A 71-year-old man with horizontal gaze paralysis, loss of speech ability, and quadriplegia, this disease must be thought of | Clinical Reasoning

Have you mastered the diagnosis and differential diagnosis of rhombohedral encephalitis? The latest issue of the Journal of Neurology Clinical Reasoning Series reported on a 71-year-old male patient with horizontal gaze paralysis, complete loss of speech and quadriplegia.

Through this case, let's learn about the differential diagnosis of rhombotic encephalitis.

The patient with medical history was a 71-year-old man with right-handed hands.
He presented to the doctor for "subacute onset of nausea, vomiting, and gait instability for 1 week".

Physical examination showed normal body temperature, blood pressure of 155/82mmHg, heart rhythm of 62bpm; ataxia on the right side, wide step base.

The head and neck CTA suggested an ischemic stroke without vascular abnormalities.

The cardiac examination was normal.

Previous non-smoking, type 2 diabetes, high blood pressure, and chronic lymphocytic leukemia (CLL) that does not require treatment.

The patient received antiplatelet therapy and risk factor control therapy.

Symptoms worsened after discharge, including intractable nausea, vomiting, weight loss, slurred speech, and loss of independent walking ability, leading to re-admission 2 weeks later.

The re-examination images indicated mild extension of the lesion.

Despite the application of antiplatelet therapy, the patient deteriorated, became speechless, could only communicate with gestures, and eventually became unresponsive except for opening his eyes.

Subsequently, the patient underwent tracheal intubation and tracheotomy, and was referred to a higher-level hospital 3 months after the first visit.

A physical examination at a higher-level hospital showed that her body temperature was normal, blood pressure was normal, and there was no meningitis.

The patient does not speak, his eyes open naturally, and he can blink; the eyeballs have normal vertical movement, can see vertical written commands, vertical saccades and tracking are normal, but horizontal movement is limited; pupils and corneal reflexes are normal, but coughing is impaired; limb spasms , No spontaneous movement, unchecked muscle strength; painful stimulation can cause upper limb extensor posture and lower limb flexion; deep tendon reflexes are active, and bilateral plantar Pap sign is positive.

Further inquiry of the medical history revealed that the patient was born in India and immigrated to Canada 40 years ago; he had no previous infectious diseases or systemic symptoms; no recent travel history, no history of tuberculosis or patient contact.

 Questions to ponder: 1.
Location diagnosis? The location diagnosis of the right limb ataxia and wide gait at the initial visit was consistent with the lesions of the ipsilateral cerebellar hemisphere shown on CT.

After the cerebellar symptoms worsened, there were new low-density foci in the middle foot of the right cerebellum (Figure 1A).

Figure 1A.
The head CT scan showed low density of the right cerebellar hemisphere with infarction of the right cerebellar midfoot (see arrow) and no supratentorial abnormalities.

 The subsequent deterioration of the nervous system and the maintenance of alertness, but complete loss of speaking ability, horizontal gaze paralysis and spastic tetraplegia, suggesting that the lesion has extended to the brain stem, especially the ventral side of the pons, which is clinically consistent with atresia syndrome.

Debrain rigidity suggests lower-level brainstem involvement.

Pontine basal lesions involving bilateral corticospinal and cortical medullary tracts can cause quadriplegia, upper motor neuron signs, oropharyngeal and facial paralysis.

Horizontal gaze paralysis and normal blinking and vertical eye movements are the result of the involvement of selective pontine circuits, including the VI cranial nerve nucleus and the parapontine reticular structure, but the dorsal side of the midbrain, which controls the vertical eye movements, is not affected.

The preservation of consciousness may be the result of the preservation of the network structure.

Head MRI showed an abnormal T2/FLAIR signal in the midfoot of the cerebellum, which extends to the junction of the cerebellum, pons, and medulla pontine (Figure 1B).

Figure 1B 1 month after the first CT, MRIT2/FLAIR of the head showed that bilateral cerebellar midfoot lesions extended to the junction of the cerebellum, pons, and pontine, with extensive abnormal high signal; these areas also have limited diffusion and no enhancement (Not shown).

Questions to ponder: 1.
What are the differential diagnoses? The gradual progress of the differential diagnosis of clinical and imaging is not consistent with the initial diagnosis of acute stroke.
This progressive brainstem involvement is more indicative of infectious, inflammatory, malignant or toxic/metabolic lesions.

Rhomboencephalitis is inflammation of the pons, medulla oblongata, and cerebellum.
The causes include infection, autoimmunity, and paraneoplastic causes.

Listeria, Enterovirus 71, and Herpes virus are the most common causes of infection.

Progressive multifocal leukoencephalopathy (PML) is caused by the reactivation of JCV.
It is usually seen in immunosuppressed patients and can lead to subtentorial lesions.

Although this patient has stable CLL and has never received immunosuppressive therapy, CLL itself may destroy innate and adaptive immunity.

Rare bacterial causes include infections such as Mycobacterium tuberculosis, Brucella, Borrelia, Salmonella, Legionella, and Mycoplasma.

In view of gastrointestinal symptoms, Whipple disease needs to be considered.
There have been reports of rhomboid encephalitis in patients with rheumatoid arthritis treated by methotrexate.

Neurobehcet's disease is the most common autoimmune disease, but the patient does not meet the typical age and demographic characteristics of neurobehcet's disease, and has no systemic symptoms such as mucosal skin ulcers, uveitis, or skin rashes.

Rhomboencephalitis has also been reported in systemic lupus erythematosus and recurrent chondritis.

Primary central nervous system vasculitis should also be considered because it can affect any part of the central nervous system.

However, this patient is unlikely, because his symptoms gradually progress with the expansion of the original lesion, and there is no enhancement, bleeding, and vascular abnormalities (such as arterial beading).

Considering age and demographic characteristics, demyelinating diseases such as multiple sclerosis (MS), optic neuromyelitis, and acute diffuse encephalomyelitis are unlikely.

Neurosarcoidosis is another inflammatory disease with various manifestations and needs to be considered.

Considering ataxia and ophthalmoplegia, Bickerstaff's brainstem encephalitis should also be considered, although the patient has no previous history of infection.

Chronic pontine vasculitis with steroid-responsive peri-pontine vasculitis (CLIPPERS) is an inflammatory syndrome of the brainstem, especially the pons, which usually manifests as punctate enhancement on imaging, which is not seen in this patient.

Paraneoplastic causes are usually related to anti-Yo, anti-Tr, anti-Hu, anti-Ri, anti-Ma, and anti-amphoteric antibodies, which need to be considered.

Taking into account the patient’s age and immunosuppression, in addition to rhombohedral encephalitis, tumorous causes (such as lymphoma or brainstem glioma) should also be considered.

Possible toxic/metabolic causes of this appearance include the brainstem variants of the reversible posterior encephalopathy syndrome (PRES) given a history of CLL, but the patient has never used immunosuppressive drugs, and the blood pressure was not at the time of presentation.
Significantly higher, so it is unlikely.

Finally, although the clinical history is not suggestive, the osmotic demyelination syndrome caused by the rapid correction of sodium usually manifests as a high signal change in the central pontine T2 and limited diffusion.

 Questions to ponder: 1.
What inspections should be performed? 2.
What treatment should I start? Treatment peripheral blood lymphocyte count is normal.

There was no abnormality in serum protein electrophoresis, rheumatology examination and inflammation markers.

The patient was treated with broad-spectrum antibiotics (including acyclovir and ampicillin) until lumbar puncture showed no significant changes in cell count (1×106/L white blood cells, 4×106/L red blood cells), protein 339mg/L and culture Negative.

The subsequent enhanced MRI of the head showed no obvious enhancement.

Lumbar puncture after referral showed normal cytology and no abnormality in JCV test.

CSF HSV, VZV and enterovirus PCR were all negative.

The serology of HIV, CMV, EBV, VZV, Brucella, Bartonella, Histoplasma capsulata and Cryptococcus was negative.

Tuberculosis interferon-γ release test was negative.

Paraneoplastic antibodies, angiotensin converting enzyme and oligoclonal bands were negative, and the IgG synthesis rate was normal.

The patient subsequently received steroid pulse therapy, intravenous immunoglobulin, and plasma exchange (PLEX) therapy, but there was no improvement.

CT scans of the chest, abdomen, and pelvis and ultrasonography of the testicles were unremarkable.

The duodenal biopsy for Whipple was negative.

EEG showed diffuse encephalopathy.

In the end, CSF detected JCV DNA, which diagnosed rhombohedral encephalitis secondary to PML.

The patient started to use mirtazapine, but despite receiving supportive treatment, the clinical and imaging conditions continued to deteriorate.

Re-examination of MRI showed that the lesions extended to the midbrain and bilateral internal capsule hindlimbs and subcortical white matter (Figure 1C).

Four months after the initial visit, the patient eventually died of respiratory failure.

Figure 1C Re-examination of MRI after 2 months showed that in addition to the increase of subcortical white matter lesions, the high-intensity lesions also extended to the midbrain and hind limbs of the internal capsule.

 The autopsy revealed extensive PML, corresponding to abnormalities in the cranial fossa area after MRI and microscopic lesions in the white matter of the frontal and parieto-occipital cortex (Figure 2).

Figure 2 Histopathological results of PML.

A) White matter macrophage infiltration; B) Abnormal morphology of astrocytes with enlarged nucleus (arrow); C) LuxolFast Blue staining shows demyelination; D) SV40 strong positive indicates active replication of polyoma virus in glial cells (arrow) .

Scale bars: 100µm (A), 50µm (BD).

 Discussion PML was first reported in 1958 in patients with CLL and Hodgkin's lymphoma.

80% of cases were found in HIV/AIDS patients in the 1980s.

In mid-2000, the application of new therapeutic monoclonal antibodies led to a second wave of PML, such as natalizumab for MS and other immunosuppressive agents for autoimmune diseases and organ transplants.

PML is rare in monitored stable CLL patients, and currently only one case has been reported.

JCV is a double-stranded DNA virus of the polyoma virus family, which is widely present in most asymptomatic individuals, and the seropositivity rate is between 33-90%.

After the initial infection, it is dormant in tissues including the kidneys, bone marrow, and possibly CNS.

The mechanism of virus reactivation is not fully understood, but immune system dysfunction is a common underlying factor that induces disease.

Therefore, it can be considered that a complete immune function can keep the virus dormant and prevent the emergence of diseases.

After activation, the infected oligodendrocytes will expand, with obvious nuclear inclusions and dissolution, resulting in the loss of myelin sheath.

The clinical manifestations of PML are diverse, and subacute focal or multifocal neurological deficits may initially be mistaken for stroke.

Symptoms and signs depend on the affected area of ​​the central nervous system.

Previous reports have shown that PML can be manifested as atresia syndrome.

Seizures can occur in 20% of patients.

PML should be considered when immunosuppressed patients have subacute progressive neurological symptoms.

CSF JCV DNA detection is the least invasive diagnostic method, with a sensitivity of 74%-92% and a specificity of 92%-100%.

MRI can sensitively display typical bilateral, diffuse, and confluent T2 hyperintensity white matter lesions.

The lesion is usually unenhanced and may have limited diffusion.

There is currently no direct anti-JCV therapy, and the clinical outcome depends on the recovery of immune system function or immune reconstitution.

If possible, stopping immunosuppressants and using antiretroviral therapy against HIV are the key to treatment.

PLEX has been used in MS patients secondary to natalizumab with PML.

Within the first three months of diagnosis, PML is still incurable, the mortality rate is high, and the prognosis is poor due to increased CSF viral load and involvement of key central nervous system regions (such as the brainstem).

 Original Index: IkreetCheema, Nicole Ng and Tychicus Chen.
Clinical Reasoning: A 71-year-old Malewith Horizontal Gaze Palsy, Anarthria, and Quadriparesis.
Neurology publishedonline April 14, 2021.
DOI 10.
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