Progressive multifocal leukoencephalopathy in common variable immunodeficiency: mitigated course under mirtazapine and mefloquine

Abstract

Demonstration of survival and outcome of progressive multifocal leukoencephalopathy (PML) in a 56-year-old patient with common variable immunodeficiency, consisting of severe hypogammaglobulinemia and CD4+ T lymphocytopenia, during continuous treatment with mirtazapine (30 mg/day) and mefloquine (250 mg/week) over 23 months. Regular clinical examinations including Rankin scale and Barthel index, nine-hole peg and box and block tests, Berg balance, 10-m walking tests, and Montreal Cognitive Assessment (MoCA) were done. Laboratory diagnostics included complete blood count and JC virus (JCV) concentration in cerebrospinal fluid (CSF). The noncoding control region (NCCR) of JCV, important for neurotropism and neurovirulence, was sequenced. Repetitive MRI investigated the course of brain lesions. JCV was detected in increasing concentrations (peak 2568 copies/ml CSF), and its NCCR was genetically rearranged. Under treatment, the rearrangement changed toward the archetype sequence, and later JCV DNA became undetectable. Total brain lesion volume decreased (8.54 to 3.97 cm(3)) and atrophy increased. Barthel (60 to 100 to 80 points) and Rankin (4 to 2 to 3) scores, gait stability, and box and block (7, 35, 25 pieces) and nine-hole peg (300, 50, 300 s) test performances first improved but subsequently worsened. Cognition and walking speed remained stable. Despite initial rapid deterioration, the patient survived under continuous treatment with mirtazapine and mefloquine even though he belongs to a PML subgroup that is usually fatal within a few months. This course was paralleled by JCV clones with presumably lower replication capability before JCV became undetectable. Neurological deficits were due to PML lesions and progressive brain atrophy.

Neurologic Complications of Common Variable Immunodeficiency

“…In general, however, the benefit of higher or more frequent dosing of IgG for viral illnesses associated with CVID is not well investigated. Multiple other factors, such as environmental (43) Adenovirus meningoencephalitis (2) [25] Bacterial meningitis (22) [1,[26][27][28][29] BKV encephalitis and optic neuritis (1) [30] CMV encephalomyelitis (1) [31] Echovirus meningoencephalitis (1) [25] Histoplasmosis (1) [28] HSV encephalitis (3) [9] Mumps encephalitis (1) Poliovirus (1) [32] Progressive Multifocal Leukoencephalopathy (6) [3][4][5][6][7][8] Toxoplasma encephalitis (2) [33,34] Varicella angiitis (1) [35] Varicella zoster encephalitis (1) [1] West Nile meningitis (1) [36] Autoimmune/Inflammatory (13) optic neuritis (1) [37] myelitis (4) [10,11,38,39] limbic encephalitis (1) [12] Guillian Barre Syndrome (1) [40] granulomatous mass (4) [41][42][43][44]45] chronic inflammatory demyelinating polyneuropathy (1) [39] acute disseminated encephalomyelitis (2) [14,46] Unknown etiology (10) encephalopathy (4...…”

“…Notably, the variety of infections is broad, including bacterial, fungal, and viral, with six patients with reported progressive multifocal leukoencephalopathy (PML) [3][4][5][6][7][8]. Three patients with HSV encephalitis were diagnosed as adults [9].…”

The Use of Antimalarial Drugs against Viral Infection

“…In many cases, MQ was combined with mirtazapine, an antidepressant that, acting on the 5-HT2A serotonin receptor, is able to inhibit JCPyV entry into glial cells, preventing the diffusion of the infection in oligodendrocytes. The outcomes of this treatment are controversial, leading to the resolution of the infection, with a claimed effect of MQ and mirtazapine treatment [86,87,[89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105], and to the resolution of the infection probably due to other factors [96,[106][107][108][109] or to the death of the patient, which was not always directly related to the unsuccessful therapy [87,96,[110][111][112][113][114][115][116]. In one case, the suspension of the therapy was necessary due to the side effects [117].…”

JC Polyomavirus Attachment and Entry: Potential Sites for PML Therapeutics

“…VP1-based vaccine combination treatment to boost anti-VP1 immunity have led to clinical improvements in PML patients [29, 30], and VP1-specific mAbs represent a new potential treatment option [31]. Following attachment, JCPyV enters cells by 5-HT 2 Rs [20, 85], and although antagonists to 5-HT 2 Rs have shown some clinical promise [93, 94], there are other instances in which no clinical improvement has been observed [95, 96]. Novel small molecule inhibitor Retro-2 that blocks retrograde transport of the virus from the ER at lower concentrations shows promise in vitro [22, 32].…”

“…Interestingly, case reports have indicated varying degrees of efficacy following mirtazapine treatments in PML patients. Several studies show that treatment with mirtazapine dramatically improves prognosis for individuals diagnosed with PML, including decreased neurological deterioration and undetectable viral loads [93, 94]. However, other reports have described instances where treatment with mirtazapine had little beneficiary effect, as patients rapidly deteriorated regardless of 5-HT 2 R antagonist treatment [95, 96].…”