Rare diseases with mystifying presentations are sometimes seen in some of the patients’ cases. An ailment is classed as mysterious if the specialist is unable to identify it. For decades, mysterious diseases have confounded the medical community. It may be necessary to examine the possibility of a rare diagnosis if there is sufficient suspicion and evidence.

Some of the case studies of mystery illnesses are discussed below:

Vasogenic edema

After 5 hours of breath-hold diving, a 39-year-old male had a headache and transitory aphasia. He did 30 breath-hold dives, each lasting two minutes, throughout this time frame. There was a white matter lesion with no mass effect at the level of the left frontal lobe on MRI. The symptoms went away after hyperbaric oxygen therapy, and the lesion had almost completely retreated.

The answer to this conundrum is eminently biological. The patient collected nitrogen in his blood during the breath-hold workouts, which caused endothelial dysfunction and a disruption of the blood–brain barrier. As a result of the blood–brain barrier’s hyperpermeability, vasogenic edema developed.

Toxic leukoencephalopathy
A 48-year-old woman with alcoholism presented with a month-long change in mental status. She had one-week morphine, oxycodone, and heroin binge two months prior. She felt drowsy for about a day after the binge, and she struggled with arousal for two days. She subsequently went back to normal without any symptoms until 3 weeks later, when she fell and struck her head, resulting in a severe headache.
She began acting strangely the day after she struck her head. Sleeping with cremated ashes, cleaning her teeth with a comb, washing while dressed, and not recognizing family members were among her acts. She was finally taken to the hospital, where she was neurologically examined and found to be exclusively orientated to herself. She had apraxia, aphasia, and selective mutism, as well as patella hyperreflexia, a wide-based gait, and the palmomental reflex, all of which could be signs of cerebral pathology.
The blood, urine, and cerebrospinal fluid (CSF) tests all came back normal. An EEG, on the other hand, revealed occasional, widespread, reactive polymorphic delta slowing, which could indicate encephalopathy. White matter signal alterations and modest cortical edema were seen on a brain MRI without contrast, indicating diffuse encephalitis.
A diagnosis of toxic leukoencephalopathy (TLE) was made after tests, including a brain biopsy, and in light of her long opiate history. Benzodiazepines, oxycodone, methadone, and methotrexate are all drugs that might cause TLE. TLE’s mechanism is still unknown, and few cases have been reported, making it difficult to predict who may acquire the disease. TLE is treated with supportive measures that include avoiding future toxin exposure.

Acute flaccid myelitis

A 9-year-old girl with a headache, sore throat, left earache, neck pain, and a history of fever reaching 101.0 °F presented to the emergency department. During the previous two weeks, she had cough and congestion symptoms. She developed neck weakness and imbalance two days later, making it difficult for her to walk and forcing her to use a wheelchair.

She also had left facial paralysis and was admitted to the hospital as a result of her symptoms. Her neck, facial, and upper extremity weakness deteriorated for the first two days of her hospitalization and then improved over the rest of her stay.

Despite the fact that no infectious etiology was discovered by CSF and blood tests, she was given ceftriaxone to treat suspected meningitis. Pleocytosis, or an increase in cell count, was observed in her CSF. Although the spinal MRI indicated myelitis, the follow-up MRI was within normal ranges.

Acute flaccid myelitis (AFM) is a condition that affects the gray matter of the spinal cord, weakening muscles and reflexes. The Centers for Disease Control and Prevention is now investigating this unusual condition. Enteroviruses are now suspected as the culprit, with more than 90% of affected patients reporting minor respiratory infections or fever prior to the beginning of AFM symptoms.


A 35-year-old married woman with no family history or previous history of psychiatric illness or neurodevelopmental delay had been complaining to the psychiatry outpatient department for the past two months about devouring paper and cardboard whenever she was alone. Her symptomatology began eight months after she gave birth, with an insidious onset and gradual progression. She would continually smell the cardboard boxes as she unloaded toys for her child, and she developed a strong preference for them.

She felt like tasting the cardboard papers when she was alone at home and ate a few pieces. The first time she ate a few pieces, there were no bad results, which piqued her attention even more. She gradually began biting on the ends of pencils and ice cream sticks over the course of a week. She’d go through two to three A4 size sheets in one sitting on certain days. When alone, the worry of being caught in the act caused great anguish, but it aided worsened consumption. She had been in a bad mood for the past two months, according to a more extensive examination, since she felt confined to her home because she couldn’t go to work like she used to.

There were no mental or perceptual hiccups. Her cognitive abilities were assessed and confirmed to be normal. Her Hamilton Rating Scale for Depression score was 24, according to the results. Hemoglobin was 10.8 mg/dl on a complete blood count, and all other blood parameters were within normal limits. The urine routine examination, the X-ray abdomen, and the ultrasound abdomen were all normal.

According to ICD 10 diagnostic criteria, she was diagnosed with Pica as a result of acute depression without psychotic symptoms.

Morgellons Disease

This is an uncommon Morgellons disease case presentation of a 52-year-old female from Hertfordshire, United Kingdom. She was a professorial researcher and an academic. The patient was initially misdiagnosed as having dyshidrotic eczema. Her lesions deteriorated after that, causing her social life and academic performance to suffer. As a result, the patient sought the advice of a psychiatrist, who used a comprehensive approach. The absence of any organic pathology was confirmed by extensive laboratory and radiological studies, including an MRI, and the final diagnosis was determined to be an idiopathic case of Morgellons illness.

Lyme disease

A 50-year-old woman from Virginia presented to a local clinic with fever, headaches, generalized joint discomfort, increased thirst, and a huge, spreading circular rash on her back with a bulls-eye look.

The rest of her physical checkup went without a hitch. Her medical and surgical background are unimportant in this scenario. The patient remembered going on a walk in the woods three weeks before her exam, but she denied finding a tick on her body.

The patient’s white blood cell and platelet counts, as well as his hemoglobin and hematocrit levels, were all within acceptable limits. Except for increased glucose, borderline low alkaline phosphatase, and mildly depressed osmolality, her serum chemistry was unremarkable.

In the serologic test for LD (by ELISA antibody response to B. burgdorferi), it showed negative results in the first set and it was positive in the second set, which demonstrated the presence of immunoglobulin (Ig)-M without IgG antibodies to B. burgdorferi, which confirmed the diagnosis of Lyme disease.

Langerhans cell histiocytosis

A 32-year-old Middle Eastern man with a family history of thyroid disease, who smoked 20 cigarettes per day and drank occasionally presented to an emergency room with multiple painful anal lesions that began to appear a few weeks prior to presentation, with occasional bleeding and purulent discharge. After persistent complaints of polyuria and polydipsia, his previous medical history was significant for diabetic insipidus 10 years ago. He began complaining of a nonproductive cough and exertional dyspnea when he was 26 years old.

A chest X-ray and computed tomography (CT) scan performed at another facility revealed bilateral lung cystic lesions involving the upper lobes. He was misdiagnosed with pulmonary fibrosis and chronic obstructive lung disease, and two years later was put on high-dose orally administered prednisone therapy, followed by daily budesonide/formoterol therapy with no clinical improvement.

A high-resolution multi-detector CT scan of his chest four years later revealed extensive honeycombing cystic alterations in both lung fields, with mixed fibrosis in the spaces in between. Histiocytosis X was suspected based on the findings. The diagnosis of adult pulmonary LCH was confirmed by a transbronchial biopsy of the lung lesions.

Langerhans cell histiocytosis (LCH) is a poorly known disease with a wide range of clinical manifestations, from localized bone involvement to widespread disease with life-threatening consequences. Patients with LCH can benefit from a greater understanding of the disease, as well as early suspicion and diagnosis.

To know more about LCH, meet Dr. Michael M. Henry, an hemato-oncologist working at Phoenix Children’s Hospital, on February 3rd, 2022 || 09:30 PM IST for a free live webinar of 1 hour on “Langerhans Cell Histiocytosis”.

You will get insights on the initial recognition, diagnostic and treatment options, and cell-signaling processes involved in Langerhans cell histiocytosis.