Investigation and Management of Confusion in an Individual With Diffuse Corpus Callosum Lesions

Case Presentation

SB, age mid-20s, who had type 1 diabetes (T1D), arterial hypertension, end-stage renal disease (ESRD) requiring hemodialysis 3 times/week, and systolic and diastolic heart failure, was admitted to the hospital because of fevers and a subjective concern of confusion, noted by SB as well as SB’s relatives. SB had a recent history of disseminated skin rash and upper airway infection treated at home with over-the-counter medications. Four months earlier, SB had been started on hemodialysis after developing decompensated heart failure and uremic syndrome. The chronic renal disease was attributed to microvascular complications of T1D. Diagnosis of T1D had been made when SB was 5 years old, and SB had a history of poor glycemic control. Medical records also showed multiple episodes of hypoglycemia in past months.

During the initial neurologic evaluation, SB described the symptom of confusion as fatigue, excessive sleepiness, and feeling “somewhat down.” On general physical examination, SB had elevated blood pressure (145/113 mm Hg), tachycardia (116 bpm), unlabored breathing (respiratory rate 17; saturation of peripheral oxygen [SpO2] 99% on room air), and he was euglycemic. On neurologic examination, SB was drowsy and slow to follow commands. SB was oriented to self, place, time, and situation. Cranial nerves were unremarkable except for proliferative diabetic retinopathy in both eyes. SB had normal strength, coordination, and muscle stretch reflexes in the upper and lower limbs, except for a left Babinski sign. Sensory examination showed reduced pinprick sensation in the bilateral lower extremities. SB walked with the support of a cane with a wide-based gait.

Diagnostic Process

Initial noncontrast brain MRI showed diffuse T1 hypointensity, T2 fluid-attenuated inversion recovery (FLAIR) hyperintensities of the corpus callosum, and scattered nonspecific signal changes in the periventricular and subcortical white matter of the cerebral hemispheres on T2/FLAIR images, which were greater in the right centrum semiovale. There were no diffusion abnormalities. Noncontrast MRI studies of the cervical and thoracic spine were unremarkable (Figures 1 and 2). Ancillary investigations showed an elevated C-reactive protein level (9.0 mg/L [reference, <8.1 mg/L]), elevated sedimentation rate (101 mm [reference, 0 to 15 mm]), and mild changes in the basic metabolic panel (Table 1). Additional serologic studies for hepatitis B, hepatitis C, and human immunodeficiency virus were negative. A rheumatologic laboratory screening was also performed. Cerebrospinal fluid (CSF) analysis demonstrated a colorless fluid with 17 red blood cells/mm3, 0 white blood cells, glucose level 109 mg/dL (serum glucose level 160 mg/dL), and protein level 70 mg/dL. Oligoclonal bands were present in CSF and serum. Other results included an immunoglobulin G (IgG) index of 0.44 (reference, <0.66), albumin index in CSF of 42 (reference, 8 to 42), IgG index in CSF of 5.9 (reference, 0.8 to 7.7), IgG index in serum of 988 (reference, 600 to 1640), albumin index in serum of 3.1 (reference, 3.5 to 5.2), and angiotensin-converting enzyme of 4 U/L (reference, ≤15 U/L). A more comprehensive mental status assessment (eg, neuropsychologic evaluation) would have improved understanding of cognitive function, but this assessment was not performed during hospitalization because of the acute nature of the symptom presentation.

During the initial assessment, several etiologic hypotheses were explored to evaluate the presenting findings of altered mental status, lesions in the corpus callosum, and elevated CSF protein level. Given the rash and recent respiratory illness, a possible immunologic trigger caused by Streptococcus sp. was suggested, but anti-Streptococcus antibodies were negative (Table 1). Other infectious etiologies, such as central nervous system (CNS) Lyme disease, were considered, because SB had been traveling in high-risk regions during the months before the onset of neurologic manifestations. However, encephalopathy in CNS Lyme disease is rare, and usually accompanied by CSF pleocytosis. SB did not meet clinical or imaging requirements for a diagnosis of multiple sclerosis (MS).

In consideration of neurologic disorders presenting with leukodystrophies, we compared SB’s current MRI results with a previous MRI scan from 2012, and the lesions found on the current MRI scan were not present in the older study. A possible diagnosis of Susac syndrome was strongly considered because of the imaging characteristics of the corpus callosum lesions and medical history.

Case Resolution

SB was treated empirically with intravenous (IV) methylprednisolone 1000 mg for 5 days followed by IV immunoglobulin (IVIg) 2 g/kg for an additional 5 days. After the third day of IVIg treatment, overall neurologic status improved, including mental status and gait.

SB was discharged from the hospital and referred for audiology and ophthalmologic outpatient evaluations. Audiogram results were normal, and ophthalmology confirmed the bilateral proliferative diabetic retinopathy, but no evidence of branch retinal artery occlusion (BRAO) was noted.

SB has been followed in the neurology outpatient clinic for almost 2 years, and despite the persistence of the corpus callosum lesions (Figures 1 and 2), has not presented with new neurologic symptoms. Radiologic findings ruled out the hypothesis of cytotoxic lesions of the corpus callosum, which usually are transient and show cytotoxic edema features (eg, restricted diffusion in the diffusion-weighted imaging sequence), which were not found in this case. Because of SB’s clinical stability, we decided against continuous immunosuppressive therapy but continue to monitor clinical and imaging findings. SB’s clinical status has been assessed every 6 months. Brain imaging (noncontrast brain MRI) was obtained every 6 months for the first year, and once a year after that. SB is on the waiting list for pancreas and kidney transplantation.

Discussion

The corpus callosum (from the Latin corpus, meaning “body,” and callosum, meaning “hard” or “tough”) is a C-shaped white matter structure connecting the right and left brain. It has 4 main regions (ie, rostrum, genu, trunk or body, and splenium).¹ The corpus callosum is the largest of the commissural fibers, and each one of its regions connects different parts of the brain hemispheres. The genu and the forceps minor connect the medial and lateral surfaces of the frontal lobes, the fibers in the rostrum connect the orbital surfaces of the frontal lobes, the corona radiata passes through the body of the corpus callosum, and the forceps major, passing through the splenium, connects the occipital lobes.¹ The abundant vascular supply to the corpus callosum is predominantly delivered by the pericallosal arteries and the posterior pericallosal arteries, which are branches of the anterior and posterior cerebral arteries, respectively.¹

Corpus callosum abnormalities can be explored by considering the most common diagnoses using the VINDICATE acronym (vascular, infectious, neoplastic, demyelinating, idiopathic, congenital, autoimmune, traumatic or toxic, emboli; see Table 2).² A review by Krupa and Bekiesinska-Figatowska provides a comprehensive overview of congenital and acquired causes of corpus callosum lesions.³ Based on the radiologic findings observed in SB, we considered demyelinating diseases affecting the corpus callosum, the most common of which are MS, Marchiafava-Bignami disease, progressive multifocal leukoencephalopathy (PML), acute disseminated encephalomyelitis (ADEM), and Susac syndrome.²

In MS, callosal involvement is typical and correlates with cognitive impairment observed in individuals with MS.^2,4

Marchiafava-Bignami is a rare clinical syndrome usually seen in the context of alcohol abuse and malnutrition. The course of this syndrome is variable, with patients typically presenting motor or cognitive deficits associated with dementia.^3,4 The physiopathology involves necrosis with subsequent atrophy of the corpus callosum. In SB, the MRI findings in the corpus callosum could suggest this diagnosis, but SB did not fulfill the associated clinical findings.

PML is caused by reactivation of JC polyomavirus in the setting of profound cellular immunosuppression (eg, human immunodeficiency virus infection, immunomodulatory therapy, organ transplantation) or malignancy (eg, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma). Although classic PML lesions are found extensively in the supratentorial white matter on MRI scans, symptoms are more typical of cortical involvement (eg, aphasia, cortical blindness, seizure). SB’s 2-year follow-up course is more suggestive of a monophasic or a relapsing disease than a progressive, fatal disorder, such as PML.^4,5

ADEM usually presents as a monophasic acute inflammation and demyelination of the CNS white matter, often following a viral illness or vaccination. ADEM is more prevalent in children and adolescents and has no female predilection (unlike MS). Individuals usually recover well, and MRI lesions tend to disappear over time after treatment with glucocorticoids and IVIg.³

Other transient lesions also may be observed in the corpus callosum; for example, cytotoxic lesions of the corpus callosum, such as mild encephalitis or encephalopathy with a reversible isolated lesion (MERS), and reversible splenial lesion syndrome are seen more often in the splenium. Epilepsy, antiseizure medications, and infections (eg, COVID-19) have also been associated with callosal involvement.⁵ The 2-year follow-up findings in SB allowed us to rule out these conditions.

The physiopathologic processes resulting in the classic findings of Susac syndrome (ie, encephalopathy, BRAO, sensorineural hearing loss) are thought to include autoimmune-mediated damage to the endothelial cells of the CNS microvasculature.^6,7 Neuropathologic findings corroborating this hypothesis include extensive perivascular inflammation of small arteries in the leptomeninges and brain parenchyma in individuals with Susac syndrome. An increase in effector memory CD8+ T cells, but not CD4+ cells, has been found in the CSF and peripheral blood of these individuals, which suggests a possible chronic and strong antigenic stimulus causing this T-cell population shift.^6,7

The most recognizable symptom of Susac syndrome is the acute onset of an encephalopathic syndrome characterized by mental confusion, behavioral changes, delusions, paranoid ideation, or fluctuation in level of consciousness, sometimes progressing to coma. Visual disturbances as an initial manifestation were observed in at least 50% of individuals.⁴ Other common symptoms include migraine (80% of individuals) and progressive cognitive impairment (eg, memory loss, loss of concentration, and executive dysfunction).^3,4,6 Motor and sensory syndromes and cerebellar findings, such as slurred speech and ataxia, also have been described.^3,4,6 The classic triad of encephalopathy and retinal and auditory changes is seen in only 13% to 30% of individuals at onset, leading to lack of recognition and resultant underdiagnosis.⁶ Susac syndrome may present as a monophasic, polycyclic, or chronic and continuous disease.^4,6,8 A follow-up study demonstrated that after 24 months, most individuals initially considered as presenting a monophasic course experienced a relapse of symptoms.⁹

Diagnostic investigations in Susac syndrome include brain MRI (abnormalities may be found in the white matter, meninges, or gray matter), in which the T1 sequence is crucial for detecting infarction areas in the corpus callosum (Figure 1) and in other brain areas, such as the middle cerebellar peduncles or brainstem.^4,9 BRAO can be detected using retinal fluorescein angiography, and optical coherence tomography is useful in differentiating Susac syndrome from MS.⁶ An audiogram may show unilateral or bilateral sensorineural hearing loss.^1,4,9

The European Susac Consortium established that a definitive diagnosis of Susac syndrome could be made in the presence of the 3 classic symptoms (encephalopathy, BRAO, and sensorineural hearing loss); the presence of 2 of them makes the diagnosis probable, and the absence of classic findings in the context of highly suspicious clinical presentation is sufficient to establish a possible Susac syndrome diagnosis.^4,10,11 A possible diagnosis is essential because it stimulates consistent monitoring,¹¹ as was performed in our case.

The general recommendation for treatment of Susac syndrome is IV methylprednisolone or IVIg to treat acute manifestations.¹⁰ Some guidelines also advocate an initial stratification according to severity of CNS involvement (extremely severe, severe, moderate, or mild).¹² Treatment in all cases involves corticosteroids or IVIg, but with different dosage recommendations. Some authors have suggested that plasmapheresis may be considered in the context of corticosteroid failure in extremely severe cases. Other options, such as mycophenolate mofetil, rituximab, or cyclophosphamide, are also recommended in acute refractory cases.^4,10

Immunosuppressive regimens need to be adapted according to disease severity and stability. No clear consensus on medications or their duration exists.^4,10 Our case report illustrates an individual with multiple comorbidities, and in neurology practice, individuals commonly present with multiple comorbidities. Because of our uncertainty regarding a diagnosis, we discussed the benefits and possible adverse effects related to long-term immunosuppression with SB, who decided not to pursue continuous immunosuppressive treatment. Regarding individuals with ESRD, immunosuppression regimens must be adapted accordingly; some drugs require therapeutic drug monitoring (eg, mycophenolate mofetil) or frequent dose adjustments (eg, cyclophosphamide, azathioprine), and, although methotrexate is contraindicated in individuals with ESRD, the pharmacokinetics of biologic agents (eg, rituximab) are not affected.¹³

The recommended brain MRI monitoring protocol for individuals with Susac syndrome (whether definitive, probable, or possible) involves serial MRI studies during the first 3 to 4 months after presentation of symptoms, followed by 4 to 6 months during the rest of the first year, and every 9 to 12 months thereafter, in the presence of stable lesions.¹⁰ Retinal vasculature must be monitored with serial fluorescein angiography (FA). Guidelines recommend an initial FA study, even in the absence of visual symptoms, and subsequent FA is strongly recommended, with individualized frequency. When FA is repeated, it should be compared with previous results.¹⁰ Audiograms are also part of the initial assessment and should be repeated in the context of new hearing concerns.¹⁰

Conclusions

Lesions in the corpus callosum observed on MRI scans must be investigated further, and a long list of differential diagnoses must be considered. SB, who had T1D, presented acutely with encephalopathy and MRI lesions in the callosal structures. The neurologic symptoms improved markedly after IV methylprednisolone and IVIg treatments. SB has been monitored closely for 24 months, clinically and radiologically. We and SB collectively decided against immunosuppression; nevertheless, no evidence of clinical relapse has occurred, despite maintenance of lesions in the corpus callosum—a pattern similar to that observed in radiologically isolated syndrome. Although our main hypothesis remains that this is a possible case of Susac syndrome, continuous follow-up should allow differentiation among other immune-mediated neurologic disorders, such as atypical presentations of MS or ADEM.

Key Messages

A majority of training during neurology residency occurs in the hospital setting, where neurologic evaluations are often requested for individuals with multiple clinical comorbidities presenting with new neurologic symptoms, and a crucial initial step is determining whether the symptoms are primarily neurologic or a resulting effect of systemic conditions. Imaging abnormalities in the corpus callosum may align with a wide range of neurologic manifestations, and a thorough history, physical examination, and appropriate ancillary tests must be obtained to rule out the most common etiologies (Table 2). Despite extensive investigation, a definitive diagnosis might not be reached. A possible diagnosis of Susac syndrome can be established in a highly suspicious scenario—presence of symptoms, radiological findings, the exclusion of most common pathologies, and the classic triad of encephalopathy, BRAO, and sensorineural hearing loss will not be present initially in most individuals. Despite the lack of diagnostic clarity, clinical judgment might warrant empirical immunosuppressive treatment.