Diagnostic mimics
Conditions to consider when the diagnostic trail goes cold
Why diseases present atypically:
Diseases in real life seldom present themselves in the way that they are described in textbooks.
This is partly because the textbook description of the disease is usually decades or even centuries old, based on extreme examples of the condition when it first came to be recognised. In the intervening years diagnostic techniques have often advanced resulting in recognition of “less than full-blown” forms (“formes fruste”) of the disease or of features that were not initially associated with the disease (for example cough as a manifestation of oesophageal reflux).
Atypical presentations can also result from failure of disease to produce symptoms localising to specific areas of the body as a result of immunosuppression.
a young woman with a renal transplant on immunosuppressant treatment presents with fever, vomiting and diarrhoea that proves to be due to pneumonia rather than gastroenteritis.
Comorbidities and their treatments can also confuse symptoms.
Disease in very old people often does not “follow the rules” and can be characterised by unusual presentations. Examples include sepsis in the elderly causing hypothermia rather than fever and myocardial infarction occurring without chest pain.
Common conditions which are often difficult to diagnose.
In previous posts I dealt with several conditions where the diagnosis can easily be missed because of atypical or nonspecific clinical presentations.
Such conditions are characterised by symptoms that are difficult to localise to any organ system. Alternatively they may cause symptoms that lead one away from the correct diagnosis. An example is the presentation of ruptured abdominal aortic aneurysm with acute back pain.
Because clinicians fear missing the diagnosis of these conditions, atypical presentations are favourites for discussion at grand rounds.
Each clinician will have their particular “bugbear diagnoses” depending on their speciality. As I described in my previous two posts, my personal bugbears are pulmonary embolism and giant cell arteritis.
Coeliac disease and hypothyroidism used to be missed frequently but sensitive, specific and relatively-cheap investigations for these two conditions are nowadays widely available and are usually included in the investigation protocols of a wide range of symptoms.
Diagnostic mimics:
These are conditions that closely resemble one another or may share presenting features with many other conditions. Always consider these mimicking conditions if the diagnostic process appears to be running dry with no answer in sight.
Mimics occur in all specialities but are particularly important in neurology, rheumatology and infectious disease.
In neurology:
Stroke mimics are a subject in themselves. At least 20% of strokes are due to non-stroke conditions.
Since the advent of thrombolysis for effective treatment of acute ischaemic stroke the exact diagnosis of stroke-like symptoms has become vitally important because thrombolysis carries significant risks. If thrombolysis is administered for a condition in which it has no chance of success the only possible response is a side-effect.
Many neurological and other conditions may present as psychiatric disorders. This is a particularly fraught area for physicians; attribution of a patient’s confusion, cognitive loss or hallucinations to a psychiatric disorder when they in fact they are suffering from a treatable condition such as herpes simplex encephalitis, hypothyroidism or subdural haematoma can be disastrous.
Additionally as disease-modifying treatments for relapsing multiple sclerosis (MS) come increasingly into use, the importance of diagnosing relapsing MS at a stage of the disease when it is most-amenable to these treatments may grow.
In rheumatology:
SLE can cause disease in literally every body system and could be considered as the prime diagnostic mimic.
With its variety of presentations SLE is perceived by many physicians as a mysterious, elusive condition. Unfortunately once an unusual clinical presentation has been labelled as “possible lupus ” thinking about other diagnostic possibilities often tends to cease, even if the patient has a negative or only weakly positive antinuclear antibody (ANA).
It is helpful, when weighing up the possibility of SLE, to remember that the 2019 Eular / ACR classification criteria for systemic lupus erythematosus, although not strictly diagnostic criteria, provide considerable diagnostic support, with very high degrees of sensitivity and specificity for SLE.
Key features of the 2019 criteria are that they perform well in East Asian and paediatric populations as well as in adult populations in Western countries, and that a positive ANA is an entry criterion to a diagnosis of SLE; fewer than 5% of cases of SLE worldwide have a negative ANA.
The patient with a negative or weakly positive ANA thus has a very low likelihood of having SLE.
In other areas of internal medicine:
There is a large group of clinical presentations that often resemble one another but that can be easily differentiated and often confidently diagnosed by appropriate targeted investigation, which usually includes biopsy, tissue culture or serology.
These conditions are not strictly mimics. Rather, they are a group of conditions that one does not readily think of, but which you should always consider in the differential diagnosis when dealing with unusual clinical presentations or with a very wide range of possible diagnoses.
The fact that treatments are available for most of these conditions, or that their causative factors can easily be removed, adds to their importance.
The table below shows how a number of diagnostic mimics (other than the neurological mimics, SLE and the other mimics that I have described above) may present. You will note that in several of the presentations the context in which the symptoms occurs is important.
100 years ago tuberculosis , brucellosis and syphilis were at the top of the list of conditions that could resemble a wide range of other conditions; lymphoma, HIV infection and Lyme Disease displaced these at the head of the list in the developed world in the 1980s and other conditions were added later.
All these causes remain high on the list of diagnostic mimics although their relative position on the list shifts around over time. Sarcoidosis (for which no infective agent has yet been isolated) is a classic diagnostic mimic as is the currently-mysterious multisystem fibrosing condition IgG4-Related Disease.
When nothing adds up diagnostically one should consider the diagnostic mimics above.
Infective causes of medical conditions previously thought to be non-infective:
Knowledge of what causes disease and of the links between different diseases continues to advance; some conditions previously not attributed to infection are now known to have infective origins.
The close association of the stomach bacterium Helicobacter Pylori with peptic ulceration is now widely recognised. Before H Pylori was recognised as a cause of disease, peptic ulceration was regarded as a problem purely of overproduction of gastric acid or of a fault in the mucous membrane lining the stomach and duodenum.
Similarly, until the early 1990s little was known about why people developed Guillain-Barre Syndrome. It is now recognised that gastroenteritis due to the gram negative bacterium campylobacter jejuni is (certainly in the UK) one of the most common precipitating factors for the condition.
Likewise viral Hepatitis E, spread by the faecal-oral route, can occasionally cause conditions outside the liver including pancreatitis, encephalitis or haemolytic anaemia.
The rare Whipple’s Disease (characterised by various combinations of weight loss, chronic cough, abdominal pain, malabsorbtion and arthritis) has been found to be due to the bacterium Tropheryma Whipplei. There may be a genetic predisposition to the condition linked with HLA-B27 and other genetic factors.
The above are all conditions where for decades, despite improvements in diagnostic tools, an infective aetiology was never considered likely. In the same way other apparently non-infective conditions may with time be found to be due to infections.
In my next post I plan to discuss medically-unexplained symptoms.