From ophthalmoplegia to brainstem encephalitis

Being able to recognize disease is human nature, and being able to recognize it is an attribute of
disease itself.

Ophthalmoplegia is a common clinical symptom and sign in neurology, mainly manifested as ptosis, diplopia, eye movement disorders and pupillary changes, which can occur in the cerebral cortex, brainstem, cavernous sinus and supraorbital fissure to any part of the orbit, divided into subnuclear peripheral, nuclear, internuclear and supranuclear ophthalmoplegia, wherein, because the supranuclear pathway is innervated by bilateral cerebral cortex, and the cerebral cortex innervates the eye coordinated movement, so supranuclear ophthalmoplegia is only manifested as synergistic movement disorder, that is, gaze paralysis
。 In 1951, Bickerstaff and Cloake reported 3 cases of patients with ophthalmoplegia, ataxia, impaired consciousness and a series of central nervous system symptoms as the main manifestations, which immediately aroused the attention of clinicians to such diseases, and with subsequent in-depth research, Bickerstaff proposed the concept
of "brainstem encephalitis" in 1957.

Brainstem encephalitis refers to the inflammatory response that occurs in the brainstem, is a manifestation type of sporadic encephalitis, mainly invades the brainstem, can also involve its adjacent tissues, mostly acute or subacute onset, mainly manifested as acute ophthalmoplegia, ataxia, consciousness impairment and a series of central nervous system symptoms, most patients have a good
prognosis.
In the diagnostic criteria for autoimmune encephalitis proposed by Graus in 2016, brainstem encephalitis has once again attracted the attention
of clinicians as an important differential diagnosis disease.

As early as 1951, Bickerstaff and Cloake reported 3 patients with lesions mainly invading the brainstem, but also involving bilateral cerebral hemispheres, and after active medical treatment, the prognosis of the patients was good; According to the clinical features of acute onset, unipolar course and complete recovery of such diseases, after ruling out cerebrovascular disease, central nervous system tumors, metabolic diseases and toxic diseases, the disease is considered to be caused by poliovirus infection, and named encephalitis and rhombusiveencephalitis
according to the site of involvement.

In 1956, Fisher reported that three patients with acute extraocular muscle paralysis, ataxia, and the "triad" of loss of tendon reflexes had cerebrospinal fluid protein-cell dissociation, and this "triad" was later named Miller-Fisher syndrome (MFS).

。 In 1957, Bickerstaff reported 5 more patients with the same clinical manifestations, and performed autopsy on one of them, only brainstem edema but no inflammatory cell infiltration, lymphocytic infiltration around the portal vein, combined with the clinical characteristics of acute onset and unipolar course, considered as a marginal disease of acute infectious polyneuritis, and named this disease manifested as acute symmetric extraocular muscle paralysis, ataxia, impaired consciousness and/or pyramidal sign as brainstem
。

In 1966, Maran isolated herpes simplex virus (HSV) from a patient with brainstem encephalitis, but its clinical manifestations did not match herpes simplex virus encephalitis (HSE), so it was considered that brainstem encephalitis was not related to herpes simplex virus encephalitis
.
In 1972, Dayan et al.
reported 2 cases of brainstem encephalitis caused by herpes simplex virus infection, and early antiviral therapy was effective
.
It was not until 1978 that Bickerstaff again elaborated on such diseases, pointing out that the cause was not only herpes simplex virus infection, and named it Bickerstaff brainstem encephalitis; They also proposed that it may be a subtype of
Guillain-Barré syndrome (GBS) based on its clinical features of acute onset, unipolar course, simultaneous involvement of the central and peripheral nervous systems, and good prognosis.

In 1982, Al-Din et al.
conducted a comprehensive analysis of the head CT, electroencephalogram and pathological results of 18 patients with Bickerstaff brainstem encephalitis, overturning Biekerstaff's previous conclusion, that is, denying that the disease is one of the subtypes of Guillain-Barré syndrome, believing that it is caused by upper respiratory tract infection caused by viruses, and then forming a secondary immune response centered on the brainstem, but unfortunately, relevant immunological studies
have not been conducted.

In 1992, Chiba et al.
first discovered Miller-Fisher syndrome-specific antibodies, that is, anti-GQlb antibodies
, in the process of determining serum anti-glycolipid antibodies in 6 patients with Miller-Fisher syndrome by enzyme-linked immunosorbent assay (ELISA) and thin-layer chromatography (TLC).

In 1993, Yuki et al.
found that serum anti-GQlb antibody positive only exists in Bicherstaff brainstem encephalitis patients with long beam signs, and ophthalmoplegia and ataxia rapidly appear during the course of the disease, and the anti-GQlb antibody titer fluctuates with the condition, and the anti-G01b antibody is a specific antibody for Miller-Fisher syndrome, so it is believed that the two may belong to the same autoimmune disease, and named it Fisher-Bickerstaff syndrome
。

Miller-Fisher syndrome and Bickerstaff brainstem encephalitis have a similar history of prodromal infection, common autoimmune antibodies and pathogenesis, similar clinical manifestations, and are closely related to Guillain-Barré syndrome, indicating that the two have continuity and are part of the same autoimmune disease spectrum of
the central nervous system and peripheral nervous system.

In 2001, Odaka et al.
simultaneously detected anti-GQlb antibodies in the serum of patients with Miller-Fisher syndrome, Bickerstaff brainstem encephalitis, Guillain-Barré syndrome and acute ophthalmoplegia, and the clinical features of the four groups of diseases overlapped, considering that they had the same autoimmune pathogenesis, thus proposing the concept of
"anti-GQlb IgG antibody syndrome" 。 The proposal of this concept is conducive to understanding the continuous disease spectrum with the same etiology and different clinical manifestations, and the positive serum anti-GQlb antibody plays an important role in the diagnosis of such disease spectrum, but the pathogenesis of each subtype of anti-GQlb lgG antibody syndrome has not been fully elucidated, and the pathogenesis of such disease spectrum needs to be further studied to find more effective diagnostic commonalities
。 And Miller-Fisher syndrome also has the unique cerebrospinal fluid protein-cell separation phenomenon of Guillain-Barré syndrome, but patients who do not see protein-cell separation in cerebrospinal fluid examination in the early stage of onset still cannot exclude Miller-Fisher syndrome, which further proves the need to
find diagnostic commonalities.

At present, the pathogenesis of brainstem encephalitis is not very clear, and combined with its clinical features, it should be differentiated from the following diseases:

(1) Hormone-responsive chronic inflammatory lymphocytic pontine perivascular enhancement (CLIPPERS):

It is an inflammatory or immune disease of the central nervous system whose etiology and pathogenesis are not yet clear, and the clinical manifestations are relief disorders, diplopia, facial paresthesia, dysarthria, intention tremor, pseudobulbar palsy (such as forced crying, forced laughter), abnormal taste, numbness of the tongue, and manifestations of spinal cord injury (such as paraplegia, quadriplegia, sensory plane, and urinary and defecation disorders
).
Typical MRI shows diffuse symmetrical punctate or curved enhancement (pepper-like) of the pons on T1WI contrast and slightly or moderately elevated signal
on T2WI or FLAIR imaging.
After high-dose hormone pulse therapy, its clinical symptoms and imaging manifestations improved
rapidly.

(2) Neuromyelitis optica spectrum diseases (NMOSDs):

In 2015, Wingerchuk et al.
proposed new diagnostic criteria for neuromyelitis optica spectrum disease, the core symptoms include: 1.
optic neuritis; 2.
acute myelitis; 3.
symptoms of the extreme posterior area of the brain (ie, episodic hiccups, nausea, vomiting, and cannot be explained by other reasons); 4.
Acute brainstem syndrome; 5.
Symptomatic narcostatic sleepiness or acute diencephalopathy with MRI manifested as typical diencephalopathy of neuromyelitis optica spectrum disease; 6.
Brain syndrome with MRI manifested as typical brain lesions
of neuromyelitis optica spectrum disease.
Brainstem involvement can also present with clinical manifestations similar to brainstem encephalitis, and serum aquaporin 4 (AQP4)-specific antibody NMO-IgG and MRI of the head and spine should be completed to confirm the diagnosis
.

(3) Autoimmune encephalitis:

Generally refers to a group of diseases caused by immune responses to central nervous system antigens, with clinical manifestations mainly acute or subacute seizures, cognitive dysfunction and psychiatric symptoms; Characteristic pathological changes are that inflammatory cells dominated by lymphocytes infiltrate the brain parenchyma and form a "sleeve" like structure around the blood vessels; There are also features
that are difficult to detect viral antigens, nucleic acids, and inclusion bodies.
Some brainstem lesions of autoimmune encephalitis are difficult to distinguish from brainstem encephalitis on radiography, and differential diagnosis should be paid attention to, and serum and/or cerebrospinal fluid specific antibody testing should be performed as soon as possible to confirm the diagnosis
.

(4) Others:

Other diseases involving the brainstem, such as cerebrovascular disease (brainstem infarction, internal carotid-basilar venous plexus fistula, etc.
), demyelinating diseases [multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), etc.
], paraneoplastic syndrome (PNS), chronic inflammatory diseases [sarcoidosis, lymphoma-like granuloma and non-Langerhans cell histiocytosis (NLCH), neuro-Behcet's syndrome (NBS), etc.
], neoplastic diseases (lymphoma, glioma), infectious diseases [ Mycobacterium tuberculosis infection, Treponema pallidum (TP) infection, adenovirus infection, histoplasmosis, blastomycosis, coccidioidomycosis, etc.
)

Brainstem encephalitis is clinically rare, and its clinical manifestations often overlap with Miller-Fisher syndrome and Guillain-Barré syndrome, and differential diagnosis is difficult, but most of the anti-GQlb antibodies
can be detected in serum.
At present, the pathogenesis of various diseases has not been fully elucidated, and further research is needed to find the common characteristics of such diseases and further clarify the nature of
diseases.