5 diabolically difficult diseases to diagnose

Naveed Saleh, MD, MS | April 28, 2021

If you’re a physician of a certain age, you may remember spending hours playing the board game Clue. This game was enthralling because players used their deductive-reasoning skills and a process of elimination to identify who was the murderer, where was the crime committed, and what weapon was used.

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Doctors consulting with each other at hospital

Some diseases and conditions are particularly difficult to diagnose and require detective skills on the part of the physician or team.

Curiously, this childhood staple that was ubiquitous in the pre-internet era draws parallels to medicine. Sometimes, we can only rule in a diagnosis via process of elimination, or by diagnosis of exclusion (DOE)—a diagnosis that is made after all differential diagnoses have been ruled out. 

But other times, the DOE, although verifiable, requires diagnostic tests either too difficult to perform or incompatible with life, such as biopsy of the mesenteric nodes to prove mesenteric adenitis, or brain biopsy to support Alzheimer disease.

In this article, we’ll take a look at five notable DOEs. 

Chronic traumatic encephalopathy

In recent years, an increased understanding of the long-term dangers of boxing, football, and other sports that result in sustained brain damage has emerged. In particular, chronic traumatic encephalopathy (CTE) is on every specialist’s radar. Clinical characteristics of this disease include cognitive impairment, impulsiveness, depression, short-term memory loss, substance misuse, and suicidality.

Despite the fact that it has been recognized for some time, CTE “remains a diagnosis that can only be made during neuropathological examination of the brain at autopsy,” according to the NIH. “Early accounts of the pathology of dementia pugilistica/CTE described nerve cell loss and accumulation of abnormal tau protein forming neurofibrillary tangles in affected brain regions. How and where the degeneration began in the brain was never clear.”

More recently, there have been reports of cases where individuals who experienced substantial exposures to trauma did not develop dementia, but in whom tau-positive neurofibrillary tangles were documented during the brain at autopsy. 

Despite increased study, the pathologic characteristics of CTE remain poorly defined. Recognition of CTE on autopsy remains limited. As such, it is not clear how often evidence of CTE goes undetected. 

Alzheimer disease

Like CTE, Alzheimer disease is a neurological diagnosis of exclusion. Various strategies can be used to determine whether a patient has “possible Alzheimer disease,” in which dementia may be caused by another etiology, or “probable Alzheimer disease,” in which no other cause of dementia is found.

Assessment of the patient includes interviews with the patient and family; diagnostic tests of memory, attention, and so forth; blood, urine, and other lab tests to rule out other causes; and MRI, CT, or PET to rule out other causes. 

According to the National Institute on Aging, “It’s important to note that Alzheimer disease can be definitively diagnosed only after death, by linking clinical measures with an examination of brain tissue in an autopsy. Occasionally, biomarkers—measures of what is happening inside the living body—are used to diagnose Alzheimer [disease].”

Reperfusion injury/white cord syndrome  

Reperfusion injury (RPI)/white cord syndrome (WCS) is a mouthful to pronounce and refers to acute postoperative paralysis that some develop after the immediate restoration of normal blood flow to compressed and under-perfused or ischemic spinal cord tissue. On MRI, classical findings involve new or expanded, and focal or diffuse, intramedullary hyperintense cord signals that indicate edema, ischemia, swelling, or intrinsic hematoma. 

According to the author of a review published in Surgical Neurology International, “RPI/WCS is a diagnosis of exclusion following multiple cervical surgical procedures; anterior cervical discectomy/fusion (ACDF), anterior corpectomy/fusion (ACF), laminectomy with/without fusion, laminoplasty, or other cervical procedures including those for tumor resection. Postoperative MR studies best document the classical intrinsic cord changes diagnostic for RPI/WCS.”

They added that to rule in RPI/WCS, MRI must exclude extrinsic cord pathology, such as extramedullary hematomas, new or residual compressive disease, and new graft or vertebral fracture. These other conditions may necessitate cervical surgery to obviate permanent neurological consequences.

Adult-onset Still disease

The prevalence of adult-onset Still disease (AOSD) is rare and difficult to assess, but estimates suggest that it’s more than 1 per 100,000 population. Nevertheless, the disease is notorious for its varied and tricky presentation and lack of gold-standard diagnostic markers.

This condition usually presents in young adults, and clinical features include high fever with spikes, pharyngitis, transient maculopapular rash, and arthralgia, as well as lymphadenopathy, myalgia, serositis, and hepatomegaly. 

The etiology of this disease is unknown, but environmental factors are implicated. The disease is associated with Epstein-Barr virus, cytomegalovirus, HIV, and other viral conditions. 

“The non-specific clinical features of AOSD make diagnosis difficult. No serological marker is currently available,” according to the authors of an article published on Orphanet. “Differential diagnoses include infections (endocarditis, occult infections, secondary syphilis, viral rash), malignancies (lymphoma) or autoimmune diseases (such as polyarteritis nodosa, vasculitis, or polymyositis).”

Mesenteric adenitis

This condition is also called mesenteric lymphadenitis, and it is a self-inhibiting inflammation that occurs at the level of the mesenteric lymph nodes in the right-lower quadrant. This condition can be due to viral or bacterial infection of multiple lymph nodes. On gross pathology, the lymph nodes appear enlarged and soft, with necrosis and pus present. Acute appendicitis presents similarly, and is a prominent differential diagnosis.

According to the authors of an article published on Radiopaedia, “Mesenteric adenitis is often a diagnosis of exclusion after ‘more serious’ etiologies have been ruled out. Definitive diagnosis at surgery is possible but is increasingly uncommon due to the ubiquity of modern imaging tools.”

Bottom line

Although it’s satisfying to be presented with a clear-cut diagnosis, like life, medicine is sometimes mysterious. Instead of finding a DOE disquieting, perhaps it is best viewed as a challenge met with rigorous documentation and attention to detail. 

In other subjects related to diagnoses, click here to learn why the eyes may be the first clue in diagnosing illness.  

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