1. ¹Academic Department of Medicine, Hippokration General Hospital, Athens, Greece
2. ²Department of Neurology, Thriasion General Hospital, Elefsis, Greece

Correspondence: SP Dourakis, 28 Achaias Str., Alhens 11523, Greece. Fax: 10 6993 696

Received 1 October 2002; Accepted 18 November 2002.

TO THE EDITOR

Hairy cell leukemia (HCL) is a lymphoproliferative disorder associated with pancytopenia, splenomegaly and the presence of typical hairy B lymphocytes in the bone marrow and/or peripheral blood. A variety of autoimmune diseases have been reported to occur with HCL.

Lambert–Eaton myasthenic syndrome (LEMS) is a rare autoimmune neuromuscular disorder usually associated with small cell lung cancer. It is clinically presented with proximal muscle weakness and autonomic dysfunction. Myasthenic weakness is caused by reduction of acetylcholine release induced by an immune response directed against the calcium channel complex of the nerve terminal. The diagnosis of LEMS is made on the basis of the clinical findings and the characteristic electromyographic patterns.¹ We report on a case of LEMS complicating HCL without evidence of small cell lung cancer. To our knowledge, this is the first case of LEMS described in the context of HCL.

In November 1991, a 70-year-old nonsmoker man presented with pancytopenia and splenomegaly. Following male bone marrow aspiration and biopsy, a diagnosis of HCL was made on the basis of typical morphological, cytochemical and immunophenotypic findings. A thorough investigation for hairy cells in the peripheral blood was unsuccessful. Interferon-2b was administered (5 million units three times a week). In October 1997, bone marrow aspiration and biopsy showed no evidence of hairy cells and interferon was discontinued. Sustained disease remission was achieved for the four ensuing years, confirmed by careful clinical survey and sequential bone marrow biopsies.

In December 2001, he presented with a 6-month history of severe fatigue, proximal muscle weakness in the arms and legs that increased in the early morning and diminished during the day, dysphonia with nasal speech, difficulties in swallowing and dry mouth. Physical examination revealed diminished tendon reflexes. Cranial nerve functions were preserved. Neither focal neurologic deficits nor eyelid ptosis were noted on neurologic examination. The patient could rise from a chair by the third attempt using his hands. Sensory and motor conduction velocities were normal with a small compound muscle action potential. The compound muscle action potentials recorded from the abductor pollicis brevis and the abductor digiti minimi muscles showed a decrement with repetitive nerve stimulation at low frequencies. During stimulation at high frequencies, the muscle response amplitude increased and became more than twice the size of the initial response, consistent with a diagnosis of LEMS. Antinuclear, gastric parietal cell, mitochondrial, microsomal, smooth muscle, antineuronal, cardiolipin, thyroid and acetylcholine receptor binding autoantibodies were all negative. TSH, B₁₂, complement components and immunoelectrophoresis were normal. The direct antiglobulin test was negative. Calcium channel-binding antibodies were not tested. Extensive imaging studies have not demonstrated any type of carcinoma.

Morphological study of the bone marrow biopsy revealed small aggregates from lymphoid cells with reniform and ovale nuclei and typical cytoplasmic configurations of hairy cells (20–25% lymphoid infiltration of the bone marrow), erythroid hyperplasia and increase in reticulin fibers. The immunostaining of bone marrow biopsy on paraffin-embedded sections was positive for leucocyte common antigen, and evaluation of lymphoid subsets showed a lymphoid cell immunoreactivity for CD20/L26 as well as a double population of DBA44 positive and negative cells. Lymphocytes were negative for CD3 immunostaining. All the above findings were consistent with a relapse of HCL. No peripheral blood count abnormalities were noted. An exhaustive search for leukemic cells in the peripheral blood was unsuccessful.

The patient was treated with a single course of 2-chlorodeoxyadenosine at 0.1 mg/kg/day, for 7 days in a continuous intravenous infusion for HCL and with pyridostigmine (120 mg/day) for LEMS. He was discharged and was followed as an outpatient. At the 6-month post-treatment follow-up, he achieved remission of HCL and improvement of his proximal muscle weakness, but no change in voice disturbance and dysphagia. His condition remained stable thereafter.

In most LEMS cases associated with cancer, the cancer is discovered either at the time of diagnosis or within the first 2 years after diagnosis of LEMS.¹ In the current case, coexistence of a second malignancy (small cell lung cancer) was not evident within 1 year from the development of neurologic symptoms despite thorough investigation. Even if the development in the future of a second malignancy could not be excluded, this seems to be unlikely.

To date, two cases of neurologic disorders (myasthenia gravis and Guillain-Barre syndrome) ^2,3 have been described in the literature in patients with HCL. On the other hand, 10 cases of LEMS have been described in patients with lymphoproliferative disorders, ^4,5 suggesting an association between these entities. Symptoms of LEMS preceded those of the hematologic malignancy in four of the cases. In the remainder, LEMS developed in a period of time ranging from 6 months to 6 years following diagnosis and treatment of the underlying hematologic disorder. The almost simultaneous occurrence of autoimmune neurologic disorder and the reactivation of leukemia in the present case does not seem to be incidental. A correlation between leukemia activity and autoimmune manifestations was previously reported.⁶ Altered immunity induced by reactivation of HCL may have triggered the immune-mediated neurologic disease. It has been suggested that the polyclonal bystander B cells rather than the leukemic clone itself was implicated in the mechanism of autoimmune manifestations in lymphoproliferative diseases.⁷ The relation of autoimmune phenomena to interferon treatment seems unlikely in our patient since interferon was discontinued more than 4 years before the clinical onset of LEMS.

There is no evidence so far in the literature that remission of HCL may imply a favorable outcome of the concurrent autoimmune disease. The reporting of further cases is needed to demonstrate whether the outcome of the immune-mediated disorder is affected by the management of underlying lymphoproliferative disease.