Results of lumbar puncture,CT and MRI in a case of quinacrine-induced psychosis involving a patient with cutaneous lupus erythematosus

Case report

A 22-year-old woman developed a facial eruption consisting of pruritic, erythematous, annular, superficially eroded papules which coalesced into plaques over the cheeks bilaterally, the right earlobe, and with a few lesions on the extremities in July 2009. She had no other symptoms. A review for other features of connective tissue disease and past medical history was negative. She took no medications. She lived with her parents, studied sciences at university and did not smoke, drink alcohol or use illicit drugs. There was no family history of connective tissue disease. A maternal aunt had psychosis which was controlled on medications.

Examination showed the cutaneous changes described above. The remaining examination was normal. Affect, comprehension and quality of speech appeared normal.

Laboratory investigations revealed: WBC 4 × 10³/mm³, normal differential, hemoglobin 107 g/l, MCV 63, beta thalassemia trait identified on electrophoresis, platelets 309 × 10³/mm³ and creatinine was 46 mmol/l. Urinalysis intermittently showed low-level hematuria but was otherwise negative. ANA was 1:1280 (speckled), 1:320 (homogeneous), DNA 541(n < 100), strong positive anti-Sm and anti-nucleosome antibodies and moderate positive anti-ribosomal P antibodies. Remaining ENA was negative. Complement C3 0.45 (n, 0.85–1.86), C4 0.10 (0.15–0.47). TSH, INR and PTT were normal. Anticardiolipin IgG 22 (n < 12), beta-2 glycoprotein 22 (n < 20). AST was 38 (n < 36) ALT 54 (n < 36), total bilirubin, alkaline phosphatase and GGT were normal. Viral hepatitis serologies were negative. Antimitochondrial antibody and anti-smooth muscle antibodies were negative.

A skin biopsy was consistent with connective tissue disease and revealed: interface dermatitis, focal hyperkeratosis, damage to basal keratinocytes, perivascular and periadnexal lymphocytic infiltrate, periodic acid–Schiff (PAS) staining showed focal thickening of the basement membrane, alcian blue staining was negative for mucin. Immunofluorescence was not performed.

A diagnosis of subacute cutaneous lupus erythematosus (SCLE) was made. Treatment included: topical corticosteroid, sun block and hydroxychloroquine 300 mg daily; her rash improved.

In March 2010, she developed direct antiglobulin test (Coombs test) positive hemolytic anemia. Hydroxychloroquine was discontinued. Over 4 months the hemoglobin returned to baseline and other markers of hemolysis resolved. Her rash subsequently worsened and in June 2010 quinacrine 100 mg daily was prescribed. Over 1 month her rash improved.

The patient wrote final exams in December 2010; she did not do as well as expected but earned her BSc. In February 2011, the patient’s family reported a change in her mental status. She expressed that she was feeling scared and that something was ‘wrong with her’. She complained of headache and of being ‘cross-eyed’, she slept little and worried that someone was possibly poisoning her drinking water.

On examination she had an intense stare, speech was pressured and rapid. She repeatedly stated “I am scared”, she exhibited echolalia and appeared to be responding to auditory hallucinations, frequently yelling out answers that were not asked of her. Comprehension was impaired. There were hyperpigmented areas on the face and extremities consistent with faded rash. The remaining general, neurologic and rheumatologic examination was normal. She was admitted to hospital 3 March 2011.

Investigations revealed a WBC of 3.0 × 10³/mm³, hemoglobin 89 g/l, normal electrolytes, negative urinalysis, ESR 32, CRP normal, LDH 376, haptoglobin and reticulocyte counts normal, Beta-hCG negative, anti-DNA 1485, blood and urine cultures were negative. A CT scan of the head was normal. An MRI scan was normal with no T2 signal changes. Her lumbar puncture was normal and showed a WBC count of 1, glucose 2.7, protein 0.26. CSF cultures were negative. EEG was normal.

She was treated presumptively for CNS lupus with methylprednisolone 750 mg IV daily for 3 days followed by oral prednisone 50 mg daily. With the return of the normal CNS investigations CNS lupus was felt to be improbable. The differential diagnosis shifted towards a primary psychiatric disorder or quinacrine psychosis. She was transferred to a psychiatry ward and treated with olanzapine, and steroids were discontinued. Azathioprine 50 mg p.o. daily was initiated. By 18 March the residual rash had resolved.

Immediately following the cessation of quinacrine her psychotic symptoms started to slowly resolve such that she was able to be discharged after 1 month of hospitalization. She was discharged on azathioprine 50 mg daily olanzapine 5 mg a.m. and 17.5 mg h.s.

At 3 weeks post-discharge she remained slightly anxious; at 9 weeks post-discharge anxiety had resolved and she was otherwise well. Downward titration of olanzapine was commenced. At 9 months post-discharge there were no features of psychiatric illness and no clinically active lupus. Medications were olanzapine 7.5 mg daily and azathioprine 50 mg daily. WBC was 3.2 × 10³/mm³, hemoglobin 92 g/l, ESR 28, creatinine 52, trace hemoglobin on urinalysis, AST 35 and ALT 27.

As of December 2015 there has been no recurrence of psychiatric illness. She has been off psychiatric medications for more than 3.5 years.

The patient provided written consent to report this case. The hospital institution does not require ethics approval for cases reported which do not disclose patient identification.

Discussion

At the present time the working diagnosis is quinacrine induced psychosis. The differential diagnosis includes primary psychiatric illness or CNS lupus. Features favoring quinacrine psychosis include the abrupt onset, followed by the rapid resolution of symptoms following discontinuation of quinacrine. Additionally a lack of prior or subsequent psychiatric history argues against primary psychiatric illness. Features against CNS lupus include a paucity of other features of active lupus, as well as entirely normal CNS imaging studies and a lumbar puncture.

Quinacrine belongs to a family of compounds which were originally developed as pigments and dyes; they were first introduced as an antimalarial therapy in the 1930. During the Second World War, American production of quinacrine rose from 1200 pounds per year (pre-war) to 2000 pounds per day, as a prophylaxis and to treat American servicemen operating in the South Pacific [Wallace, 1989]. Quinacrine has continued to be used (although in much lower quantities) for the treatment of malaria, giardiasis and tape worm infections. Its therapeutic effectiveness has also been demonstrated in controlled studies for combating refractory lupus erythematosus, rheumatoid arthritis and as an adjuvant cancer therapy. It has been also used as an intrapleural sclerosing agent for pleurodesis [Ehsanian et al. 2011]. It was first used in discoid lupus by Prokoptchouk in 1936 [Prokoptchouk, 1940].

While psychiatric side effects of quinacrine are rare; because of its extensive use during the Second World War a number of interesting reports and articles were produced. Newell reported that over an 8-month period, 28 cases of psychosis observed in approximately 14,000 soldiers undergoing treatment for malaria infection with this agent [Newell, 1946]. In 1945, Gaskill and Fitz-Hugh described two types of psychiatric responses following quinacrine use in adults. The first type involving two-thirds of affected patients, and is characterized by a sudden increase in motor and psychomotor activity, frequently accompanied by visual and auditory hallucination, delusions, ideas of reference, and an affect of euphoria with expansiveness. The second, less common symptom complex begins insidiously with gradual clouding of the sensorium, disorientation, amnesia, withdrawal, bewilderment and fearfulness [Gaskill and Fitz-Hugh, 1945].

The mechanism by which quinacrine can induce psychosis is not fully understood. Engel and colleagues demonstrated increased CNS symptomatology with increased dose and plasma concentrations [Engel et al. 1946].

Since the Second World War, very few instances of psychiatric/CNS complications of quinacrine have been reported. Only one involved a patient with connective tissue disease (discoid lupus) [Engel et al. 1946]. None have included a full description of a modern workup for acute onset of psychiatric/CNS illness with: CT scan, MRI, lumbar puncture and EEG.

We have reported here the case of a 22-year-old woman with SCLE who presented with an acute and serious psychiatric/CNS disease, ultimately attributed to quinacrine, who had an extensive and modern medical workup.

It is important for clinicians to be aware of rare but potentially serious complications of medications that they prescribe. A knowledge of investigative results found by others in this setting may be of potential benefit.