A 33-year-old man presented with diffuse lymphadenopathy and multiple skin lesions from which tissue cultures were positive for MAC, and a diagnosis of disseminated MAC infection involving the skin, lymph nodes, and bone marrow was made. He was seen at the NIH and was diagnosed with immunodeficiency secondary to nuclear factor-kappa B essential modulator (NEMO) deficiency (IKBKG c.-16 + 1G > C leading to disruption of the intron-1 splice site). Despite long-term anti-mycobacterial treatments, with adjuvant interferon-gamma and interleukin-2, microbial burden fluctuated, with multiple episodes of clinical and laboratory worsening, including the development of lung, liver, and spleen involvement. At 40 years of age, he developed additional abdominal lesions, which were thought to be consistent with his known mycobacterial disease, and it was decided to surgically remove these to promote response to treatment. Following abdominal surgery, he experienced an acute change in mental status with visual hallucinations, and an MRI of the brain with gadolinium was normal, although no T2 fluid-attenuated inversion recovery (T2-FLAIR) sequence was acquired. Lumbar puncture showed mildly elevated opening pressure (25 cm H₂O), but CSF was normal with a negative acid-fast bacilli (AFB) smear, fungal culture, and negative PCR for viral pathogens. A later generalized tonic–clonic seizure was treated with levetiracetam and lacosamide and required intubation. Three days later, a brain MRI demonstrated lesions in bilateral occipito-parietal and cerebellar regions with a high diffusion signal suggesting vasogenic edema and a few superimposed small foci of restricted diffusion in the cerebellum thought to be posterior reversible encephalopathy syndrome (PRES). In addition, there was diffuse hyperintensity with restricted diffusion involving the right pulvinar nucleus, right hippocampus, and amygdala, possibly suggesting seizure-induced changes (Figures 1A–D). He gradually improved and was extubated 4 days later. Two subsequent unenhanced MRI scans showed improvement in hyperintensities and diffusion restriction findings. The patient died a few weeks later of abdominal surgical complications. At autopsy, brain sections showed diffuse microglial activation with microglial nodule formation, parenchymal vacuolization, gliosis, and clusters of histiocytes. These changes were particularly prominent in the hippocampus, with evidence of neuronal dropout. Cultures were positive for MAC from multiple organs, including the brain (positive at 3 days and 20 h). CSF culture from earlier in the disease course was also positive for MAC at 28 days and 5 h. This case has been previously reported as Patient B.II.3 in a brief report on NEMO deficiency leading to chronic disseminated mycobacterial infections (9).

A 28-year-old man with a past medical history of recurrent childhood sinusitis presented with a 9-month history of elbow and facial rash, and 2 weeks of headaches and vomiting, right facial numbness, and gait instability. MRI of the brain showed multiple nodular and ring-enhancing lesions of the brainstem (Figure 2A) and upper cervical cord (Figure 2B) with associated edema, in addition to one focus of enhancement in the left frontal lobe. Biopsies of the skin and frontal lobe lesions showed necrotizing granulomatous inflammation with AFB without identification of a specific mycobacterial species. He was started on an empiric antituberculosis regimen, including isoniazid, rifampin, pyrazinamide, and ethambutol. However, 4 months later, while he was recovering from a hospital-acquired Pseudomonas aeruginosa pneumonia, molecular results from the biopsy identified Mycobacterium haemophilum, and he was switched to rifabutin, ciprofloxacin, and clarithromycin, but a month later was admitted again due to vomiting and ataxia. Brain MRI showed worsening edema, and he was treated with dexamethasone. Over the following months, symptoms recurred whenever steroids were tapered. He was subsequently treated with clofazimine, amikacin, and linezolid, and ciprofloxacin was switched to moxifloxacin. Two months later, he was first admitted to the NIH. Blood tests revealed low CD4+ lymphocyte count (203 cells/mm³), and he underwent whole genome sequencing wherein a pathogenic hemizygous mutation in NEMO was identified (IKBKG c.-16 + 1G > C leading to disruption of the intron-1 splice site). On examination, he had decreased facial sensation on the right, subtle impaired dexterity in his left limbs, with hyperreflexia and an extensor plantar response on the left. He was given a multi-antimycobaterial regimen including clarithromycin, moxifloxacin, rifabutin, pyridoxine, bedaquiline, clofazamine, dexamethasone, and linezolid. A month later, a brain MRI showed improvement in hyperintensities, swelling, and enhancement in the brainstem, with minimal punctate residual enhancement at the pontomedullary junction and medulla. CSF showed no white blood cells (WBCs) with elevated protein (62 mg/dL) and normal glucose (66 mg/dL). At this point, IFN-gamma was added to his regimen. Over the following months, his hospital course was complicated by multiple ICU admissions for hypoxemic and hypercapnic respiratory failure, being attributed to rhombencephalitis, with exacerbation from sedating medications used intermittently for agitation associated with respiratory distress. He had progressive quadriparesis with preserved ocular movements. Brain MRI showed extensive brainstem signal abnormality (Figure 2C) and progressive bi-thalamic and right basal ganglia signal changes on FLAIR (Figure 2D) with subtle enhancement. Following a 5-month hospitalization, he developed profound hypotension with tachycardia and died. At autopsy, gross examination of coronal sections revealed abnormal brainstem with midbrain and pons showing areas of softening and discoloration. Microscopically, the sections showed mycobacterial encephalitis with infarcts and numerous perivascular and parenchymal histiocytic aggregates loaded with mycobacteria. The hypothalamus, basal ganglia, brainstem, and cerebellum were involved. Mycobacterium haemophilum DNA was detected in the brainstem using a 16S ribosomal RNA gene primer set.

A 58-year-old man with a past medical history of untreated HIV infection since the age of 32 years presented with 3 months of progressive right-sided weakness and numbness, visual disturbance, and recurrent falls. His examination showed mild impairment of attention, mild dysarthria, right central facial palsy, left oculomotor nerve palsy, and mild right hemiparesis. CD4+ cell count was 110 cells/mm³, and HIV RNA viral load was 79,400 copies/mL. Brain MRI showed a large enhancing lesion in the left midbrain (Figure 3A) with central hypointensity on susceptibility-weighted imaging. There was edema associated with the lesion but no restricted diffusion. Additionally, other small enhancing lesions were present in the left frontal lobe and deep gray matter (Figure 3B). Loss of volume of the cerebral hemispheres and confluent white matter signal abnormalities were also present, consistent with HIV encephalopathy. Serum Toxoplasma gondii IgG and IgM were negative, and chest-abdomen-pelvis CT scan was normal. CSF showed 9 WBCs per mm³, with elevated protein (85 mg/dL) and normal glucose (76 mg/dL). CSF was positive for EBV-DNA (491 copies/mL), with a negative PCR for Toxoplasma gondii. The main differential diagnosis at this point was primary CNS lymphoma vs. CNS toxoplasmosis. Due to the high-risk location of the large lesion, he was transferred to the NIH for further management. At the NIH, he was first treated empirically for toxoplasmosis for 7 days. A whole body FDG-PET scan showed evidence of esophagitis and dental abscesses with no evidence of systemic lymphoma. The left midbrain lesion showed high FDG uptake in the periphery (maximal standardized uptake value = 12.8, Figure 3C) with an area of decreased uptake centrally that corresponded to the area of hemorrhagic transformation seen on MRI. Eventually, a stereotactic left midbrain biopsy was performed, and histologic sections showed a fibrinous matrix containing numerous neutrophils and few admixed mononuclear cells, with stains positive for numerous AFB and a positive auramine-rhodamine stain (Figure 3D). Pan-Mycobaterium SecA1 real-time PCR assay identified the pathogen as Mycobaterium avium subspecies paratuberculosis. He was treated with rifabutin, ethambutol, azithromycin, and moxifloxacin, in addition to a 4-week intravenous course of meropenem to treat dental abscesses and the possibility of polymicrobial brain abscesses. Oral steroids were also given (dexamethasone and later prednisone). Brain MRI 1 week after initiation of anti-mycobacterial regimen showed interval growth of enhancing lesions, but a scan 2 weeks later showed mildly decreased size of the left midbrain lesion (not shown). At this point, antiretroviral treatment was initiated, and he was also treated for biopsy-proven CMV esophagitis. His post-antiretroviral treatment course was initially complicated by clinical and radiological features of immune reconstitution inflammatory syndrome, requiring an intermittent increase of steroid dose, yet on subsequent follow-up, right hemiparesis gradually improved, which correlated with a gradual decline in size and associated edema of the brain lesions on MRI. The patient fully recovered clinically with only residual radiological findings, including a small hemorrhagic ring-enhancing lesion in the left midbrain and subtle residual foci of enhancement in the left frontal lobe.

A 56-year-old man with a history of hypertension, chronic lower back pain, and multiple abdominal surgeries due to a gunshot wound around the age of 20 years presented to the emergency room with worsening lower back pain and right leg pain 8 weeks after he received a corticosteroid epidural injection for his chronic pain. Initially, a lumbar MRI showed only focal arachnoiditis, and he was treated with oral corticosteroids, but a week later, he had a fever and worsening pain, and a repeat MRI showed an epidural phlegmon with a focal abscess which displaced the thecal sac to the left from L4-L5 to mid-S1. He was treated empirically with IV antibiotics and underwent L5-S1 laminectomy and evacuation of the epidural abscess without complications. Pathology showed fragments of granulation tissue with focal giant cell reaction and was AFB+, while tissue culture was positive for Mycobacterium abscessus sensitive to amikacin. HIV testing was negative. Three weeks after antibiotic regimen initiation (unclear documentation), the MRI revealed continued enhancement with no fluid collections. A repeat MRI 3 weeks later showed a phlegmon extending from L2-L5 with fluid pockets impinging the dural sac and causing severe canal stenosis, in addition to focal osteomyelitis in the right sacrum. There was also an extension of abnormal enhancement along the right-sided sacral nerve roots in the right presacral region. A repeat laminectomy and drainage procedure was performed, and he was given amikacin, linezolid, meropenem, and azithromycin. He was then transferred to the NIH. Upon arrival, his examination showed minimal weakness in the right leg. Lumbar MRI showed stable epidural abscess and sacral osteomyelitis (Figures 4A,B), with some resolution of the fluid in the post-laminectomy space. In addition, thickening and enhancement of the lumbar nerve roots were noted, consistent with arachnoiditis. Tigecycline was added to the antimicrobial regimen, and eventually, amikacin was stopped because of concern for ototoxicity. Serial MRI scans showed a decrease in the amount of post-operative fluid collection, and additional neurosurgical intervention was determined unnecessary. He continued this antimicrobial regimen for 7 months, then continued linezolid and azithromycin for an additional 5 months. One year after completing treatment, he had no symptoms and no signs of recurrence.

A 39-year-old man with sarcoidosis diagnosed at 35 years by lung biopsy, previously treated with prednisone for 2 years, had a motor vehicle accident due to a possible seizure. Head CT demonstrated multiple enhancing intracranial masses. A biopsy of a left frontal mass revealed MAC by culture, for which monotherapy with IV amikacin was initiated. A few months later, a right parietal mass was resected with cultures again confirming MAC, and he was started on clarithromycin, ethambutol, and rifampin. At this point, he was referred to the NIH. Neurologic examination showed mild dysarthria, mild left hemiparesis, and right cerebellar signs. Serial brain MRI scans showed an enlarging right cerebellar lesion (Figure 4C) without hydrocephalus. Treatment with gamma-interferon was considered, but there was concern that this might increase cerebral edema, and, therefore, he underwent resection of his cerebellar lesion. MAC was again identified in the tissue. The patient improved clinically over the next few months, and a follow-up brain MRI showed post-operative changes (Figure 4D) with a stable appearance of a left posterior parasagittal enhancing nodule, which was not resected. After completing his initial course of antimicrobial treatment, he remained on secondary prophylaxis with azithromycin. He was found to have a heterozygous Interferon Regulatory Factor 8 (IRF8) variant (c.536C > T, p.ALA179VAL) of uncertain significance. The patient had no recurrence of his mycobacterial disease on annual follow-ups, although he did have several exacerbations of sarcoidosis. Clinical information regarding this case has been previously reported before the identification of the additional underlying genetic association (10).

A 31-year-old woman originally from the Philippines, previously healthy, presented with recurrent fevers, headaches, and painful post-auricular nodules. She was empirically treated with azithromycin for possible sinusitis without improvement. Brain MRI showed a 3 cm X 2 cm left post-auricular lesion with erosion through the bone (Figure 5A), as well as a right frontal extra-axial convexity lesion (Figure 5B). Sputum and aspirate from a skull biopsy were AFB positive and grew MAC. She was initially treated with amikacin, azithromycin, and ethambutol (had an anaphylactic reaction to rifampin) and underwent drainage of left occipital and left paraspinal abscesses. Further investigations showed that she had anti-IFN-gamma autoantibodies and, therefore, rituximab 1 g once monthly was started. However, the patient’s headaches persisted, and she developed blurry vision with bilateral optic disc edema. A lumbar puncture revealed an opening pressure of 31 cm H₂O with lymphocytic meningitis, at which point moxifloxacin and linezolid were added. Her headaches persisted, so a lumbar drain was placed for 1 week. She was then referred to the NIH, where bedaquiline and meropenem were added to her regimen. Following 5 additional months of rituximab and an antimicrobial regimen (initially including azithromycin, ethambutol, linezolid, moxifloxacin, and clofazimine), she still had evidence of clinical and radiological progression. Tidezolid and meropenem were added, and to decrease autoantibody production, bortezomib (a small-molecule proteasome inhibitor used in the treatment of multiple myeloma) was initiated at 1.3 mg/m² subcutaneous injection following the standard regimen but was discontinued after 3 months due to hepatotoxicity. Despite the continuation of rituximab to maintain CD20 numbers undetectable, clinical and radiographic disease progressed. To further reduce autoantibody production, she was started on daratumumab, an anti-CD38 monoclonal antibody (16 mg/kg intravenously weekly) also used in the treatment of multiple myeloma. She initially had worsening headaches and altered mental status, with a brain MRI showing an extension of epidural abscess into the right frontal parenchyma (Figures 5C,D). A lumbar puncture showed an opening pressure of 33 cm H₂O and pleocytosis (59 WBCs per mm³), mildly increased protein (61 mg/dL), and low glucose (47 mg/dL, CSF to serum ratio of 0.4). She underwent abscess evacuation without complications. Following this, she continued treatment with daratumumab along with IVIG for secondary hypogammaglobulinemia, with clinical and radiographic improvement, reduced pain, and disappearance of multiple soft tissue lesions. The successful use of daratumumab in this case has been previously reported (11).