A 51-year-old man with well-controlled HIV (CD4+ count 791 cells/muL and undetectable viral load) on tenofovir alafenamide, emtricitabine, and dolutegravir presented to the emergency room with several weeks of headache, right-sided hearing loss, and memory impairment. He smoked one pack of cigarette per day and marijuana but did not use other drugs. He had lived in the San Francisco Bay Area for over 20 years and was an avid gardener. He did not have a history of incarceration, homelessness, or international travel (Figure 1A).
In the emergency department, he had a witnessed seizure and an MRI of the brain showed swelling of the right cerebral cortex, with abnormal diffusion, T2/FLAIR hyperintensity, and patchy enhancement, and without abnormal susceptibility weighted imaging (Figure 1B). The imaging was consistent with meningoencephalitis, and serial lumbar punctures (LP) revealed a neutrophil-predominant pleocytosis (WBC: 260-756/muL with 12-70% neutrophils), mild hypoglycorrhachia (nadir 33 mg/dL), and elevated protein (76-95 mg/dL). Gram stain and bacterial culture in CSF were negative, as was cryptococcal antigen. He was started on empiric valacyclovir and broad-spectrum antibiotics.
After 3 weeks of inpatient antimicrobial treatment, the patient failed to improve. Comprehensive serological and cerebrospinal fluid (CSF) testing for infectious etiologies was non-diagnostic including serum toxoplasmosis IgG and CSF fungal cultures, microbial antigen and antibody testing, VDRL, universal bacterial, fungal, and mycobacterial PCR, and metagenomic next-generation sequencing (mNGS). Diagnostic biopsy of the leptomeninges overlying the right cerebrum revealed dense connective tissue with a mixed inflammatory infiltrate including granulocytes, and B and T cells (Figure 1C), suggestive of an infectious etiology. The underlying cortical brain tissue was also biopsied and showed no significant pathological abnormality. Histochemical stains for acid-fast bacillus (AFB), Grocott's methenamine silver stain (GMS), and period acid-Schiff (PAS) stains on the brain tissue were negative, arguing against mycobacterial or fungal infection and Whipple's disease. A Quantiferon Gold TB test was negative. However, given the insensitivity of CNS TB diagnostics, the lack of clinical improvement, and a persistent neutrophil-predominant CSF pleocytosis with mild hypoglycorrhachia, he was started on empiric therapy for TB meningoencephalitis with isoniazid, rifampin, ethambutol, and pyrazinamide and transferred to an outpatient rehabilitation facility.
One week after discharge (week 7), the patient presented to the emergency department with new-onset expressive aphasia, hyponatremia, and ataxia. EEG revealed right greater than left diffuse background slowing and disorganization without epileptiform activity. Repeat LP again showed a neutrophilic pleocytosis (WBC 194/muL with 50% neutrophils), protein 75 mg/dL, elevated IgG index (0.7, ref. <=0.6), and five restricted oligoclonal bands (OCBs). Brain MRI showed persistent meningoencephalitis with new ventriculomegaly. A large volume LP was performed. The opening pressure was 25 cm and the patient regained his speech after 1 h later, had improved gait, and improved mental status. He proceeded to get a ventriculoperitoneal shunt and continued on anti-TB therapy.
A CSF autoimmune encephalopathy panel was reported as positive for NMDA receptor autoantibodies (1:8 tissue titer) as well as putatively non-specific additional staining on tissue. The whole body PET and scrotal ultrasound were negative. A repeat autoimmune encephalopathy panel was NMDA receptor antibody positive on cell-based assay but negative on reflex tissue staining. Because the clinical phenotype was markedly inconsistent with anti-NMDAR encephalitis, empiric anti-TB therapy was initially continued. Nonetheless, an autoimmune etiology was increasingly considered as a result of the repeatedly negative infectious workup and lack of improvement in antibiotic therapy. In this context, he received a 5-day course of methylprednisolone 1 gram daily on week 8 followed by a prednisone taper with dramatic improvement in his memory and language. Anti-TB therapy was ultimately discontinued after ~1 month of treatment.
Over the following months, attempts to taper off prednisone resulted in clinical and radiological deterioration. Surveillance brain MRIs demonstrated worsening of meningoencephalitis with a new focus on enhancement in the left amygdala. A second brain biopsy of glucocorticoids at month 10 showed severe granulomatous and suppurative meningoencephalitis with a perivascular and intraparenchymal lymphocytic infiltrate, diffuse astrogliosis, and microglial activation. The pattern of inflammation was again suspicious for mycobacterial infection; however, AFB and AFB-FITE stains and AFB culture of the brain tissue were negative, as were mycobacterial universal PCR and metagenomic next-generation sequencing.
Three weeks after the second biopsy, the patient was retreated with IV methylprednisolone followed by oral prednisone maintenance with subsequent clinical improvement over the next few months. Repeat imaging 3 months after the resumption of glucocorticoid treatment demonstrated near the total resolution of leptomeningeal enhancement and non-progression of his encephalitis. The patient was then transitioned empirically to mycophenolate mofetil and successfully weaned off prednisone without recurrence of his meningoencephalitis. He remained seizure-free on antiseizure therapy. Repeat CSF at 26 months post-presentation showed normal cellularity (3 WBC/muL with 87% lymphocytes and 17% monocytes), normal glucose (57 mg/dL), mildly elevated protein (67 mg/dL), persistent elevated IgG index (0.7 ref. <=0.6), and two oligoclonal bands. MRI brain every 6 months showed stable multifocal T2/FLAIR cortical and white matter hyperintensities without associated enhancement. Following 3 years of immunosuppressive therapy, 4.5 years after his initial presentation, mycophenolate mofetil was stopped and the patient remained stable. Neurological assessment documented fixed sequelae consisting of dysarthria, executive dysfunction, and episodic memory impairment.