Can you diagnose these 7 mystery illnesses?

By Naveed Saleh, MD, MS, for MDLinx
Published November 13, 2019

Key Takeaways

In the 1940s, Dr. Theodore Woodward, a medical researcher and educator at the University of Maryland, famously quipped, “When you hear hoofbeats, think of horses, not zebras.” The maxim is a clever reminder that clinicians should seek to investigate and diagnose obvious common causes of a medical illness before thinking of more unlikely options (ie, “chasing zebras”). In medicine, chasing zebras can oftentimes result in wasted time, resources, and costs. However, it’s important to keep in mind that, although rare, “zebras” do exist. And with due suspicion and evidence, it may be prudent to consider the possibility of a rare diagnosis, as illustrated by the following seven case studies with mystifying presentations.

Case 1: Deep diving

A 39-year-old man experienced headache and transient aphasia after going breath-hold diving for 5 hours. During this time interval, he did 30 breath-hold dives each lasting 2 minutes. On MRI, there was a white matter lesion at the level of the left frontal lobe with no mass effect. After hyperbaric oxygen therapy, the symptoms disappeared, and the lesion had almost fully regressed.

What happened?

The explanation for this stumper is exquisitely biochemical. During the breath-hold exercises, the patient accumulated nitrogen in the blood, which likely led to endothelial dysfunction that disrupted the blood-brain barrier. Thus, vasogenic edema resulted from hyperpermeability of the blood-brain barrier.

Case 2: It’s the drugs

A 48-year-old woman with alcohol dependence presented with altered mental status lasting a month. Two months previously, she binged on morphine, oxycodone, and heroin for 1 week. Following the binge, she experienced lethargy for about 1 day, and difficulties with arousal for 2 days. She then returned to baseline without symptoms until falling and hitting her head 3 weeks later, from which she developed acute headache.

One day after hitting her head, she began acting strangely. Her actions included sleeping with cremated ashes, brushing her teeth with a comb, showering with her clothes on, and not recognizing family members. She was finally brought to the hospital and, upon neurological examination, demonstrated that she was only oriented to self. She expressed apraxia, aphasia, and selective mutism, as well as hyperreflexia of the patella, a wide-based gait, and the palmomental reflex, which may be indicative of cerebral pathology.

Tests of the blood, urine, and cerebrospinal fluid (CSF) were all within normal limits. However, results of an EEG showed intermittent, generalized, reactive polymorphic delta slowing indicative of encephalopathy. Brain MRI without contrast demonstrated white matter signal changes and mild cortical swelling that was also suggestive of diffuse encephalitis.

What happened?

Unless you’re a neurologist or addiction psychiatrist, the diagnosis here may be foreign. Following a battery of diagnostic studies including brain biopsy, and in light of her extensive opioid history, a diagnosis of toxic leukoencephalopathy (TLE) was made. Substances that can cause TLE include benzodiazepines, oxycodone, methadone, and methotrexate. The mechanism of TLE remains to be elucidated, and it is difficult to predict who will develop this condition, with few cases having been reported. Treatment of TLE is supportive and involves eliminating any further exposure to toxins.

Case 3: Tall order

A mother brought in her 12-year-old daughter with concerns about her daughter’s extremely short height—even in comparison with other family members—and asked whether she should receive growth hormone therapy. The girl grew less than 1 inch in the past year; had no relevant past medical history; and faced no stressors at home or school, such as bullying, over her stature. Her father is 5 ft 10 in tall and her mother is 5 ft 3 in tall—on par with the average height measurements for men and women globally. Neither parent experienced delays in height growth. The girl is prepubertal, 4 ft 4 in tall (< 5th percentile for children her age), and weighs 77 lb (25th percentile for her age).

What’s going on?

If you’re a pediatrician, you’ll immediately recognize this as a case of idiopathic short stature. Idiopathic short stature is due to familial factors, constitutional growth delay, or both. This condition is defined as height more than two standard deviations below the mean height per age, sex, and population. About 80% of kids who see a physician for short stature are given a diagnosis with this condition.

Growth hormone treatment in those with idiopathic short stature works, and can add about 3 inches in height during 5-6 years of treatment. It’s important to note, however, that the total financial cost is steep and not readily covered by insurance—about $300,000. Furthermore, the adverse effects of growth hormone therapy are not well understood, but it is known to increase the risk of diabetes.

More children are getting growth-hormone treatments, and the demand is high—especially among more affluent parents who, some argue, have glommed to designer height as a new status symbol. It could take years before all the effects of growth hormone in adolescents are elucidated. Thus, all practicing physicians should be familiar with this controversial treatment.

Case 4: A viral appetizer

A 9-year-old girl who was previously healthy presented to the emergency department with headache, sore throat, left earache, neck pain, and history of fever to 101.0 °F. She had symptoms of cough and congestion during the previous 2 weeks. Two days later, she exhibited neck weakness and imbalance, which made it hard to walk and required her to use a wheelchair. She also experienced left facial weakness and was subsequently hospitalized in light of her symptoms. Weakness of her neck, face, and upper extremities worsened for 2 days of hospitalization and subsequently improved during the course of her stay.

Although no infectious etiology was identified per CSF and blood tests, she was treated with ceftriaxone for possible meningitis. Of note, her CSF exhibited pleocytosis, or increased cell count. Follow-up MRI was within normal limits, although spinal MRI was indicative of myelitis.

What happened?

This patient had acute flaccid myelitis (AFM), which affects the gray matter of the spinal cord, and weakens muscles and reflexes. Currently, the CDC is exploring this rare condition. Investigators now suspect that enteroviruses may be the cause, with more than 90% of affected patients experiencing mild respiratory illness or fever prior to the onset of AFM symptoms.

AFM is difficult to diagnose and can be confused with transverse myelitis external icon or Guillain-Barre syndrome. No specific treatment exists, with rehabilitation recommended in some.

Case 5: Biological threads

A 60-year-old man came into the clinic complaining of bulbs and fibrous material emerging from his skin. He also presented with a skin infection that appeared excoriated, and was successfully treated for the skin infection.

What’s going on?

A quick rundown of one of the most controversial diagnoses in medicine—and we’re not talking about the accompanying skin infection! The patient had Morgellons disease, a skin condition that involves the presence of filaments of different colors embedded in the skin. Some patients complain that these filaments “stick out.” The disease first made headlines in 2002, but likely has a longer, more fascinating, history. People with the condition often think they are experiencing a bug or parasite infestation.

Many physicians immediately write off Morgellons disease as a delusional disorder. But not everybody agrees. According to a review article:

“Recent studies from that point of view show an association between [Morgellons disease] and spirochetal infection in humans, cattle, and dogs. These investigations have determined that the cutaneous filaments are not implanted textile fibers, but are composed of the cellular proteins keratin and collagen and result from overproduction of these filaments in response to spirochetal infection. Further studies of the genetics, pathogenesis, and treatment of [Morgellons disease] are warranted.”

Case 6: From the field

A 50-year-old woman from Virginia presented to a local clinic with fever, headaches, generalized joint pain, excessive thirst, and a large, progressive circular rash on her back with a bulls-eye appearance.

What’s going on?

Okay, the telltale rash gives this one away: it’s Lyme disease. But what happens if there weren’t a rash, as is the case in 25% of patients? Not so easy now, huh?

Lyme disease is a multisystem disease that can be difficult to diagnose. First, symptoms are generalized, including dizziness, headaches, and body pain. Second, as mentioned, not everybody has erythema migrans, the annular rash that is pathognomonic for the disease. Third, current diagnostic tests don’t always flag Lyme disease early because antibodies can take time to rise to detectable levels.

Because Lyme disease affects multiple organ systems, it is of interest to various specialists.

Case 7: The great imitator

A 26-year-old woman presented to the emergency department with a 2-day history of generalized edema, worsening dyspnea, chest pain, and nonproductive cough. The patient was tachycardic and tachypneic, but afebrile. She had peripheral oxygen saturation of 94% on 40% supplemented oxygen, and she appeared obtunded. An effusion at the level of the heart, abdomen, and lungs was confirmed. She had a 6-month history of inflammatory joints, including the interphalangeal joints, knees, and elbows, for which she was prescribed glucocorticoids. She also had what appeared to be a case of urethritis. Symptoms waxed and waned.

What’s going on?

This final case could be mistaken for arthritis or fibromyalgia. But if the patient had presented with the characteristic malar (butterfly) rash, you would have likely guessed the diagnosis: systemic lupus erythematosus. Keep in mind, however, that only about 30% of patients present with malar rash, and it doesn’t always appear on the bridge of the nose and cheeks.

To make things even more complicated, there is no gold-standard diagnostic test for lupus. Instead, physicians consider it a diagnosis of exclusion and lean on medical history, family history, and physical exam for help. Biopsy of the kidney or skin are helpful in picking out autoimmune disease, but antinuclear antibodies picked up in blood and urine have low specificity.

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