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Transfer factor is an active substance of unknown structure present in dialysable leucocyte extract which is assumed to transfer cell mediated immunity in an antigen specific fashion.1The mechanisms of action of transfer factor are still far from clear; in vitro dialysable leucocyte extract increases macrophage activation and interleukin (IL) 1 production and enhances leucocyte chemotaxis and natural killer function. Transfer factor has been reported to stimulate the cell mediated antigen specific response in patients with various infections1; therefore, treatment with transfer factor has been suggested in patients with selective deficits in cell mediated immunity such as in some refractory neoplasms and chronic infections. Moreover, it has been used in the treatment of uveitis.2Administration of dialysable leucocyte extract has seemed to be free of hypersensitivity, long lasting side effects, or complications, except for transitory hyperpyrexia.1
We report on a patient in whom multiple cerebral white matter lesions developed after taking dialysable leucocyte extract orally for uveitis. A 28 year old man was admitted to hospital because of headache, mental confusion, and right hemiparesis. He had had recurrent bilateral uveitis from the age of 12 to 14 with residual cataract of the right eye. In January 1995 retinal vasculitis was diagnosed at fundoscopy and in July 1995 he started oral transfer factor as dialysable leucocyte extract twice a week. He complained of generalised weakness after the second dose and the referring symptoms developed after the third dose.
Neurological examination on admission showed mental confusion and severe right spastic hemiparesis with right Babinski's sign. No fever or meningismus were present.
Laboratory examinations on admission showed a slight increase in total serum protein (8.4 g/l, normal 6.0–8.0 g/l, although the serum protein fraction was normal), antistreptolysin titres (355 UI/ml, normal <200 UI/ml), and anticardiolipin IgG (30 UI/ml, normal< 12 UI/ml). Negative results were obtained for routine tests and serum immunoglobulins, venereal disease research laboratory test, erythrocyte sedimentation rate, fibrinogenaemia, C reactive protein, rheumatoid factor, Waaler-Rose, protein electrophoresis, antinuclear, anti-DNA, antimitochondrial, anti-ENA, anti-smooth muscle, and antineutrophil cytoplasmic antibodies, lupus anticoaugulants, cryoglobulins, immune complexes, complement fractions, and neoplastic markers.
Serological investigations showed IgG but not IgM against cytomegalovirus (CMV), Herpes simplex, Varicella zoster, Epstein-Barr viruses, and Toxoplasma gondii; the Paul Bunnel reaction, anti-HIV, and the markers of hepatitis virus B and C infection were negative.
Cell, protein, and glucose concentrations in CSF were normal. No oligoclonal bands or antibody against CMV, Herpes simplex, Varicella zoster, Epstein-Barr virus,Coxsackie, Adenovirus, Enterovirus or Borrelia burgdorferi were present. Polymerase chain reaction search forHerpes simplex 1 and 2, Varicella zoster, CMV, Epstein- Barr virus, and JC virus in the CSF was negative.
Brain MRI showed several extensive asymmetric lesions in the subcortical and periventricular cerebral white matter, some of which exerted a mass effect on the nearby CSF spaces. All lesions exhibited thick ring-like enhancement after intravenous contrast administration (figure). The brain stem, cerebellum, and cervical spinal cord were spared.
The patient had a progressive spontaneous remission of symptoms and signs. The neurological examination 20 days after onset showed slightly increased deep tendon reflexes on the right side and was normal 40 days later; all laboratory analyses were normal except for antistreptolysin titres (265 UI/ml). Two MR scans at 1 and 4 months after onset showed progressive reduction of the extension of cerebral white matter lesions, which did not show contrast enhancement. A final MR scan 20 months after onset showed further regression of lesions without contrast enhancement but a new large lesion in the left occipital white matter, which showed moderate contrast enhancement. At present, after 5 years, the patient is in a good state of health and neurological examination and laboratory tests are normal.
The close temporal relation between assumption of dialysable leucocyte extract therapy and appearance of cerebral white matter lesions in our patient supports the possibility that the association of the two events might not be casual. Despite the absence of biopsy, we reasonably excluded the diagnosis of vasculitis or neuro-Behçet's disease although in the absence of biopsy. In fact, the clinical, laboratory, and MRI findings were not typical and a low titre of anticardiolipin antibodies is found in 2% of healthy subjects.3
The occurrence at different time of focal cerebral white matter lesions highly supports the diagnosis of multiple sclerosis, but some clinical and laboratory findings in the our patient are not typical for this condition. Mental confusion is not common at the onset of multiple sclerosis whereas it is often found in acute disseminated encephalitis.4 In addition, CSF without oligoclonal banding argues against a diagnosis of multiple sclerosis, whereas it is commonly found in acute disseminated encephalitis.4 On the other hand the possibility that acute disseminated encephalitis may recur has been accepted5 and on the basis of the patient's clinical picture and CSF, we favoured such a diagnosis.
The pathogenic mechanisms underlying the triggering, development, and duration of multiple sclerosis and acute disseminated encephalitis are still far from clear despite the progress made in unravelling them. Some findings suggest that acute disseminated encephalitis and multiple sclerosis lie at the two poles of an autoimmune range, in which autoantigen reactivity is only temporary and direct against a single antigen in acute disseminated encephalitis and multiple antigens in multiple sclerosis.
Although the hypothesis that dialysable leucocyte extract had triggered an autoimmune disorder in our patient cannot be proved, our finding is in line with the report of multiple cerebral lesions after therapy with IL-2 in patients with malignancies or HIV infections.6
On the other hand, the fact that acute disseminated encephalitis is often correlated with the administration of foreign proteins, such as during vaccinations or viral infections4 led us to postulate in this patient a cell mediated immunological mechanism. Therefore, an immunological cross reaction between viral antigens (or other foreign material contained in vaccines) and various parts of the nervous system resulting in acute disseminated encephalitis might have occurred. As already noted, dialysable leucocyte extract contains a multitude of immunostimulating or potentially activating substances so it is impossible to pinpoint which one could have been responsible for the demyelinating effect seen in our patient. This notwithstanding, our finding indicates that neurological surveillance is worthy in patients assuming dialysable leucocyte extract therapy.
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