pseudotumor. The first, using medications to lower the rate of spinal fluid production, is not optimal, Liu said, because it doesn’t address the underlying cause. The second involves running a shunt from the brain to the belly to relieve pressure on the brain; shunts require replacement and can become blocked. The third and newest option, devised about a decade ago, involves using a metal stent to open the blocked veins, relieving the pressure and restoring blood flow.

“Stenting made the most sense to me — if it could be done safely,” said Liu, who specializes in treating blood vessel disorders. But, he noted, the procedure is new — it is not clear how long the stents will last — and the devices are designed for adults, not children. Most are threaded up the femoral vein in the groin and into the transverse sinuses.

[Her brain tormented her, and doctors couldn’t understand why]

Liu had a long conversation with the Almarodes during which he presented the options and said he thought that stenting posed the best chance for a good outcome. Bentley’s parents agreed.
On March 10, Liu and his colleagues tried for an hour to thread the stent from Bentley’s groin to his skull. Liu said the procedure had to be aborted when it was clear the stent could not be safely pushed into the sinus.

At that point, Liu said, he wondered whether the best approach might be to access the vein by drilling a tiny hole in the back of Bentley’s skull. Liu had used such an approach to treat blood vessel disorders and cancer, but never pseudotumor. Nor was he aware, he said, of other doctors who had done so.

“I wanted to make sure I wasn’t crazy,” he added, so he contacted nearly a dozen neurosurgeons in Charlottesville and around the country. Opinions were decidedly mixed. “Half of them said, ‘You’re crazy,’ and the other half said, ‘It makes sense.’ ”

“I was very open with the family,” Liu recalled, when presenting the novel approach. Among the risks were a brain bleed or a blood clot.

Kim Almarode said Liu sidestepped her question to him: What would you do if it was your child? She said she and her husband were supportive because they trusted the neurosurgeon who had used such an approach successfully in other cases. “It wasn’t new to him,” she said.

On March 12, Liu and his colleagues performed the procedure. Within 24 hours Bentley’s intracranial pressure began dropping. Three days after his operation, Bentley was well enough to go home.

Two weeks later, a follow-up MRI showed that the Chiari had begun to recede, something Liu said he has never seen. A recent MRI was normal, Almarode said, and Bentley appears to have fully recovered.

Almarode said the experience convinced her of the importance of trusting her instincts when it comes to her children’s health. “One of the worst parts of this,” she said, “was hearing over and over again that I was overreacting.”

 

For half her life, doctors told her to lose weight. But something else was going on.


To Deborah E. Savage, a trip to the doctor was frequently an exercise in humiliation.

For more than 15 years, Savage’s doctors doled out the same advice: You need to stop gaining weight. When Savage replied that she had tried watching her diet and exercising, only to pack on more pounds, it was clear they simply didn’t believe her. Her family was equally skeptical.

“I would eat like my sister, and I would gain weight but she wouldn’t,” recalled Savage, a civil engineer who lives in Montgomery County and turns 31 next month.

Last year, after Savage had trouble getting pregnant, an inability she suspected was linked to her irregular periods, she consulted a new obstetrician/gynecologist. The doctor suggested that Savage’s constellation of problems might have a single cause. But it took a second OB/GYN to conduct the proper tests, which led to a definitive diagnosis of a common — and consequential — disorder.

“It’s frustrating to me that so many doctors” didn’t think of this, she said. “If I’d known, I would have made changes years ago.”

Comparisons rankled

From the time she was 12, Savage recalled, her inability to lose weight became one of the defining elements of her life. And because she is short — 5-foot-3 — extra pounds were particularly noticeable. Her family’s comparisons with her older, thinner sister rankled.

Savage said she was too intimidated to ask her doctors why her weight didn’t budge much, even when she faithfully followed a diet and worked out.

Nor did she mention the other problems that plagued her. “The facial hair thing was embarrassing, so I didn’t want to talk about it,” she recalled. “Same with the acne. I felt so sensitive about it.”

Savage wasn’t sure what to make of her irregular menstrual periods, but doctors did not seem concerned. At times she went three months without a period; at other times they lasted for two weeks. She managed to lose a little weight in college, but her acne and other problems persisted.

To regulate her menstrual cycle and tame her acne, the doctor prescribed oral contraceptives, which helped clear her skin and made her periods somewhat less irregular.

When she got married in 2010, Savage and her husband joined a popular weight-loss program to see whether they could motivate each other.

Savage said she lost only about eight pounds after several months, while her husband, who followed the same diet, had no trouble shedding much more weight.

“It was very frustrating,” she recalled. “I was serious about following the rules, but it didn’t pay off. I kind of gave up.”

In March, sheswitched gynecologists. Her new doctor zeroed in on her irregular periods and her weight and asked Savage whether she had heard of a metabolic disorder called polycystic ovarian (or ovary) syndrome.

What is polycystic ovarian syndrome?

Polycystic ovarian (or ovary) syndrome is a condition that affects up to five million American women, but it often goes undiagnosed. Here are the basics. (Gillian Brockell/The Washington Post)

Savage replied that a friend in college had been diagnosed with PCOS. She was surprised when the doctor responded that she suspected Savage might have it, too.

An explanation at last

PCOS is a common hormonal imbalance that often begins in puberty and affects as many as 10 percent of women. Its cause is unknown, but heredity appears to play a role: Women whose mothers or sisters have the disorder are at higher risk. Many women with PCOS have enlarged ovaries containing fluid-filled cysts that produce excess androgens — male sex hormones, which interfere with ovulation. Other signs of PCOS include irregular, absent or prolonged periods, acne and excess facial and body hair, a condition known ashirsutism.

Because it also disrupts the regulation of insulin, many women with PCOS are overweight or obese. The disorder, which can be controlled but not cured, also increases the risk of Type 2 diabetes, high blood pressure and heart attack.

Savage declined. Two weeks later, she consulted a third OB/GYN, Neil Horlick, who practices in Montgomery and Frederick counties.

Horlick, after taking her history and performing an exam, said he suspected she had PCOS. When Savage told him she had been told there was no test for it, he assured her that testing was available and that he would order it.

Because abnormalities of the thyroid or adrenal glands can cause similar symptoms, those must be ruled out first. PCOS is essentially a diagnosis of exclusion, made on the basis of blood tests, a patient’s symptoms and an ultrasound of the ovaries.

Horlick said he was surprised that Savage’s condition went undiagnosed for so long. “PCOS is always on our radar” when a patient with irregular periods complains of weight gain and hirsutism, Horlick said.

He told Savage that her best chance of getting pregnant involved losing weight. Horlick prescribed metformin, a diabetes drug that can promote weight loss. Metformin is commonly given to PCOS patients and may help promote ovulation as well.

Savage decided to take a new approach to food. She began following a paleo diet, which emphasizes meat, vegetables, nuts and fruit, and drastically reduces the intake of carbohydrates, sugar and processed foods.

The first month, she said, she was elated to discover that she had lost 15 pounds; between April and September, she shed 50 pounds and her cholesterol dropped 20 points. Her acne also improved, her level of testosterone dropped, and her menstrual cycle became more regular.

Savage said she asked relatives whether anyone else had been diagnosed with PCOS. “My parents had never heard of it,” she said.

In October 2015, she and her husband were elated to learn that she was pregnant with identical twin boys. Savage spent six weeks hospitalized at Maryland’s Shady Grove Medical Center under close observation, because her twins have a rare condition in which they share a single amniotic sac and placenta, a condition unrelated to PCOS. The babies were born April 22.

Savage said she hopes that her experience will spare other women from “struggling for years the way I did.”

“This isn’t a bizarre disorder,” she said. “It shouldn’t take [this many] doctors to find out, when I have a textbook case.”

 

Doctors thought it was a simple foot infection. They were so wrong.


Melissa Curley Bogner was baffled: Why did her feet feel suddenly hot — in January?

The 41-year-old management analyst for the Navy had grown accustomed to periodic bouts of neuropathy — numbness in her hands and feet — the apparent legacy of a severe allergic reaction to a drug she took in 2000 to treat a gynecological infection.

But this 2015 episode was different. Along with the sensation that her feet felt unusually warm, the skin on the second toe of her right foot looked inflamed. Weeks later, she noticed a small blister.

Bogner, who lives in Southern Maryland, initially shrugged it off. She figured that whatever was wrong would go away on its own.

“It’s been life-altering,” Bogner said of the diagnosis. Summer, a time of year Bogner once eagerly anticipated, has become the season she finds hardest to endure. To cope with her new reality, she has sought to channel her energy into a self-help group for people diagnosed with the little-known malady.

A fungal infection?

At first, Bogner tried to largely ignore the problem, assuming that her shoes were to blame. Changing footwear didn’t help. Sometimes her toe would itch and feel tingly. At other times, the redness seemed to lessen, but it never disappeared entirely.

In April, when she took her son to an urgent care center for treatment of a skateboarding injury, she asked the doctor what he thought might be wrong with her toe. He told her it looked like a fungal infection and suggested she try an over-the-counter remedy. Bogner took his advice but discovered that the ointment irritated her toe. Instead of clearing up, there were signs that the redness was spreading to her third toe.

At the time, Bogner was preoccupied with more pressing medical problems. During a three-day hospitalization for a hysterectomy, she asked doctors about her toe. They were reassuring; if it was serious, Bogner said they told her, the problem would affect all her toes, not just one or two.

In fact, Bogner said, the cream, which she used for about a month, exacerbated the problem. What had been a small blister “blew up into a cyst on the top of my toe,” she said. The sensation of heat and the tingling were undiminished.

“I thought, ‘When is this toe going to give me a break?’ ” Bogner recalls.

Rare condition felt like feet ‘burning into a pile of ashes’

Spreading redness

Next stop was a podiatrist, whom Bogner saw in June. By then, three toes on her right foot sometimes turned crimson and the problem seemed to be affecting her left foot as well. The podiatrist was concerned that although Bogner did not have diabetes, her toe discoloration might signal a vascular problem that was impeding circulation in her legs. She sent Bogner to a cardiologist.

Testing by the cardiologist found nothing to account for the skin discoloration or tingling, such as peripheral artery disease. “I thought, ‘I’m back to square one,’ ” Bogner recalled. By this time, the problem had spread from her toes to the rest of her feet.

Increasingly alarmed, Bogner said she “began obsessively Googling ‘burning red feet.’ ” One possibility was a condition called small fiber neuropathy, a form of peripheral neuropathy that can cause a burning sensation and severe foot pain.

Another option was erythro­melalgia (EM), a rare and poorly understood disorder; the term literally means “red limb pain.” First described in 1878, the condition is characterized by red, hot and painful extremities, usually the feet and less commonly the hands. In some patients, the ears or face are affected.

Numbers are imprecise, but EM is estimated to affect about 1 in 100,000 Americans, many of them white women who develop the condition in middle age, although some people are affected as children. “I thought, ‘I can’t believe that I’m that 1 in 100,000,’ ” Bogner recalled, fearing that in fact she was.

Desperate for guidance, Bogner called the National Organization for Rare Disorders, a Connecticut-based clearinghouse and advocacy group that provides information about more than 1,200 conditions, including several of the possibilities Bogner had found. A staff member suggested she print out the information about EM, which most closely matched her symptoms, and take it to the neurologist she had seen over the years for treatment of her neuropathy. She was also advised to take pictures of her red feet during a flare to show the neurologist.

Ahmed Kafaji, a neurologist who practices in St. Mary’s County, saw Bogner in early July.

Her hands, he recalled, looked fairly normal but felt hot. When she showed him cellphone pictures of her feet, their appearance was consistent with EM, which he had seen previously once or twice in his career. Kafaji said he also noted that the skin on Bogner’s hands seemed somewhat coarse, which is consistent with EM.

“If doctors haven’t seen a case, it’s often misdiagnosed as eczema or allergies,” he said. As a result, some patients go from doctor to doctor without an accurate diagnosis.

Blood tests ruled out cancer, Lyme disease, various auto­immune or bone-marrow problems, and a genetic mutation known to cause EM. After seeing two neurologists, a rheumatologist and a hematologist, Bogner was told that she had primary idiopathic EM — meaning the cause was unknown.

‘A dreadful season’

The definitive diagnosis plunged Bogner into the despair that can accompany the wrenching adjustment required to live with a disabling, possibly permanent, condition.

While EM can improve, or even largely disappear, that doesn’t happen often.

A study of 168 patients treated at the Mayo Clinic between 1970 and 1994 found that 10 percent reported that their EM resolved after an average of nearly nine years. Of the others, about one-third reported that it worsened and one-third that the problem improved but did not disappear. The rest reported no change.

Bogner’s condition has not improved. She takes medicines to help her sleep and to try to blunt the worst of the flares, which can last from five minutes to all day.

“The heat can be like submerging your toes into burning water,” she said. When her ears are affected, “it feels like my head is on fire.”

“Summer is a dreadful season,” she said. Trips to the pool or beach are now out of the question. Alcohol and spicy food can trigger a flare, so Bogner largely avoids both, but misses having a glass of wine with friends.

She holds out hope that there will be more effective treatment in her lifetime. “Doctors don’t understand the depression that goes along with this,” she said.

Involvement in an online group has been her most important source of support, Bogner said, and has enabled her to feel less isolated and lonely and to help others in similar or more difficult circumstances.

“We talk people off the ledge,” she said. “Our bond is very strong.”

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