Acute and Chronic Anti-ganglioside Neuropathies: From Theory to Practice in Buenos Aires, Argentina
Keywords: Anti-ganglioside neuropathies, CANOMAD, Miller Fisher syndrome
Gangliosides are complex molecules resulting from combining one or more sialic acids, a ceramide and an oligosaccharide.,, In humans, they are highly concentrated both in the peripheral and Central Nervous System, although their pathological involvement usually results in peripheral neurological syndromes, commonly polyneuropathies.,
Among gangliosides, a family is characterized by sharing a disialosyl group linked to the internal galactose and antibodies against them have been described in patients with the particular features of ophthalmoparesis and/or ataxia.
In the past decades, different combinations of antibodies and epitopes (ganglioside complexes) have been reported and associated with particular phenotypes., However, there is no current evidence clarifying if these antibodies are pathogenic or bystanders to the underlying process.,
Nevertheless, their characterization is not always available in the clinical practice during patient diagnosis or even follow-up, which highlights the need to recognize the described clinical phenotypes.
We present two patients with an acute and chronic presentation of anti-ganglioside polyneuropathy diagnosed during 2017 in our department along with a review of the literature which we consider can contribute to this purpose.
A 70-year-old man was admitted to our emergency department complaining of nasal voice and gait ataxia since awakening. He had a history of hypertension, acute myocardial infarction, right retinal infarct with residual low visual acuity and dyslipidaemia. On neurological exam, he had bilateral palatal palsy and a widen base of support during gait with brisk reflexes and no other findings at his neurological exam. His laboratory, head CT and lumbar puncture showed no acute pathology. The following day, he developed left incomplete ptosis, absent deep tendon reflexes, and hours later, lateral gaze palsy and he was transferred to the Intensive Care Unit with the diagnosis of Miller Fisher Syndrome. His electromyogram during the second day had no acute signs of neuropathy and lumbar punctures at 10th and 14th days showed no albuminocytological dissociation. During the third day of symptomatology, he added complete bilateral external ophthalmoplegia, distal hypopalestesia, areflexia and generalized weakness, requiring orotracheal intubation due to inappropriate management of airway secretions and mild respiratory deterioration and he was treated with 140 grams of intravenous gammaglobulin. He had a subacute complete recovery in 3 months. His second electromyogram (day 40 after symptom onset) showed a demyelinating sensorimotor polyneuropathy of the four limbs with mild spontaneous muscular activity limited to his right tibialis anterior muscle. He had GM1, Gq1b and GT1a positive total antibodies (negative GM2/GM3/GM4/GD1a/GD1b/GD2/GD3/GT1b).
A 63-year-old man consulted our department referring a 20-year history of distal feet hypoesthesia that evolved to gloves and stockings distribution. Four years later, he developed intermittent diplopia, unilateral ptosis and sensory ataxia. He had a history of hypertension and acute myocardial infarction. Pathological findings at neurological examination included right fatigable ptosis, 30 seconds evoked diplopia, four limb areflexia, medical research council strength scale 4 + at feet dorsiflexion, diminished pinprick and temperature sensation on hands and feet with absent vibration and joint position sensation at his toes and severe sensory ataxia with a tabetic gait. His complimentary exams included a laboratory with IgM monoclonal gammopathy (663 mg% by immunoturbidimetry, normal value: 22-240), negative anti-MAG antibodies, normal CPK blood levels, negative AChRA (radioimmunoassay), negative repetitive nerve stimulation and a severe sensorimotor demyelinating polyneuropathy with mild spontaneous activity in his electromyography. He had been diagnosed with sensory-motor demyelinating neuropathy with GM1 antibodies and later with relapse-remitting CIDP. His symptomatology difficulted but did not impaired his daily life activities and he had been treated with plasma exchange, azathioprine (2 mg/kg), cyclophosphamide and intravenous immunoglobulin with moderate and transitory improvement of his ataxia with the latter. Further examinations were performed which included a positive cold agglutinins test (1/128 with a normal value up to 1/64) and pathological anti-ganglioside antibodies panel with positive GD1a, GD1b and GQ1b total antibodies besides the already known GM1 (negative GM2), therefore diagnosing a Chronic ataxic neuropathy with ophthalmoplegia, IgM paraprotein, cold agglutinins and disialosyl antibodies (CANOMAD). His symptomatology is nowadays stable under treatment with intravenous immunoglobulin every 6 months.
As it has already been stated, neurological anti-ganglioside pathologies involve the peripheral nervous system (both acute and chronic presentations) and eventually, like in Bickerstaff encephalitis, specific targets in the CNS.
The most common phenotype of acute neuropathy is symmetrical flaccid areflexic weakness associated with non-disabling distal paresthesia or lumbar pain also known as Gillain-Barré Syndrome (GBS).,, The physiopathological presentation distinguishes two forms: demyelinating (Acute Demyelinating polyneuropathy or AIDP) and axonal (Acute Motor Axonal Neuropathy or AMAN), with the latter usually having more severe weakness, worst prognosis and a moderate association with antibodies against GM1 ganglioside and a preceding Campilobacter Jenuni infection.,,
The most common variant (5-10% of cases) is the Miller Fisher Syndrome (MFS) which classically presents with the triad of ophthalmoplegia, ataxia and areflexia, generally with rare respiratory involvement and a good prognosis.,,,, Anti-GQ1b antibodies are usually present and nowadays considered to be diagnostic in the correct clinical setting.,,,
The infrequent Bickerstaff brainstem encephalitis accounts for the today known example of CNS involvement in ganglioside pathology. There is doubt as to whether it is not actually the full spectrum of the MFS rather than an independent entity because it commonly shares the same clinical features of the MFS with the addition of consciousness impairment and pyramidal involvement.,
The first patient (CASE 1) developed a mixed peripheral clinical syndrome as it started as an MFS with lower cranial nerve involvement but evolved to severe quadriparesis and respiratory failure like in GBS, which is now known as MFS-GBS overlap syndrome. His speedy and complete recovery (like in classic MFS,,,) helped to distinguish it from GBS with bulbar and ophthalmologic involvement. However, during the first day of hospitalization the acute installation of symptoms and his normoreflexia made topography determination (and therefore etiology discrimination) difficult. Moreover, initial complimentary examinations yield no aid and it was his clinical evolution with the addition of ophthalmoparesis and areflexia that allowed diagnosis making. As already published, we found no initial or late albuminocytological dissociation and the anti-ganglioside panel result was available after the first week of hospitalization, when the patient had already been diagnosed and was being treated and monitored in the Intensive Care Unit.
With regards to chronic pathologies, two entities account for the majority of cases: Multifocal motor neuropathy (MMN) and CANOMAD.,
MMN is a multifocal motor demyelinating neuropathy with a typical onset in upper limbs and subacute progression. It is widely known mostly because it is the principal treatable differential diagnosis to Amyotrophic lateral sclerosis in patients presenting without initial pyramidal involvement.
As the name states, CANOMAD affected patients usually develop a disabling gait and limb ataxia disproportional to any sensory deficit, along with areflexia and most commonly a relapsing evolution.,, Although being an infrequent adult pathology, the presence of ophthalmoplegia and ataxia should be red flags to consider this diagnosis,,, bearing in mind that ocular signs and symptoms and cold agglutinins are the most common features not to be present. It has been hypothesized that the IgM paraprotein present (that has been demonstrated to bind to gangliosides) can explain the chronic course of this entity.
The second patient (CASE 2) had been followed without diagnosis for over 15 years. There is actually no consensus regarding first and second line treatments for CANOMAD, and luckily the patient did not deteriorate with any of the received ones. Nevertheless, accurate diagnosis helps to improve the general knowledge of the disease and ameliorates the anguish associated with diagnosis uncertainty, making a 15-year delay in diagnosis, not the recommended scenario.
Laboratory method and nomenclature
There is actually no consensus regarding the best laboratory method for ganglioside antibodies detection. In Buenos Aires, Argentina, the widest used methods are line immunoassay (LIA), which was used for antibody detection in the first patient (CASE 1) or enzyme-linked immunosorbent assay (ELISA), which was used for antibody detection in the second patient (CASE 2). Anti-ganglioside complex antibodies are not available for clinical analysis in Argentina and some laboratories only measure total antibodies (IgM plus IgG, without discriminating between one or the other).
The ganglioside to which antibodies react is commonly named based on the chromatography migration. The starting G stands for “ganglio-series ganglioside” to distinguish them from other glycosphingolipids such as lacto, arthro, etc. M, D and T imply that a mono-di ant tri-sialosyl groups are present (A for none, Q for quatri, P porpenta, H for hexa and so on). Generally but not always, “b” implies the presence of a disialosyl group linked to the internal galactose. The disialosyl subgroup includes GD1b, GD2, GD3, GT1a, GT1b and GQ1b gangliosides.
All the known gangliosides and the frequently affected in neurological syndromes,, are shown in [Table 1], with the disialosyl subgroup in bold.
Anti GQ1b antibodies (IgG isotype), are found in approximately 90% of the MFS cases,, and frequently cross-react with GT1a antibodies., The GQ1b ganglioside is believed to be located at the dorsal root ganglion and paranodal myelin of the III, IV and VI cranial nerves,,, which could account for the phenotype of ophthalmoplegia seen in MFS, BBE and GBS with ophthalmoparesis, to which it has also been associated.
Anti GT1a antibodies (IgG isotype), as it has already been stated, usually cross-react with anti GQ1b antibodies. They have been described in a clinical variant with bulbar involvement (pharyngeal-cervical-brachial) as well as acute and chronic ataxic neuropathies.,
Anti GM1 antibodies (IgM isotype for MMN or IgG subtype for AMAN) are associated with predominantly motor neuropathies, and occasionally with ophthalmoplegia. Their localization is controversial although some studies reported a higher concentration in ventral roots of the spinal nerves in comparison with dorsal roots, which could explain the reported phenotypes.,
Anti GM2 antibodies (Ig M and IgG isotypes) have been associated with AIDP in context with CMV infections.
Anti GD1a antibodies (IgG isotype), are associated with the AMAN variant of GBS.
Anti GD1b antibodies (IgM isotype) have been found in MMN, GBS and cases with ophthalmoplegia. Their localization is uncertain, but there is some evidence pointing to a dorsal root ganglion localization.
Anti GD2 and GD3 antibodies (IgM isotype) have been described in association with acute, and chronic ataxic neuropathies.,
Moreover, recent publications, report antibodies against ganglioside complexes, that not necessarily react with individual gangliosides. Furthermore, there have also been described antibodies against the combination of gangliosides and other complex molecules, although no clinical associations have been reported so far.
The first patient (CASE 1) had positive total antibodies against GM1, GQ1b and GT1a. Anti-ganglioside antibody class discrimination (IgG or IgM isotype) is available in Buenos Aires but due to the fact that there is no practical benefit for their differentiation, it is not routinely performed. His clinical evolution was in line with his typification: GQ1b and GMI antibodies accounting for the MFS and GBS phenotypes and GT1a antibodies cross reacting with GQ1b or more likely associated with his bulbar weakness.
The second patient (CASE 2) had positive total antibodies against GM1, GD1a, GD1b and GQ1b. Anti-disialosyl antibodies like GD1b and GQ1b are commonly associated with this pathology, as well as the non disialosyl ganglioside GD1a. Nevertheless, we found no report in the literature of CANOMAD or ataxic neuropathies associated with GM1 antibodies. Furthermore, our patient has no relevant weakness to account for the GM1 antibodies presence although his electromyogram had severely diminished CMAP amplitudes with left ulnar nerve 0.4 mV, right median nerve 0.1 mV, left peroneal nerve 1 mV and left tibial posterior nerve 0.3 mV as examples.
We advocate that a meticulous medical interview and thorough neurological exam remain to be the key features in neurological diagnosis. Nevertheless, differential diagnosis making should be revised with the newest information available, even if it is not readily accessible for clinical practice. Bearing that in mind, anti-ganglioside antibody characterization is a constantly evolving field that we strongly believe should be present in academic updates. In our particular case, both diagnoses were serologically confirmed, but we recommend anti-ganglioside pathology to be considered when hallmark findings such as ophthalmoparesis or gait ataxia are associated with polyneuropathy both in acute and chronic presentations.
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