A 66-year-old female presents with progressive encephalopathy and bilateral hearing loss in clinical reasoning

How is the diagnosis and differential diagnosis of patients with rapidly progressive cognitive changes and hearing loss? The latest issue of the journal Neurology reported a 66-year-old woman with progressive encephalopathy and bilateral hearing loss, let's
take a look at the clinical reasoning process of the case.

Translation: Reflections without a trace

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Part I

The patient is a 66-year-old woman who was previously healthy and presented with "acute cognitive changes for 3 days
.
" The patient presents with aimless, aggressive, and speech incomprehensibility for 3 days
.
Physical examination shows cognitive decline, agitation, and inability to execute commands, but no signs of weakness, dysarthria, sensory loss, vision loss, or meningitis
.
Vital signs and laboratory tests, including complete blood count, metabolic kit, urinalysis, and urine poison screen, are normal
.

Question Thinking:

1.
Location diagnosis?

2.
What are the differential diagnoses?

3.
What tests should be performed?

Part II

Envisional signs without focal signs of encephalopathy can be localized to the cerebral hemispheres
.
Differential diagnoses include metabolic, toxic, infectious, inflammatory, neoplastic, vascular, or epileptic causes
.
Initial examination should include head CT, head MRI, cerebrospinal fluid (CSF), and electroencephalography
.
CT of the head shows a 5 mm size low-density lesion on the left temporal roof with surrounding edema bands, suspected of bleeding
.
MRI enhancement of the head shows bilateral multifocal subcortical edema and punctate cortical hemorrhage involving the insula, anterior central gyrus, parietal, and lateral temporal lobes
.
CSF showed 3 white blood cells/mL (normal 0-5/mL), glucose 74mg/dL (normal 50-80mg/dL), protein 49mg/dL (normal 15-60mg/dL).

24-hour EEG shows diffuse slow waves
.
Autoimmune encephalitis was considered in the hospital, steroids and IVIg were given, and the patient was discharged after
cognitive improvement.

Four weeks later, the patient presented again presenting with an episode of encephalopathy with bilateral severe hearing loss
.
Physical examination reveals bilateral cortical dysfunction, Glasgow coma score of 11, marked startled myoclonus in the distal extremities, and inability to follow commands
.
Except for severe bilateral hearing loss, no obvious abnormalities in cranial nerves; Lower extremity muscle tone is increased, and tingling in the extremities can be seen as retraction
.

Question Thinking:

1.
What is the localization of acute/subacute hearing loss?

2.
What additional tests should be considered?

3.
What is included in the differential diagnosis at this time?

Part III

Hearing loss includes conductive (damage to the outer or middle ear) and sensorineural (damage to the cochlea, cochlear nerve, or central auditory pathway).

The afferent central auditory pathway begins in the cochlear nucleus and projects to the contralateral superior olive nucleus and lateral colliculus, hypocollius, then the medial geniculate, and finally the temporal primary auditory cortex
.
Given the acute onset of bilateral hearing loss, the likelihood of conductive hearing loss is low
.
The patient does not have any history of taking ototoxic drugs, so ototoxic deafness is unlikely
.

Patients presenting with encephalopathy and acute/subacute hearing loss may be seen in Susac syndrome, intravascular lymphoma, primary central nervous system vasculitis (PACNS), and schwannomas
.
MRI contrast scan of the head showed a strengthening lesion in the right primary auditory cortex, no reinforcement of the cochlear nerve and cochlea, and hyperintense changes in the FLAIR pathway of the left upper olive nucleus and left auditory thalamic cortex, suggesting cortical hearing loss (Figure 1).

。 Except for glutamate decarboxylase 65 (GAD65) antibody level of 0.
03 nmol/L (normal value< 0.
02 nmol/L), other CSF tests (including lymphoma cytology, RT-QuIC test, ACE test for schwannoma, demyelinating disease and schwannoma oligoclonal band test, autoimmune/paratumor test
) were negative.
48-hour EEG assessment shows diffuse slow waves without delta waves
.

Fig.
1 MRI image
of the patient's skull.
A-C: DWI images of the first (A), second (B), and third (C) hospitalization show progression of diffuse restriction lesions, eventually involving both frontal, bilateral parietal, right occipital lobes, and right cerebellar hemispheres
.
D-F: T2/FLAIR images of the first (D), second (E), and third (F) hospitalizations show subcortical hyperintensity affecting mainly bilateral frontopietal, insula, and lateral temporal lobes, progressing to bilateral rectangular gyrus, bilateral frontal parietal area, right frontal lobe, right insular lobe, right temporal lobe, right occipital lobe, and right cerebellar hemisphere
.
G-I: T1-enhanced images of the first (G), second (H), and third (I) hospitalization show progression of the intensive lesion, eventually involving bilateral rectangular gyrus, bilateral frontal parietal area, right frontal lobe, right insula, right temporal lobe, right occipital lobe, and right cerebellar hemisphere
.

Question Thinking:

1.
Given the neuroimaging findings, what else is the differential diagnosis?

2.
What further assessments are required?

Part IV

Given bilateral hearing loss and MRI findings, consideration of Susac syndrome is likely in this patient
.
However, MRI does not show typical "snowball" lesions
.
Head and neck CTA is normal, and PACNS is unlikely
given the absence of headache and focal deficits.
Given the absence of ACE and the absence of systemic manifestations of sarcoidosis in CSF, sarcoidosis is less
likely.
Ophthalmology did not reveal any ocular manifestations
suggestive of arteriolar vasculitis.
Given the patient's previous response to hormones, he was given another 5-day intravenous steroid treatment, and with treatment, his feelings improved
.
Reading, writing, comprehension are normal, and fluent speech, but hearing does not improve
at discharge.

After 5 weeks, the patient's cognitive abilities decline, manifested by disorientation, sluggishness, and restlessness
.
Repeat MRI enhancement showed that T2/FLAIR hyperintense lesions were progressing with abnormal enhancement.
New T2/FLAIR hyperintense lesions with hemosiderosin deposition
appear in the right cerebellar hemisphere.
Fluorescein angiography was performed in ophthalmology and found no arterial occlusion, vasculitis, vitreous plaques, or arteriole lesions suggestive
of Susac syndrome.

Based on the current results, patients are more likely to consider lymphoma
.
Given recent steroid sessions and lack of skin manifestations, the patient did not undergo a skin biopsy
.
Brain biopsy of the right frontal enhanced region is consistent with intravascular large B-cell lymphoma (figure 2).

The patient received high-dose methotrexate, but cognitive performance continued to deteriorate, and he died
within a month of diagnosis.

Fig.
2 Brain biopsy showing intravascular lymphoma cells consistent with IVLBCL diagnosis
.
Immunohistochemical staining (A) and H&E staining (B) showed CD20 positivity, showing prominent nucleoli in intravascular large lymphoma cells and edema in surrounding brain tissue, both of which confirmed diffuse large B-cell intravascular lymphoma
.

discuss

Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype
of large cell lymphoma.
Much of what is known about IVLBCL comes from case reports and small case series
.
IVLBCL is associated with a high
mortality rate if not treated promptly.

Specific molecular features help distinguish IVLBCL from typical large B-cell lymphoma
.
IVLBCL cells express molecules involved in cell migration and adhesion to the endothelium, but lack molecules involved in external invasion
.
Lymphocyte proliferation confined to the lumen of small vessels leads to multiple clinical manifestations of IVLBCL and is challenging to diagnose
.
Symptoms of IVLBCL include fever, night sweats, and weight loss, and involve organs
such as the skin, central nervous system (CNS), peripheral nervous system, spleen, liver, and kidneys.
The most common symptoms are usually related
to central nervous system (39-76%) and cutaneous (17-39%) involvement.
Symptoms of IVLBCL can also be caused
by arteriolar microinfarction.
Previous cases of IVLBLC presenting as Susac have been reported
.

The diagnosis of IVLBCL is based on the identification of large lymphoma cells in small vessels of affected tissue
.
In patients with cutaneous and central nervous system involvement, skin biopsy
should be considered prior to brain biopsy, given that surgery is less invasive.
The effectiveness of skin biopsy was confirmed in a study of 16 patients with suspected IVLBCL with a positive predictive value of 100%, but low soluble interleukin-2 receptors and prediagnostic steroid use may result in false-negative results
.
Common image findings include SWI sequence abnormalities and absence or change of T2/FLAIR sequences, both in this patient
.
Lumbar puncture is not helpful in diagnosis, and common cerebrospinal fluid findings are neither sensitive nor specific
.
Although lymphoma cells have been found in the intracranial vascular system, lymphoma cells
are rarely found in patients with only IVLBCL neurological findings on serum or cerebrospinal fluid cytology.
Serial lumbar punctures may increase the sensitivity
of cytology to detect lymphoma cells.

The mainstay of treatment for IVLBCL with central nervous system involvement is combination therapy with methotrexate (MTX)-based intrathecal chemotherapy and R-CHOP
.
Intrathecal MTX may also be used for prophylaxis
in patients with no central nervous system involvement at diagnosis.
Central nervous system involvement at diagnosis has a poor
prognosis.
Patients with isolated skin involvement have a better response to treatment and higher survival rates
.
In a meta-analysis of case reports, case series, and retrospective studies, including patients with and without central nervous system involvement, chemotherapy containing rituximab (typically 6 cycles) prolonged survival (450 days versus 180 days).

However, patients with central nervous system involvement rarely achieve long-term remission
after R-CHOP.

This case is a reminder to us that attention is needed for this rare lymphoma
.
Early diagnosis and initiation of treatment with appropriate skin or brain biopsy may lead to better outcomes
.
This case differs from previous reports of initial recurrence and eventual progression to encephalopathy with acute onset of persistent bilateral sensorineural hearing loss without any other systemic manifestations
.