A rapidly progressive motor neuron disease associated to a natural killer cells leukaemia

une system play a complex role, either protective or toxic, in ALS pathogenesis [1–3]. In particular, compelling evidence indicate that increased blood level of natural killer (NK) and NK-T cells may contribute to the disease development and progression [2,3]. Here, we report on a patient with an aggressive Motor Neuron Disease (MND) associated with NK/NK-T cells leukaemia. 1. Case report A 79-year-old man presented with several months-history of a progressive atrophy and weakness of the upper limbs, which quickly spread to the lower limbs. Onset was subtle and apparently occurred in the month of July (the specific date is not shown for privacy), when the patient noticed a mild weakness in the proximal muscles of the right arm. From July through August, the patient's global functioning was however roughly normal. However, between September and early October the patient experienced a rapid worsening, with a severe weakness of the shoulder girdle, of the right arm and in both legs. He was referred to our ALS Center for evaluation. The neurological examination documented marked muscle atrophy of the shoulder girdle, the right arm and both lower limbs, with bilateral foot drop. Deep tendon reflexes were absent, with the exception of the left arm. Bulbar functions were normal. Needle EMG showed widespread polyphasic MUP and fibrillation potentials, with normal sensory and motor conduction velocities and no conduction blocks. Sensory and motor nerves amplitudes in the upper limbs were within the normal range. A brain and cervical MRI was within normal range. Extensive biochemical and immunological work-up, including CSF, blood cell count, a large antibody battery which included antibodies to anti-Hu, anti-Ri, anti-Yo, and anti-gangliosides were negative. Serum creatine phosphokinase level was mildly increased. A diagnosis of a very rapidly progressing lower motor neuron disease (MND) was made, with an ALSFRS-R score of 18/ 48 and a ΔFS [4] of 10 (Fig. 1A). Although the clinical features of the patient did not fit with a formal diagnosis of ALS, a genetic testing for the major ALS related genes (C9orf72, FUS, TARDBP, SOD1, and Angiogenin) was performed, which gave negative results. In the middle of November 2016, a follow-up blood test showed a marked increase of WBC (i.e., 76,050/μL), with a high prevalence of lymphocytes. He was then admitted to the Hematology Unit in our Hospital. Blood cytofluorimetric analysis and a bone marrow biopsy showed a marked infiltration by immature NK and NK-T cells (Fig. 1B). A new CSF analysis was performed, which showed increased proteins and 360/μL WBC, of which about 70% were NK/NK-T cells. A diagnosis of NK/NK-T cell leukaemia was made. A systemic chemotherapy according to Hyper-CVAD schema was started (i.e., High Dose Dexamethasone; Hyperfractionated Cyclophosphamide; Oncovine and Doxorubicine), along with repeated intrathecal injections with Methotrexate, Ara-C and Dexamethasone. In the following weeks, the patient showed a transient improvement in muscle strength and function; a ALSFRS-R evaluation, made in December 2016, gave a score of 27/48, with a ΔFS dropping to 4.2 (Fig. 1A). Unfortunately, the general health status deteriorated over time, and in late December, the patient was referred to a Hospice, where a few weeks later he peacefully passed away. 2. Discussion We have described an aggressive lower MND, which might be paraneoplastic, associated with an NK-T leukaemia. A paraneoplastic association between either lower MND and lymphoma or the upper predominant MND and breast cancer has been reported [5–7]. The presence of a high number of NK/NK-T cells in the CSF indicates a meningeal metastasis from the acute leukaemia. These cells are most probably involved in the lower motor neuron degeneration in our patient. The clinical diagnosis of MND in this case is supported by several lines of evidence: a) the onset of atrophy and weakness occurred in the shoulder girdle, involving first the right shoulder with a rapid progression to the left shoulder, and then with a proximal-to-distal spreading to the right arm and then to the lower limbs. This pattern of spreading is consistent with a primarily MND involvement, rather than a poly/multi-neuropathy; b) the EMG/ENG pattern was also consistent with a lower motor neuron disease, as neither abnormal sensory/motor amplitudes (recorded in the upper limbs) nor conduction velocities/ blocks (recorded in both the upper and lower limbs) could be detected. It cannot, however, be excluded a contemporary involvement of the motor neurons cell bodies and the proximal section of the axons (i.e. the motor roots).