Toxoplasmic encephalitis during mycophenolate mofetil immunotherapy of neuromuscular disease

DISCUSSION

MMF is a prodrug of mycophenolic acid (MPA) that exerts its immunosuppressive effect by inhibiting purine biosynthesis.¹ Specifically, MPA suppresses DNA synthesis via a selective, noncompetitive, reversible inhibition of primarily the type II isoform of inosine monophosphate dehydrogenase, an enzyme central to the de novo production of guanosine. This cytostatic effect is relatively specific to lymphocytes, which are more dependent on this pathway than other cell types.

MMF is used in the treatment of several neuroimmunologic diseases, including myasthenia gravis, multiple sclerosis (MS), neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and inflammatory myopathy. In most studies, MMF has had an advantageous tolerability and safety profile.² We did not find any prior cases of TE occurring during the treatment of autoimmune neurologic illnesses or rheumatologic illnesses with MMF. In transplant patients, TE has been described in association with different combinations of immunosuppressives used for rejection prophylaxis. For example, TE has been reported in regimens containing cyclosporine, azathioprine, tacrolimus, and methylprednisolone.^3,–,5 Toxoplasmosis infections have recently been reported in association with newer biologic immunotherapies in the treatment of autoimmune disease. Infliximab- and adalimumab-associated TE have been reported in the treatment of rheumatoid arthritis.^6,7 Rituximab-associated TE has been described in the treatment of cryoglobulinemic vasculitis.⁸ Natalizumab-associated toxoplasmic chorioretinitis has been described in the treatment of relapsing-remitting MS.⁹

In the general US population, the overall seroprevalence of Toxoplasma is 22.5%.¹⁰ In regions where Toxoplasma is particularly endemic, such as within Brazil, seroprevalence is as high as 50%–70%.¹¹ Immunocompetent patients in the general population with latent toxoplasmosis generally have an asymptomatic natural history. Severe toxoplasmosis infection occurs when chronic T gondii infection is reactivated in the immunocompromised individual.¹² The predominant manifestation of toxoplasmosis infection in immunosuppressed individuals is TE. Focal findings may include focal seizures, ataxia, hemisensory loss, hemiparesis, and hemiplegia.¹³ Definitive diagnosis of TE requires a consistent clinical presentation, identification of >1 consistent lesion on MRI or other brain imaging, and detection of the organism by brain biopsy. PCR has been recommended for diagnosis in immunosuppressed individuals, and it has a high specificity of 96%–100%. At present, most clinicians begin treatment for TE following presumptive clinical diagnosis and rely on empiric diagnosis supported by clinical and radiographic improvement in response to antitoxoplasmosis treatment. Brain biopsy is recommended when patients do not respond to toxoplasmosis therapy.¹³ The treatment of choice is a combination of pyrimethamine, sulfadiazine, and leucovorin. Despite treatment, mortality in patients receiving immunosuppression remains high, with reported mortality rates ranging from 40% to 60%, which is higher than the mortality rate for the AIDS population (13%–31%).^14,15

The seroprevalence for Toxoplasma in the US region where our cases occurred is relatively low, around 20%.¹⁰ In our 2 cases, both patients were treated with MMF for more than 2 years prior to onset of neurologic symptoms and diagnosis of TE. Each individual received another immunosuppressive agent in addition to MMF, which may have contributed to the risk of toxoplasmosis infection. In the first case, the patient received low-dose corticosteroids (20 mg every other day), but there is little evidence to suggest that treatment with low-dose corticosteroids is associated with a significant risk of infection.¹⁶ He did have low CD4⁺ and CD8⁺ T-cell counts consistent with immunosuppression secondary to MMF. In the second case, the patient received rituximab 8 months prior to the development of neurologic symptoms. We could only find one case report of TE occurring in an individual who had received long-term rituximab.⁸ Notably, both of our patients were on MMF 3 g/day. Studies in the transplant and rheumatology patients have suggested an increased incidence of infectious events with higher MMF dosing.^17,18 The increased risk of infection should be considered in individuals on high-dose MMF (3 g/day). Despite appropriate treatment, both patients had no significant improvement, which reflects the high morbidity and mortality of TE. As earlier recognition and treatment has been reported to improve outcomes in TE, these case reports emphasize the need to consider TE in any patient receiving MMF who presents with new cognitive or neurologic defects.

The use of trimethoprim/sulfamethoxazole (TMP-SMX) prophylaxis to prevent life-threatening opportunistic infections in individuals receiving immunosuppression for treatment of autoimmune disease has previously been recommended for higher-risk individuals.^19,20 We recommend that MMF dose not exceed 2–2.5 g/day. If an MMF dose of 3 g/day is required, then prophylaxis with TMP-SMX can be considered. The utility of screening for and prophylaxis against toxoplasmosis in individuals with neuroimmunologic disorders and other autoimmune disorders who receive immunosuppressive therapy requires future study.