A 14-year-old boy presented to our institution with a 1-month history of neurocognitive decline and intermittent fevers. His history was significant for fevers, headaches, and a 10-lb weight loss. Previous examinations by multiple medical providers were significant only for bilateral cervical lymphadenopathy. Previous laboratory workup revealed leukopenia, neutropenia, and elevated inflammatory markers. Despite improvement in his laboratory values after his initial presentation, his fevers persisted, and he developed slowed and “jerky” movements, increased sleep, slurred speech, delusions, visual hallucinations, and deterioration in his school performance. A brain MRI performed at an outside hospital before admission at our institution was concerning for patchy, increased T2 and fluid-attenuated inversion recovery signal intensity in multiple areas, including the basal ganglia. After transfer to our institution and admission to the pediatric hospital medicine team, the patient had an acute decompensation. Our subspecialists will discuss the initial evaluation, workup, differential diagnosis, definitive diagnosis, and subsequent management of this patient.

A 14-year-old boy with no significant past medical history presented to our institution with 1 month of neurocognitive decline and intermittent fevers. Before symptom onset, he was described by his family as a good student who was active in football and track. His family history was unknown because he was adopted.

The patient was initially evaluated in the emergency department (ED) for 3 days of fever, coughing, congestion, headache, decreased oral intake, and a 10-lb weight loss after exposure to a relative with coxsackie virus. His examination was significant for bilateral cervical lymphadenopathy. Laboratory workup revealed leukopenia, neutropenia, and elevated inflammatory markers (Table 1). He was discharged from the hospital with a diagnosis of viral illness with a plan for follow-up with the hematology team.

TABLE 1

Laboratory Data

Laboratory TestABCD
EDHematology ClinicHematology ClinicOutside EDOutside HospitalHospital Admission
November 19November 22November 30December 11December 17December 17–January 11
WBC count 4.5–13.5 × 103/UL 1.89 4.57 5.19 3.42 2.5 2.7 
Absolute neutrophil count 1.8–8.0 × 103/UL 0.76 3.16 2.43 — — 1.94 
Hemoglobin 13.0–16.0 g/dL 9.5 9.6 11.3 9.8 8.5 8.8 
Reticulocyte 0.6–1.9, %  — 2.2 — — — 0.9 
Platelets 150–400 × 103/UL 107 225 366 142 150–160 261 
LDH 360–730 U/L 1813 1615 — — ∼1300 2914 
Uric acid 2.0–6.2 mg/dL 2.6 1.8 — — — 1.6 
Ammonia 22–48 UMOL/L — — — — — <9 
Urine drug screen result — — — — Negative  
Creatinine kinase 60–335 U/L — — — — — 678 
C-reactive protein <1.0 mg/dL — — — — ∼45 3.3 
Ferritin 10–300 ng/mL — — — — 1335 1930 
Fibrinogen 220–440 mg/dL — — — — — 419 
Triglyceride 45–203 mg/dL — — — — — 81 
CSF WBC count, per mm3 — — — — 10 18 
CSF glucose, mg/dL — — — — ∼50 54 
CSF protein 15–45 mg/dL — — — — 99 112 
CSF opening pressure, mm Hg — — — — — 38 
Influenza A and B antigen — — — Negative result B antigen–positive — 
Coxsackie A and B — — — — Coxsackie A 1:64; coxsackie B5 1:80 — 
ANA — — — — 1:1280, speckled — 
Soluble interleukin-2 receptor level 45–1105 U/mL — — — — — 808 
NK cell activity — — — — — Decreased 
Laboratory TestABCD
EDHematology ClinicHematology ClinicOutside EDOutside HospitalHospital Admission
November 19November 22November 30December 11December 17December 17–January 11
WBC count 4.5–13.5 × 103/UL 1.89 4.57 5.19 3.42 2.5 2.7 
Absolute neutrophil count 1.8–8.0 × 103/UL 0.76 3.16 2.43 — — 1.94 
Hemoglobin 13.0–16.0 g/dL 9.5 9.6 11.3 9.8 8.5 8.8 
Reticulocyte 0.6–1.9, %  — 2.2 — — — 0.9 
Platelets 150–400 × 103/UL 107 225 366 142 150–160 261 
LDH 360–730 U/L 1813 1615 — — ∼1300 2914 
Uric acid 2.0–6.2 mg/dL 2.6 1.8 — — — 1.6 
Ammonia 22–48 UMOL/L — — — — — <9 
Urine drug screen result — — — — Negative  
Creatinine kinase 60–335 U/L — — — — — 678 
C-reactive protein <1.0 mg/dL — — — — ∼45 3.3 
Ferritin 10–300 ng/mL — — — — 1335 1930 
Fibrinogen 220–440 mg/dL — — — — — 419 
Triglyceride 45–203 mg/dL — — — — — 81 
CSF WBC count, per mm3 — — — — 10 18 
CSF glucose, mg/dL — — — — ∼50 54 
CSF protein 15–45 mg/dL — — — — 99 112 
CSF opening pressure, mm Hg — — — — — 38 
Influenza A and B antigen — — — Negative result B antigen–positive — 
Coxsackie A and B — — — — Coxsackie A 1:64; coxsackie B5 1:80 — 
ANA — — — — 1:1280, speckled — 
Soluble interleukin-2 receptor level 45–1105 U/mL — — — — — 808 
NK cell activity — — — — — Decreased 

Select patient laboratory data from (A) first presentation to our ED, (B) hematology clinic follow-up on 2 dates, (C) outside hospital presentation and follow-up, and (D) hospital admission. Normal value ranges for our hospital are listed in the first column. Normal value ranges for the outside hospital were either not available or were similar to ours. UMOL/L, micromole per liter; WBC, white blood cell; —, not applicable.

He was seen as an outpatient by the hematology team. Repeat complete blood count had normalized consistent with a previous viral infection (Table 1).

Despite improvement in his laboratory values, his fevers persisted, and he developed slowed and “jerky” movements, increased sleep, slurred speech, delusions, visual hallucinations, and deterioration in his school performance.

Given this progression of symptoms, he was admitted to a community hospital, where laboratories revealed a recurrence of cytopenias and elevated inflammatory markers. Urinalysis results were negative for blood or protein, and urine drug screen results were unremarkable (Table 1). Chest radiograph and computed tomography (CT) scan of the chest were significant for bibasilar pneumonia. Brain MRI was performed and was concerning for patchy, increased T2 and fluid-attenuated inversion recovery (FLAIR) signal intensity in multiple areas, including the basal ganglia.

He was subsequently transferred to our institution, where he was evaluated by the pediatric hospital medicine team. His initial examination revealed a child who was awake, alert, responsive (but slow), oriented to place, and again noted to have significant cervical adenopathy. He had a fever (38°C), mild tachycardia (100 beats per minute), mild tachypnea (24 breaths per minute), and normal blood pressure (105/67 mm Hg). On reevaluation a few hours later, the patient was difficult to arouse, nonresponsive to questioning, and appeared “lethargic and/or altered.” His temperature, pulse, and respirations had all increased to 39.7°C, 116 beats per minute, and 26 breaths per minute, respectively, and he remained normotensive (112/63 mm Hg). He was diaphoretic. He had significant muscle weakness, had diminished deep tendon reflexes, and was unable to stand. Given concern for a stroke or bleeding, emergent head CT was performed that did not reveal any acute intracranial abnormality, including edema, hemorrhage, or herniation. He was then transferred to the intermediate care unit, and the neurology team was consulted.

We asked the neurology team to walk us through the neurologic examination. What were the abnormal findings, and how did they lead to your differential diagnosis for the patient?

When evaluating altered mental status (AMS), it is most important to distinguish decreased alertness from confusion, aphasia, or inattentiveness. This patient was sleepy, although he was aroused with minimal verbal stimulation. He was able to answer questions and follow simple commands and was oriented to person, place, and time. His language content was mostly appropriate, although at times, it was apparent he was confused.

In patients with AMS, it is also important to look for focal neurologic deficits. For example, asymmetric pupils can indicate increased intracranial pressure leading to herniation. His pupils were equal. On reflex and motor examination, it is most important to assess for asymmetry. This patient had symmetric lower extremity weakness, as evidenced by his inability to stand without support. Reflexes were diminished but present and symmetrical. The remainder of the examination was unremarkable (see Table 2 for the full neurologic examination).

TABLE 2

Initial Neurologic Examination Obtained by the Neurology Team on the Day of Admission

Neurologic ExaminationFinding
Mental status  
 Appearance and behavior Well groomed 
Dressed in a hospital gown 
Sitting in a chair 
 Speech Slow, not slurred; age appropriate content although intermittently confused 
 Thought Slow, no delusions 
 Alertness Sleepy but arousable 
 Orientation Oriented to person, place, mo, and y 
 Attention Decreased 
Cranial nerves  
 I: olfactory nerve Smell not assessed 
 II: optic nerve Pupils were equal, round, and reactive to light 
Visual fields intact to confrontation 
 III, IV, VI: oculomotor, trochlear, and abducens nerves Full extraocular movements 
 V: trigeminal nerves Intact and symmetric facial sensation to light touch 
 VII: facial nerve Symmetric facial movements 
 VIII: vestibulocochlear Hearing intact to voice 
 IX, X: glossopharyngeal and vagus nerves Palate elevates symmetrically 
 XI: accessory nerve Full strength in sternocleidomastoid muscle 
 XII: hypoglossal nerve Midline tongue protrusion 
Motor  
 Tone Normal tone 
 Muscle mass No atrophy 
 Strength At least three-fifths strength in upper and lower extremities proximally and distally without evidence of focal weakness; motor examination was difficult to obtain because of slow responses and poor cooperation 
Reflexes Depressed patellar reflexes 
Coordination No evidence of dysmetria, no tremor 
Sensation Intact to light touch in upper and lower extremities 
Gait Unable to ambulate independently 
Neurologic ExaminationFinding
Mental status  
 Appearance and behavior Well groomed 
Dressed in a hospital gown 
Sitting in a chair 
 Speech Slow, not slurred; age appropriate content although intermittently confused 
 Thought Slow, no delusions 
 Alertness Sleepy but arousable 
 Orientation Oriented to person, place, mo, and y 
 Attention Decreased 
Cranial nerves  
 I: olfactory nerve Smell not assessed 
 II: optic nerve Pupils were equal, round, and reactive to light 
Visual fields intact to confrontation 
 III, IV, VI: oculomotor, trochlear, and abducens nerves Full extraocular movements 
 V: trigeminal nerves Intact and symmetric facial sensation to light touch 
 VII: facial nerve Symmetric facial movements 
 VIII: vestibulocochlear Hearing intact to voice 
 IX, X: glossopharyngeal and vagus nerves Palate elevates symmetrically 
 XI: accessory nerve Full strength in sternocleidomastoid muscle 
 XII: hypoglossal nerve Midline tongue protrusion 
Motor  
 Tone Normal tone 
 Muscle mass No atrophy 
 Strength At least three-fifths strength in upper and lower extremities proximally and distally without evidence of focal weakness; motor examination was difficult to obtain because of slow responses and poor cooperation 
Reflexes Depressed patellar reflexes 
Coordination No evidence of dysmetria, no tremor 
Sensation Intact to light touch in upper and lower extremities 
Gait Unable to ambulate independently 

The differential diagnosis for a patient with AMS, fever, and lower extremity weakness is broad (Table 3) and includes infectious, postinfectious, autoimmune, and oncologic etiologies. This patient’s history of fever, weight loss, and elevated inflammatory markers (Table 1) appeared to be correlated more with an evolving systemic process with secondary neurologic manifestations. Considering the acute onset of weakness with diminished lower extremity reflexes and encephalopathy (an altered state of consciousness), a process involving both the central and peripheral nervous systems was favored. This initially raised concern for specific infections, such as West Nile virus1 or mycoplasma encephalitis.2 Basal ganglia lesions on MRI, although nonspecific, can be seen in West Nile encephalitis.3 

TABLE 3

Initial Differential Diagnosis Divided by Pathophysiology

Autoimmune 
 SLE (with CNS involvement) 
 Dermatomyositis 
 Primary CNS or systemic vasculitis 
 Other immune-mediated or inflammatory myopathies 
 ADEM 
 AE (including antibodies to N-methyl-D-aspartate receptor, VGKC, and GAD) 
 Multiple sclerosis and/or transverse myelitis 
 Guillain-Barré syndrome 
 Myasthenia gravis 
 ALPS 
Infectious 
 Acute viral encephalitis and/or meningitis 
 Postinfectious viral encephalitis 
Oncologic 
 Leukemia and/or lymphoma 
 Other malignancy with CNS metastasis 
 HLH 
 Paraneoplastic neurologic syndromes 
Autoimmune 
 SLE (with CNS involvement) 
 Dermatomyositis 
 Primary CNS or systemic vasculitis 
 Other immune-mediated or inflammatory myopathies 
 ADEM 
 AE (including antibodies to N-methyl-D-aspartate receptor, VGKC, and GAD) 
 Multiple sclerosis and/or transverse myelitis 
 Guillain-Barré syndrome 
 Myasthenia gravis 
 ALPS 
Infectious 
 Acute viral encephalitis and/or meningitis 
 Postinfectious viral encephalitis 
Oncologic 
 Leukemia and/or lymphoma 
 Other malignancy with CNS metastasis 
 HLH 
 Paraneoplastic neurologic syndromes 

GAD, glutamic acid decarboxylase.

There were also concerns for autoimmune causes for this patient’s symptoms. Could this be systemic lupus erythematosus (SLE) or autoimmune encephalitis (AE)? If so, how would you work this up?

Yes, it could be. Although rheumatologic diseases are rare, given his constellation of symptoms, we were most concerned about SLE with secondary central nervous system (CNS) vasculitis, AE, and/or a hemophagocytic lymphohistiocytosis (HLH) and/or macrophage activation syndrome (MAS) spectrum disorder. Given the patient’s history of subacute neurocognitive decline followed by constitutional symptoms and a sudden alteration of consciousness, we needed to perform additional testing to assess the aberrant activation of his immune system.

We recommended serologic studies to evaluate SLE, including an antinuclear antibody (ANA) profile, which revealed positive high-titer ANA, positive anti-Smith, and positive antiribonucleoprotein antibodies. A lumbar puncture was done to evaluate for opening pressure, and cerebrospinal fluid (CSF) studies were obtained to evaluate for antibodies seen in neuropsychiatric systemic lupus erythematosus (NPSLE) (his was positive for antineuronal antibody in serum and CSF). Given the concern for possible AE, serum and CSF studies were sent and had positive results for voltage-gated potassium channel (VGKC) antibody in the serum.

Given the normal head CT results, what further studies would you recommend ordering to address his rapid decline?

EEG should be considered next to identify subclinical seizures with rapid decline in mental status. Our patient’s EEG did not reveal any focal or epileptiform features but did reveal diffuse slowing, which is consistent with encephalopathy.

To evaluate infectious causes of AMS, patients should undergo lumbar puncture to examine CSF for glucose, protein, cell count, viral studies, and culture in addition to serum infectious evaluation. These CSF studies were normal in our patient with the exception of elevated protein levels (Table 1). Given his muscle weakness, a serum creatinine kinase level was sent and found to be mildly elevated (Table 1). An MRI of the brain and spine were performed to address concerns for an inflammatory or demyelinating disease. The distribution and shape of the inflammatory lesions can be helpful in narrowing the differential.4 For example, in demyelinating diseases, T2 changes are usually restricted to the white matter. Similarly, the T2 changes in acute disseminated encephalomyelitis (ADEM) are “fluffy” compared with those in viral encephalitis. We also obtained magnetic resonance angiography of the brain to assess for CNS vasculitis. In our patient’s case, spine MRI and brain magnetic resonance angiography results were negative; however, brain MRI results confirmed previously reported increased T2 and FLAIR signal intensity in cortical and deep gray matter, including the basal ganglia, as well as white matter regions (Fig 1).

FIGURE 1

Axial T2 (A) and coronal FLAIR (B) brain MRIs from the day of admission revealed changes in the basal ganglia and thalamus.

FIGURE 1

Axial T2 (A) and coronal FLAIR (B) brain MRIs from the day of admission revealed changes in the basal ganglia and thalamus.

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Basal ganglia lesions are known to cause movement disorders. Can you elaborate on this?

Basal ganglia lesions can cause hyper- or hypokinetic movement disorders, reflecting increased and decreased movements, respectively. Patients can also experience changes in muscle tone, abnormal and involuntary movements, difficulty controlling the speed of their movements, or difficulty coordinating movements. Although Parkinsonism is the most recognized hypokinetic disorder, basal ganglia lesions can be seen in SLE,5 viral infections,6 and postinfectious demyelinating diseases, such as ADEM.7 

During the first few days after admission, this patient developed increased extremity tone, resting pill-rolling hand tremor, profound bradykinesia (slowness of initiation and execution of voluntary movements and speech), rigidity, and postural deficits. This was consistent with the location of his lesions on MRI.

While in the intermediate care unit, our patient’s blood counts continued to decline. How do you think about a patient with pancytopenia?

Cytopenias can be broadly thought about in 2 ways: the bone marrow is not producing a normal amount of cells, or cells are being adequately produced but destroyed. Both mechanisms can result in low peripheral cell counts. A bone marrow biopsy was eventually performed on this patient and revealed a hypocellular marrow of 40%. Cellularity of this degree could indicate suppression from an acute illness, an underlying inflammatory condition, use of certain medications, and/or malignancy. In our patient’s case, a hypocellular marrow was an indication of either a lack of production or suppression.

Does your thought process change when addressing a patient with pancytopenia and AMS?

Yes, it would. If malignancy is suspected, the infiltration occurring in the bone marrow, which subsequently leads to low blood count production, may also be occurring in the CNS. This can be seen in malignancies such as leukemia or lymphoma or in solid tumor malignancies with metastases to the bone marrow and CNS.

In clinical scenarios involving fever, elevated inflammatory markers (especially ferritin), lymphadenopathy, and cytopenias, one must also consider diseases that are associated with immune dysregulation, such as HLH. This disorder, which is caused by a failure to downregulate macrophages, results in excessive cytokine release. Cytopenias are a common end result of this immune dysregulation, and neurologic manifestations can be seen in approximately one-third of those affected with this disorder.8,10 To diagnose diseases such as HLH, the patient must meet at least 5 of the following laboratory and/or clinical criteria: fever, cytopenias (hemoglobin <9 g/dL; platelets <100 K/μL; absolute neutrophil count <1 K/μL), fasting triglycerides >265 mg/dL and/or fibrinogen <150 mg/dL, tissue evidence of hemophagocytosis, decreased or absent natural killer (NK) cell activity, ferritin >500 ng/mL, and soluble CD25 (a cytokine released by T cells) level >2 SDs above the normal value for age.9 In our patient, HLH was less likely given the absence of bone marrow and lymph node (LN) hemophagocytosis. However, we were definitively able to eliminate HLH because he only met 4 of the 8 criteria required for diagnosis: fever, cytopenias, decreased NK cell activity, and ferritin >500 ng/mL.

Another disorder characterized by immune dysregulation is autoimmune lymphoproliferative syndrome (ALPS). Driven by a defect in lymphocyte apoptosis, symptoms of this disorder include lymphadenopathy, cytopenias secondary to autoimmune destruction, splenomegaly, and sometimes neurologic complications resulting in dementia.11 ALPS was eliminated from the differential on the basis of the lack of typical immunohistological findings on bone marrow biopsy per the hematopathologist.

If the cytopenias are thought to be occurring from a nonmalignant etiology, the AMS is usually due to the overarching disease process. For example, our patient’s initial cytopenias were thought to be related to an acute infection. Infections that affect the brain may be so severe that they cause bone marrow suppression at the same time. Similarly, states of chronic inflammation can have bone marrow–suppressive effects in addition to impacting the CNS.

What findings on a peripheral blood smear would be concerning for a malignancy? Is there utility in obtaining additional CSF studies?

In any patient who has cytopenias, a peripheral smear is essential to review. At times, malignant cells can be seen on the smear, which helps guide the direction of the workup. Our patient had a peripheral smear done at an outside facility that did not reveal any evidence of malignancy. Additionally, for a patient who is altered, examination of CSF cytology is beneficial to assess for malignant cells. Most cases of cytopenias, for which malignancy is being considered, require biopsies of the bone marrow. In fact, 1 specific concern for our patient’s case was an underlying malignancy that could be driving a process such as HLH. Because of his significant cervical lymphadenopathy, we proceeded with both LN and bone marrow biopsies. These tissue samples can be studied via flow cytometry, specific marker staining, and microscopically. Lastly, in cases with marked lymphadenopathy, imaging studies (such as a positron emission tomography [PET] or CT scans) can provide an overview of disease burden as well as allow for targeted planning of potential biopsy sites. In our patient, a PET scan revealed increased signal uptake in his cervical, axillary, and mesentery nodes.

Given that our patient had diffuse lymphadenopathy on examination of unclear etiology, he underwent an LN biopsy. What does an LN biopsy add to the diagnostic workup that cannot be provided by a bone marrow biopsy?

The patient had anemia, leukopenia, lymphadenopathy, increased lactate dehydrogenase (LDH), and increased inflammatory markers. The PET scan revealed numerous groups of enlarged LNs with increased metabolic activity, including mediastinal and supraclavicular LNs. Together with deterioration in mental status, there was a possibility of lymphoma driving an HLH-like process. Our concern was that the bone marrow would only show signs of HLH. We wanted to ensure that there were not 2 concurrent processes. The LN pathology would help address whether there was evidence of lymphoma that was driving the HLH. Superficial (right cervical) LNs provided an easy access to diagnostic material. His biopsy revealed necrotizing lymphadenitis without neutrophils (Fig 2).

FIGURE 2

Histology of LN with hematoxylin and eosin stain at ×400. The LN reveals extensive background necrosis with an absence of neutrophils. Also present are plasma cells with cytoplasmic immunoglobulins, also known as Mott cells (black arrow) and nuclear dust (hollow arrow).

FIGURE 2

Histology of LN with hematoxylin and eosin stain at ×400. The LN reveals extensive background necrosis with an absence of neutrophils. Also present are plasma cells with cytoplasmic immunoglobulins, also known as Mott cells (black arrow) and nuclear dust (hollow arrow).

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In a multidisciplinary meeting with the rheumatology, neurology, and hematology-oncology teams, we were able to review the LN biopsy results with Dr Elghetany. On the basis of these results, the patient’s leading diagnosis was SLE. What evidence on biopsy fortified this diagnosis?

The presence of extensive LN necrosis with a predominance of nuclear dust and virtual absence of neutrophils (Fig 2) are common findings in immunologically related disorders, such as Kikuchi disease and SLE.12 

On the basis of our review of the pathology specimen along with the results of the ANA profile, we concluded that the patient best fit the diagnosis of SLE.

What is the classification criteria for SLE, and how does our patient satisfy that criteria?

To establish a diagnosis of SLE, a patient must meet at least 4 of 11 American College of Rheumatology criteria, which were originally developed for research purposes and includes (1) malar rash, (2) discoid rash, (3) photosensitivity, (4) oral ulcers, (5) arthritis, (6) serositis, (7) renal disorder (proteinuria or cellular casts), (8) neurologic disorder (seizures or psychosis), (9) hematologic disorder (hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia), (10) immunologic disorder (positive antiphospholipid antibodies, anti-Smith antibodies, or double-stranded DNA), and (11) positive ANA.13 This patient met criteria for SLE with the following findings: (1) positive ANA, (2) immunologic disorder (positive anti-Smith antibody), (3) neurologic disorder, and (4) hematologic disorder (leukopenia). At time of diagnosis, the patient also had evidence of MAS given his persistent fever, lymphadenopathy, leukopenia and anemia, and elevated ferritin.

What is MAS, and how is it different from HLH?

MAS and HLH are both caused by excessive activation and expansion of macrophages and T cells, leading to an overwhelming inflammatory reaction. MAS and HLH are on a disease spectrum.13 MAS is always seen as a complication of an underlying rheumatic disease. Most commonly, it is associated with systemic onset juvenile idiopathic arthritis. Less frequently, it may be seen in patients with SLE and Kawasaki disease. It occurs in ∼1% of SLE patients. MAS is characterized clinically by fever, hepatosplenomegaly, lymphadenopathy, severe cytopenias, liver disease, coagulopathy, and encephalopathy.13 HLH can be divided into primary (familial) or secondary (reactive) HLH. Primary HLH is caused by rare autosomal recessive genetic defects of the cytolytic pathway and usually presents within the first several years of life. Secondary HLH usually affects older children and most commonly is triggered by an infection, such as Epstein-Barr virus, or by an oncologic process.13 On a cellular level, uncontrolled proliferation of T cells and macrophages leads to decreased NK cell and cytotoxic T-cell function. The hallmark of MAS is seen on bone marrow examination, where morphologically benign macrophages and lymphocytes exhibit the hemophagocytic activity of other blood cells. This can be identified by using staining for CD163 (an anti-CD163 haptoglobin receptor antibody and marker of cells of monocyte and/or macrophage lineage). The increase in macrophages can also be detected in the serum because patients have increased soluble CD25 and/or CD163 levels.14 Laboratory features of MAS and HLH are often indistinguishable. Common laboratory results include a decline of at least 2 cell lines (usually platelets first), a falling erythrocyte sedimentation rate because of decreased fibrinogen levels, elevated serum transaminases and bilirubin, as well as decreased serum albumin. Other classic laboratory abnormalities include elevated ferritin, LDH, and triglyceride. CSF pleocytosis with mildly elevated protein may be seen.13,15 

Did this patient have features of NPSLE given his AMS and encephalopathy? How do you diagnose NPSLE, and what are the autoantibodies seen in this disease?

The reported incidence of NPSLE varies greatly between 10% and 95%16,18 in pediatric patients. NPSLE is more frequent in the pediatric population and typically presents at diagnosis19,20; however, patients may develop NPSLE at any time. It has 19 manifestations in total, but patients may present with >1 manifestation at once. Headache is the most common manifestation.16,20 Other striking manifestations include psychosis, cognitive dysfunction, acute confusional state, mood disorders, cerebrovascular disease, seizures, and movement disorders.13,16,18 Tissue damage in SLE is generally caused by autoantibodies, and this holds true for NPSLE. The most common antibodies in NPSLE include antineuronal antibodies, antiphospholipid antibodies, ribosomal P antibodies, and N-methyl-D-aspartate receptor antibodies.

Our patient’s symptoms of increased extremity tone, tremors, profound bradykinesia, and AMS and cognitive dysfunction, in addition to his basal ganglia lesions on MRI and the antineuronal antibodies detected in the CSF, was consistent with the diagnosis of NPSLE. Typical brain MRI findings seen in patients with NPSLE include cerebral and cerebellar volume loss or atrophy, white matter hyperintensities, gray matter lesions, and infarctions, or in some cases, brain MRI results may be normal.21,23 

Why was the patient treated with rituximab? Was this meant to treat his SLE or MAS?

Actually, the patient had VGKC antibodies detected in the serum by using 2 separate assays. VGKC antibodies are classically associated with AE. AE is a group of neuropsychiatric disorders that present acutely or subacutely and are characterized by alterations in consciousness, cognitive decline, seizures, abnormal movements, or psychosis and may be associated with underlying systemic or CNS autoimmune disorders or paraneoplastic syndromes. When present in serum and/or CSF, they can cause a phenotype that is characterized by seizures and memory loss.12,24 Rituximab is a monoclonal anti-CD20 antibody against B cells and is used in rheumatic diseases, in which autoantibodies play a pathogenic role.25 In this patient, rituximab was chosen as adjuvant therapy given the presence of autoantibodies and the phenotypic similarity to AE.26 

What was the outpatient management plan for this patient?

At the time of discharge from the hospital, the patient continued to exhibit dysphagia, dysarthria, Parkinsonism, left hemiparesis, and spasticity. His neurocognitive and expressive deficits were greater than his receptive language deficits. He completed 3 weeks of intensive inpatient rehabilitation to address impairments in mobility, feeding (swallowing coordination), performance of activities of daily living, speech and language, and cognition. Consistent with the reports in the literature for outcomes of NPSLE,20,27,28 he made great strides. He completed outpatient rehabilitation therapies and is now independent in activities of daily living. He resumed classes via home-bound instruction and completed the school year. Six months after completing inpatient rehabilitation, neuropsychological evaluation revealed average intellectual, academic, social, and adaptive skills but below-average visuomotor and/or sensory motor, executive function, and attentional skills. He requires ongoing academic accommodations.

     
  • ADEM

    acute disseminated encephalomyelitis

  •  
  • AE

    autoimmune encephalitis

  •  
  • ALPS

    autoimmune lymphoproliferative syndrome

  •  
  • AMS

    altered mental status

  •  
  • ANA

    antinuclear antibody

  •  
  • CNS

    central nervous system

  •  
  • CSF

    cerebrospinal fluid

  •  
  • CT

    computed tomography

  •  
  • ED

    emergency department

  •  
  • FLAIR

    fluid-attenuated inversion recovery

  •  
  • HLH

    hemophagocytic lymphohistiocytosis

  •  
  • LDH

    lactate dehydrogenase

  •  
  • LN

    lymph node

  •  
  • MAS

    macrophage activation syndrome

  •  
  • NK

    natural killer

  •  
  • NPSLE

    neuropsychiatric systemic lupus erythematosus

  •  
  • PET

    positron emission tomography

  •  
  • SLE

    systemic lupus erythematosus

  •  
  • VGKC

    voltage-gated potassium channel

Drs Lapin, Lyons-Warren, Risen, Rathore, and Marcus conceptualized and designed the article, drafted the initial manuscript, and reviewed and revised the manuscript; Drs Slone and Elghetany helped draft the initial manuscript and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.

FUNDING: No external funding.

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.