CASE REPORT
Unusual cause of paraparesis in a patient with Cushing’s syndrome
Kush Dev Jarial,1 Chirag K Ahuja,2 Soham Mukherjee,1 Anil Bhansali1,3
1Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India 2Department of Radiodiagnosis, Post Graduate Institute of Medical Education and Research, Chandigarh, India 3Post Graduate Institute of Medical Education and Research, Chandigarh, India
Correspondence to
Dr Anil Bhansali, anilbhansaliendocrine@gmail. com
Accepted 30 August 2016
CrossMark
To cite: Jarial KD, Ahuja CK, Mukherjee S, et al. BMJ Case Rep Published online: [please include Day Month Year] doi: 10.1136/bcr-2016- 217304
SUMMARY
Paraparesis is a rare manifestation in patients with Cushing’s syndrome and the causes include vertebral compression fracture, hypokalaemia, spinal epidural lipomatosis, paraneoplastic syndrome and metastasis to the vertebrae and spinal cord. We report an unusual cause of paraparesis due to radiation-induced myelomalacia in a patient with adrenocortical carcinoma-associated Cushing’s syndrome, who are predisposed to radiation- induced injury.
BACKGROUND
Paraparesis is a rare manifestation in patients with Cushing’s syndrome. Aetiology of paraparesis in patients with Cushing’s syndrome include vertebral compression fracture, hypokalaemia, spinal epi- dural lipomatosis and paraneoplastic syndrome due to adrenocorticotrophic hormone (ACTH) produ- cing malignant carcinoids. We report an unusual cause of paraparesis in a patient with Cushing’s syndrome due to adrenocortical carcinoma (ACC).
CASE PRESENTATION
A 31-year-old woman presented with weight gain, excessive facial hair growth and secondary amenor- rhoea for 6 years. On examination she had moon facies, acanthosis nigricans (grade III), multiple skin tags, hirsutism with Ferriman-Gallwey score of 26/36, pink violaceous striae >1 cm wide over abdomen, cuticular and pulp atrophy. She was known to have had primary hypothyroidism for the past 6 years, dia- betes mellitus for 4 years and hypertension for 2 years. Biochemical investigations showed Na+143 mmol/L, K+4.3 mmol/L, Mg+ 2.4 mmol/L, Cl- 103 mmol/L, urea 25 mg/dL, creatinine 0.82 mg/ dL, phosphate 3.6 mg/dL, calcium 9.5 mg/dL, total serum proteins 6.8 mg/dL, albumin 4.43 mg/dL, serum bilirubin 0.85 mg/dL, aspartate aminotrans- ferases 27 U/L, alanine aminotransferase 34 U/L and alkaline phosphatase 98 U/L. Haemogram showed haemoglobin 12.2 g/dL, total leucocyte count 9400/ mm3 and platelet count of 332×109/L. Hormonal evaluation revealed, 08:00 plasma cortisol 771 nmol/ L (Normal (N) 171-536), 08:00 plasma ACTH <1 pg/mL (N: 5-60), dehydroepiandrosterone sulfate 972 µg/dL (N: 98-340), testosterone 6.63 nmol/L (N: 0.2-2.9), tri-iodothyronine (T3) 1.8 ng/ml (N: 0.8-2.0), tetra-iodothyronine (T4) 10.2 µg/dl (N: 4.8-12.7), thyroid-stimulating hormone (TSH) 3.5 pIU/ml (N: 0.27-4.2), prolactin 7.7 ng/ml (N: 4.7-23), luteinizing hormone 1.04 mIU/mL (N: 2.4- 12.6), follicle-stimulating hormone 0.155 mIU/mL
(N: 1.5-12.4), overnight dexamethasone suppression test (ONDST) 331 nmol/L (<50), low-dose dexa- methasone suppression test (LDDST) 894 nmol/L (<50) and glycated hemoglobin 6.4%. Contrast-enhanced CT (CECT) abdomen showed 6.0×4.5 cm right adrenal heterogeneous mass with increased vascularity without any evidence of metastasis.
A provisional diagnosis of ACTH-independent Cushing’s syndrome due to ACC was considered and patient was subjected to right laparoscopic adrenalectomy. Resected mass weighed 66 g, size 6×5×4 cm and macroscopic capsular invasion sug- gestive of R2 resection. Histopathological examin- ation was suggestive of ACC with modified Weiss score of 6/7, Ki 67 index <5% and immunohisto- chemistry showing positivity for melan-A and calre- tinin. Patient received conformal radiotherapy to the tumour bed after 2 months of surgery at the dose of 45 Gy delivered in 25 fractions over 5 weeks, followed by boost of 9 Gy in 5 fractions, while adequately sparing the spine, and limiting the maximum point dose to 45 Gy without any signifi- cant adverse events.
Patient remained asymptomatic until 6 months postradiotherapy when she presented with grad- ually progressive ascending spastic paraparesis (power 3/5), associated with sensory symptoms and signs, urinary incontinence and constipation. Differential diagnoses of metastatic disease involv- ing vertebrae and spinal cord, radiation-induced myelitis, paraneoplastic syndrome and neuromyeli- tis optica were considered. Hormonal profile during this admission showed 08:00 plasma corti- sol 132 nmol/L, TSH 4.02 pIU/mL, T4 8.7 µg/dL, T3 1.11 ng/mL, testosterone 0.08 nmol/L and pro- lactin 10.3 ng/mL. Other routine workup was unre- markable. Cerebrospinal fluid (CSF) analysis revealed proteins 56 mg/dL, glucose 83 mg/dL, and absence of leucocytes or malignant cells. Visual evoked potential was normal. CECT abdomen and chest revealed hypodense soft tissue of size 2.2×1.3 cm in right suprarenal region.
Contrast-enhanced MRI (CEMRI) spine showed segmental cord signal changes with patchy incom- plete peripheral enhancement diffuse and mild expansion of spinal cord from T10 to conus medul- laris which was suggestive of postradiotherapy changes (figure 1A-D). A 18-fluorodeoxyglucose positron emission tomography (18FDG PET)-CT revealed non-FDG-avid ill-defined density in the right suprarenal region and no evidence of FDG-avid lesion elsewhere in the body (figure 2A, B).
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Unexpected outcome (positive or negative) including adverse drug reactions
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OUTCOME AND FOLLOW-UP
Patient was initiated on prednisolone 60 mg/day and is currently on tapering doses of the same. Urinary incontinence did improve however, no clinically appreciable improvement of power in lower limbs was observed after 2 weeks of therapy. Follow-up CEMRI is planned after 3 months of steroid therapy.
DISCUSSION
ACC is a rare malignancy with an incidence of 0.7-2 cases/ million population per year, more frequent in women with highest incidence in fourth and fifth decade of life.1 2 Most adult patients (40-60%) present with signs and symptoms of hormone excess and rapidly progressing Cushing’s syndrome
Unexpected outcome (positive or negative) including adverse drug reactions
with or without virilisation. Non-functioning ACC presents with abdominal discomfort or pain, back pain, fever, weight loss and loss of appetite.3 4 Open adrenalectomy is regarded as standard treatment for ACC with aim of R0 resection with locoregional lymph node dissection, however, even with R0 resection both local and distant recurrence is common with recurrence rates of up to 85%, clearly indicating need for adju- vant treatment options.5 6 According to European Society for Medical Oncology clinical practice guidelines on adrenal cancers adjuvant radiotherapy is indicated in incomplete/R1 resection or Rx resection.7
Adjuvant radiotherapy is usually given to tumour bed and locoregional lymph nodes within 3 months of surgery in fractio- nated doses of 1.5-2 Gy/day for 5 days/week over 4-6 weeks with total dose range from 40 to 60 Gy. Common adverse events after radiotherapy include gastrointestinal disturbances, dermatological manifestations, fatigue, anorexia, pneumonitis or pulmonary fibrosis and haematological side effects.8-11
Radiation-induced myelitis is one of the most dreaded com- plication of radiotherapy and it is a diagnosis of exclusion. Criteria’s for radiation-induced myeltis are (1) spinal cord must have been included in the radiation field, (2) main neurological lesion must be within the segment of cord exposed to radiation and (3) metastasis or other primary spinal cord neoplasm must be ruled out as the cause of the neurological disorder.12 Radiation-induced myelomalacia may have four different pre- sentations: first, an acute transient myelitis distinguished by the presence of Lhermitte’s sign; second, syndrome due to infarc- tion of spinal cord defined by acute onset paraplegia or tetra- plegia; third, selective paralysis of second motor neuron and fourth, the most frequent syndrome is chronic progressive radi- ation myelopathy.13 Radiation myelitis has become a rare com- plication in recent times, due to expertise in dose prescription and delivery with sophisticated techniques and is more common with single high dose or reirradiation. 14-16
Patients with hypercortisolemia are predisposed to radiation- induced nervous tissue damage.17 The higher incidence of radi- ation sequelae in patients with hypercortisolemia may be explained by increased capillary permeability and capillary thrombosis caused by hypercortisolemia.18
Index patient presented with chronic progressive myelopathy after 6 months of radiation therapy. She received total dose of 50 Gy in 30 fractions with 1.8 Gy in each fraction over 7 weeks which is well within the tolerated dose for spinal cord described in the literature, however myelopathy has been reported with
Learning points
Radiation myelopathy can occur despite fractionated bed radiotherapy for adrenocortical carcinoma.
It is a diagnosis of exclusion and metastatic disease must be ruled out.
Hypercortisolemia predisposes to radiation-induced nervous tissue injury.
Treatment is mainly steroid therapy for prolonged period with limited success and the role of other therapies such as bevacizumab is still limited.
lower doses also.19 This is the first case report showing that radiation-induced myelomalacia can occur following tumour bed radiotherapy for ACC even after sparing the spinal cord. We are certain about the diagnosis because of typical MRI find- ings which include lack of disproportionate perilesional oedema, complete rim enhancement and no significant mass effect (cord expansion) that favour radiation myelopathy rather than metastasis. Normal 18FDGPET-CT and CSF cytology denies the diagnosis of metastasis. The mainstay of treatment is steroid therapy for prolonged period; however, therapies such as hyperbaric oxygen and monoclonal antivascular endothelial growth factor-A (bevacizumab) have been tried with limited success. 20 21
Contributors KDJ wrote the manuscript. CKA helped in the radiological investigations and confirming the diagnosis. SM edited the manuscript and helped in management of the case. AB identified the case and supervised the treatment of the patient.
Competing interests None declared.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES
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13 Reagan TJ, Thomas JE, Colby MY. Chornic and progressive radiation myelopathy. Its clinical aspects and differential diagnosis. JAMA 1968;203:106-10.
14 Supe SS, Ganesh KM, Naveen T, et al. Spinal cord response to altered fractionation and re-irradiation: radiobiological considerations and role of bioeffect models. J Cancer Res Ther 2006;2:105-18.
15 Wong CS, Fehlings MG, Sahgal A. Pathobiology of radiation myelopathy and strategies to mitigate injury. Spinal Cord 2015;53:574-80.
16 Lewitzki V, Andratschke N, Kuhnt T, et al. Radiation myelitis after hypofractionated radiotherapy with concomitant gefitinib. Radiat Oncol 2015;10:29.
17 Aristizabal SA, Boone ML, Laguna JF. Endocrine factors influencing radiation injury to central nervous tissue. Int J Radiat Oncol Biol Phys 1979;5:349-53.
18 Berdjis CC, Brown RF. Histopathology of the effect of cortisone on the irradiated rat lung. Dis Chest 1957;32:481-92.
19 Lilia G. Radiation tolerance of the spinal cord: doctrine, dogmas, data. Arch Oncol 2000;8:131-4.
20 Calabrò F, Jinkins JR. MRI of radiation myelitis: a report of a case treated with hyperbaric oxygen. Eur Radio/ 2000;10:1079-84.
21 Dimitri P, Camille T, Francois D, et al. Bevacizumab in late-onset radiation-induced myelopathy. Neurology 2016;86:454-7.
Unexpected outcome (positive or negative) including adverse drug reactions
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