Initial assessment

A 64-year-old female patient with type 2 diabetes mellitus, hypertension, and major depressive disorder, who attempted suicide in the past year, presented to the emergency department a month prior. She reported symptoms of sadness, irritability, aggressiveness, loss of appetite, fatigue, and progressive, symmetrical, distal-to- proximal weakness in her lower limbs, eventually affecting her upper limbs. This weakness resulted in a fall from a height, causing a traumatic brain injury (TBI) secondary to the muscle weakness, although she did not experience a loss of consciousness.

Following the trauma, she developed disorientation and experienced significant limitations in performing daily activities, requiring assistance. On physical examination, the patient was disoriented to time, place, and person. Cranial nerve function was intact. She displayed symmetrical, progressive motor impairment starting distally and moving proximally, with a positive Babinski sign (extensor plantar response). Muscle strength was reduced, graded as 3/5 in the upper limbs and 2/5 in the lower limbs. Reflexes were generally hypoactive, and there were deficits in vibration and proprioception.

Diagnosis

On admission, a non-contrast cranial CT scan revealed a chronic right frontoparietal subdural hematoma without significant mass effect. Cerebrospinal fluid analysis demonstrated elevated protein levels (180 mg/dL), a cell count of 1 cell/mm³, and glucose of 83.10 mg/ dL. Refractory hypokalemia was identified and managed, but severe weakness persisted.

Electromyography and nerve conduction studies showed findings consistent with left peroneal nerve mononeuropathy, supporting the diagnosis of Guillain-Barré Syndrome. Additionally, Urinary free cortisol levels were markedly elevated at 2027.4 µg/24 hours (Reference Value: 4.3-176 µg/24 hours), with post-1 mg dexamethasone cortisol levels of 31.3 µg/dL and ACTH levels of 37.56 pg/mL, confirming ACTH-dependent Cushing’s syndrome Table (1 - Relevant laboratory test results). Hypokalemia was attributed to hypercortisolism. Hypophyseal MRI revealed an 8 mm microadenoma on the right side of the gland Figure (1 - T1-weighted magnetic resonance). In the context of an atypical and severe presentation, with biochemically confirmed hypercortisolism and a medium-sized pituitary lesion, petrosal sinus catheterization was considered, which further confirmed central hypercortisolism, solidifying the diagnosis of Cushing’s disease Table (2 - Petrosal sinus catheterization results).

Treatment

The patient underwent a five-day course of intravenous immunoglobulin therapy, resulting in significant improvement in her previously described weakness. Refractory hypokalemia persisted and was managed with both intravenous and oral potassium supplementation, maintaining potassium levels at the lower end of the normal range. Following the confirmation of Cushing’s disease, transsphenoidal surgery was performed approximately 60 days after admission without immediate complications. Histopathological analysis revealed an adenoma characterized by small foci of grouped cells, loss of the reticular pattern, PAS-positive material adjacent to the nucleus, nuclear atypia, and a perinuclear ring of pale hyaline material. Immunohistochemical staining demonstrated ACTH immunoreactivity, confirming the diagnosis of an ACTH-producing Crooke’s cell adenoma. Shortly after surgery, hyperkalemia resolved completely.

Figure 1. : MRI of the sella turcica, T1 sequence Note. Figure 1a. T1-weighted magnetic resonance sagittal section of the sella turcica after the application of contrast medium in dynamic sequences. An 8-mm nodular lesion is observed in the right lateral portion of the sella turcica that has less enhancement than the pituitary parenchyma. Figure 1-b. T1-weighted magnetic resonance coronal section of the sella turcica. An isointense nodular lesion is observed in the pituitary parenchyma in the sequence without contrast. In addition, there was a deviation of the pituitary infundibulum (red arrow) to the left (contralateral to the lesion).

Source: The authors

Follow-up and outcomes

One month later, the patient underwent transsphenoidal surgery for resection of a microadenoma, which was completed without intraoperative complications. She had a positive postoperative recovery, with improvements in mobility, electrolyte balance, and mood disorder. At the time of discharge, neurological examination showed an improvement of strength, sensitivity, and proprioception.

Discussion and conclusions

Dr. Harvey Cushing first identified Cushing’s syndrome in 1932 based on clinical observations of a distinct phenotype in patients, which was subsequently linked to adenomatous growths in the pituitary gland (6). CS is an entity with a low prevalence and an incidence of 2-3 patients/ million population. CS is more common in women (3:1) during the third and fourth decade of their life (7). The high prevalence of diseases that have overlapping clinical characteristics with CS, such as obesity, metabolic syndrome, diabetes, and polycystic ovary syndrome, may compromise its early diagnosis (8). It is estimated that the prevalence of undiagnosed CS is 76 people/million population, or 24,000 people worldwide (9).

Neurological and psychiatric signs and symptoms were noted in the earliest publications on Cushing’s syndrome, reflecting their presence within the spectrum of clinical manifestations (4). It has been demonstrated that several higher mental functions are impaired at the time of diagnosis (10). Affective disorders constitute the most frequent psychiatric complications of CS (4); depression can reach a prevalence of 57% - 68% of patients. In 12% of cases, depression is the first manifestation of CS (5). Our patient had a long-standing depressive disorder and a history of a suicide attempt in the year prior to the consultation. We do not rule out the possibility that her depressive symptoms were an early manifestation of Cushing’s disease.

Guillain-Barre syndrome is a polyradiculopathy that affects the function of the sensory and motor systems, and the symptoms can vary from weakness of the limbs and cranial nerves to respiratory compromise and death. The study of the CSF shows cytological albumin dissociation (11-12). In our patient, a progressive ascending weakness was observed, with clinical examination revealing decreased strength in the lower limbs, greater than in the upper limbs, but symmetrical. Additionally, generalized hyporeflexia was documented, which could have contributed to the patient’s fall. Since the weakness persisted even with serum potassium levels within the lower limits of normal ranges, we excluded this electrolyte disturbance as the underlying cause. Also, according to Asbury’s criteria our patient presented progressive bilateral weakness of arms and legs, decreased tendon reflexes in affected limbs, progressive phase lasts of more than 4 weeks, increased protein level in cerebrospinal fluid with only one mononuclear cell, and electrodiagnostic features of motor neuropathy (13). Infectious and immunological triggers, malignancies, and pregnancy have been described as disease initiators (14). There are a few cases reports documenting concomitance between CS and GBS, two from the Lahey Clinic and another from the Mayo Clinic in 1959 (15). In these case reports, a respiratory infection was documented as a precipitating factor, and CS preceded neurological compromise; in our case, it was not possible to document infection as the cause of GBS. Subsequently, a report was published in Iran in 2020 that described the case of a pregnant patient (16) with a subacute viral infection that was documented as the initiator, although pregnancy could also have play an important role.

In the patients described with concomitant GBS and CS, adrenal hyperplasia was identified. In our case, ACTH-dependent CS was confirmed, with imaging studies revealing a sellar adenoma consistent with CD. Due to the atypical and severe clinical presentation, inferior petrosal sinus sampling was performed, which further corroborated the diagnosis. This is the only reported case of this type to date. A histopathological study revealed a Crooke cell- type ACTH-producing pituitary tumor. This type of tumor is very rare, accounting for less than 1% of pituitary adenomas (17-18). Currently, no classification system exists to predict its behavior. However, there are characteristics such as young age, severity of the disease, presence of depression, a high urinary cortisol level, and posttreatment ACTH that could increase the risk of recurrence (19). In some cases, this type of tumor may be clinically silent; however, in others, like in this patient, they can function as ACTH- producing tumors. These tumors are typically aggressive, with a high recurrence rate and a low likelihood of cure despite surgical interventions and/or radiotherapy (20). Currently, our patient remains under follow-up without evidence of relapse.

Comment

Cushing syndrome is a diagnostic challenge to clinicians given the wide range of clinical manifestations such as obesity and diabetes, and neuropsychiatric symptoms. Guillain-Barre syndrome is a polyradiculopathy that affects the function of the sensory and motor systems most of the cases are sporadic but there are a few cases reports documenting concomitance between CS and GBS.