Neuropsychiatric sequalae in cancers may be due to direct effects of the cancer on the nervous system, indirect effects related to systemic complications, paraneoplastic effects and exogenous agents such as chemotherapy and radiation therapy. It is often difficult to distinguish between the various factors that may have neurologic effects, and these factors often act in concert.
A 20-year-old single, male university student (A) first presented to another hospital with intermittent fever and bilateral leg rashes in June 2008. He was diagnosed with a cutaneous T-cell lymphoma and started on chemotherapy that comprised doxorubicin, cyclophosphamide, dexamethasone and vincristine. History from his family suggests that A became confused and withdrawn after starting chemotherapy. This confusion persisted unabated for a few months even after chemotherapy had ended. When he spiked a fever in October 2008, his family brought him to our hospital and he was then referred for psychiatric assessment.
From his family we learned that before this illness A was a friendly and hardworking university student. There was no past or family history of psychiatric disorders or substance abuse. During the psychiatric assessments, he was awake but inattentive, oriented to person and place but not to time. He appeared to be responding to internal stimuli and at times he would talk to himself or communicate to people who were not present. He had bouts of agitation and verbal aggressiveness and manifested odd arm gestures. His mental status fluctuated during the course of the day, often worse in the evenings. On physical examination, he was febrile with stable vital signs. There were scattered hyperpigmented macules, scaly plaques and weepy ovoid lesions on both of his lower limbs. There were no focal neurological deficits. During the hospitalisation, he was treated empirically with various combinations of antibiotics – piperacillin/tazobactam, cefepime, meropenam, vancomycin and acyclovir. Repeated blood cultures turned out to be negative. He was also given haloperidol 0.5–1 mg three times a day but anticancer chemotherapy was withheld. He became afebrile and his mental status improved somewhat. He was more attentive, calmer and coherent, and the family reported that he was closer to his normal self. However, 5 days later, while still afrebrile and on antibiotics, he relapsed into his previous delirious state.
Extensive investigations yielded the following, in abstracted form: Hemoglobin 9.6, leucocytes 2.78, neutrophils 82.1%, platelets 500 000; absolute CD4 count 152, CD4/CD8 ratio 1.0; normal electrolytes; toxicology screen and autoimmune workup were negative. Onconeural antibodies Hu-Ab, Yo-Ab and anphiphysin-Ab were negative. Chest X-ray examination on three occasions were normal. Magnetic resonance imagine of the brain, computed tomography scan of the abdomen and pelvis were normal.
Cerebrospinal fluid (CSF) studies showed a normal opening pressure, CSF protein of 0.4g/l, glucose of 3.0 mg/dl (blood glucose of 7.6 mg/dl), and 5 leucocytes; Gram stain, VDRL, cytomegalovirus (CMV), herpes simplex virus (HSV), toxoplasma, AFB, fungus were all negative.
Bone marrow studies showed erythroid hyperplasia with a few atypical lymphoid cells, a small population of natural killer (NK)/T cells expressing CD56+, CD7+, CD2+, CD8+. Hence a diagnosis of NK/T-cell lymphoma was made.
During this hospitalisation, he developed several new macular erythematous lesions on the face, back, abdomen and limbs, painful oral ulcers and erosive lesions around the glans penis. Although he remained afebrile, his mental status did not improve. The consultant hematologists recommended that he commence on the ESHAP protocol comprising etoposide, methyprednisolone, cytarabine, cisplatin and mannitol, and we recommended that he remained on haloperidol. The family was advised of the guarded prognosis and they chose to return to their original hospital that was much closer to their home.
Comment
A had sudden onset delirium ostensibly after being started on chemotherapy for lymphoma, and the delirium persisted long after the three courses of chemotherapy were completed. The chemotherapeutic drugs first given to A – doxorubicin, cyclophosphamide, dexamethasone, vincristine – were not usually associated with delirium. Reference Franco-Bronson, Williams and Skeel(1) However, there had been rare reports of delirium associated with vincristine. Reference Legha(2) Corticosteroids have been implicated far more in mood changes than in delirium, but severe neuropsychiatric symptoms occur in less than 5% of patients on corticosteroids. Reference Lewis and Smith(3,Reference Warrington and Bostwick4).
The non-specific changes in the CSF investigations including depressed CSF glucose, normal-high protein and leucocyte counts suggest a possibility of an underlying central nervous system (CNS) inflammation or infection. There was no overt CNS involvement based on neuroimaging but occult infiltration cannot be ruled out. However, occult infiltration does not usually lead to such severe mental status changes. In any case, NKT lymphomas do not commonly involve the CNS and one author estimates CNS involvement to be 3% Reference Luther, Greenfield, Chadburn and Schwartz(5).
Paraneoplastic neurological syndromes, e.g. limbic encephalitis or encephalomyelitis were also considered. Limbic encephalitis is characterised by subacute onset of confusion, retrograde and anterograde amnesia, possibly seizures, depression and hallucinations. They are generally rare and are most commonly associated with small-cell lung cancer, testicular cancer and breast cancer. Onconeural antibodies associated with this condition include Hu-Ab, CV2-Ab, amphiphysin-Ab, and Ma2-Ab Reference Honnorat and Antoine[6]. This syndrome may result from the production and release of antibodies, enzymes, fetal proteins and cytokines. There is one report of subacute demyelinating neuropathy associated with NKT lymphoma Reference Wills, O’Connor and McMillan(7), but delirium or other neuropsychiatric syndromes have not, to our knowledge, been reported.
Pathophysiological mechanisms to account for delirium in these patients are not well described. Alhes argued that shared genetic risk factors for the development of cancer and vulnerability to cognitive impairment. These include low-efficiency efflux pumps, deficits in DNA repair mechanisms and/or a dysregulated immune response. These defects may also render the CNS more susceptible to the deleterious effects of chemotherapy Reference Ahles and Saykin(8).
While such neuro-oncologic issues are being investigated, it is important to keep in mind the psychological state of the patient.
A’s delirium and possible psychotic symptoms are likely to have been the consequence of multiple factors. This case presents an intriguing perspective that NK/T-cell lymphoma may have varied, and yet undefined, effects on the nervous system that merit further investigation.
