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Variants of Guillain-Barre Syndrome

Several variants of GBS are recognized. These disorders share similar patterns of evolution, recovery, symptom overlap, and probable immune-mediated pathogenesis.

  1. The Miller-Fisher syndrome is a common variant of GBS and is observed in about 5% of all GBS cases. The syndrome consists of ataxia, ophthalmoplegia, and areflexia. Ataxia primarily is noted during gait and in the trunk with lesser involvement of the limbs. Motor strength characteristically is spared. The usual course is one of gradual and complete recovery over weeks to months. A close association exists between antiganglioside antibodies and the Fisher variant. Anti-GQ1b antibodies, triggered by certain C jejuni strains, have a relatively high specificity and sensitivity for the disease. Dense concentrations of GQ1b ganglioside are found in the oculomotor, trochlear, and abducens nerves, which may explain the relationship between anti-GQ1b antibodies and ophthalmoplegia.
  2. The acute motor axonal neuropathy (AMAN) variant is associated closely with enteric C jejuni infections and high titers of antibodies to gangliosides (GM1, GD1a, and GD1b). Patients with AMAN have pure motor symptoms and appear clinically very similar to patients with the demyelinating form of GBS with ascending symmetric paralysis. AMAN is distinguished by electrodiagnostic study results that are consistent with a pure motor axonopathy. Biopsies show Wallerian-like degeneration without significant lymphocytic inflammation. Many cases have been reported in rural areas of China, especially in children and young adults during the summer months. Pure axonal cases may occur more frequently in other parts of the world outside Europe and North America. AMAN cases also may be different from cases of axonal GBS described in the West. Prognosis is often quite favourable and recovery is rapid.
  3. The axonal form of GBS, also referred to as acute motor-sensory axonal neuropathy (AMSAN), often presents with rapid and severe paralysis with delayed and poorer recovery compared to the electrophysiologically similar AMAN cases. Like AMAN, axonal GBS also is associated with preceding C jejuni diarrhea. Pathologic findings show severe axonal degeneration of motor and sensory nerve fibres with little demyelination.
  4. A pure sensory variant of GBS has been described in the medical literature, typified by rapid onset of sensory loss and areflexia in a symmetric and widespread pattern. Lumbar puncture studies show albuminocytologic dissociation in the cerebral spinal fluid (CSF) and electromyography (EMG) results show characteristic signs of a demyelinating process in the peripheral nerves. Prognosis is generally good, but immunotherapies, such as plasma exchange and intravenous immunoglobulins (IVIG), can be tried in patients with severe disease or slow recovery.
  5. Acute pandysautonomia without significant motor or sensory involvement is a rare presentation of GBS. Dysfunction of the sympathetic and parasympathetic systems results in severe postural hypotension, bowel and bladder retention, anhidrosis, decreased salivation and lacrimation, and pupillary abnormalities.
  6. The pharyngeal-cervical-brachial variant is distinguished by isolated facial, oropharyngeal, cervical, and upper limb weakness without lower limb involvement. Other unusual clinical variants with restricted patterns of weakness are observed only in rare cases.
  7. MUTIFOCIAL MOTOR NEUROPY (MMN) MMN is a curious chronic demyelinating neuropathy that differs from CIDP in two important respects. First , the demyelination is restricted to motor axons – those that control the muscles. Therefore, MMN patients have weakness but no numbness, tingling or pain. Second, the demyelination is very patchy, affecting nerves in a seemingly random pattern and affecting only very short segment of the nerves. Therefore, the weakness only affects a few muscles. Like CIDP, this demyelination is thought to be immune mediated. The most obvious effect of this motor nerve demyelination is weakness, although the initial symptoms, at least in retrospect, may be muscle cramps or muscle twitching (called fasciculations). Most patients also develop muscle atrophy (wasting). The symptoms develop very slowly and usually progress over many years. Patients often do not seek medical advice until they have had the disease for 10 years or more. They may be completely unaware of muscle weakness in some areas and seek medical advice only when important functions, such as hand function, are affected. One of my patients had virtually complete paralysis of the biceps muscle and had subconsciously developed trick movements to bend his elbow, and he remained completely unaware of that weakness until the hand became weak and he could no longer manipulate his nail clippers. Another curious feature is that the weakness is most often worse in the arms and hands, whereas most neuropathies including CIDP, mainly affect the legs. The development of weakness, muscle atrophy, and fasciculations led to several patients with MMN being diagnosed with amyotrophic lateral sclerosis (Lou Gehrig’s disease). Distinguishing MMN for Lou Gehrig’s is critically important since MMN is a benign disease and is treatable, whilst Lou Gehrig’s disease is always fatal and has no treatment. Peripheral nerves in patients (with Lou Gehrig’s) may be endangered enough to feel on clinical examination or enlargement can be seen with magnetic resonance imaging (MRI scan). On rare occasions, the enlargement may be so striking that it is thought to be a tumour. One of my patients developed a large swelling above the clavicle (collar bone) that was thought to be a tumour. The “tumour” was removed and found to be a hugely enlarged nerve. Similar nerve enlargement can be seen in CIDP but it is much less common.

How is MMN Diagnosed?

Electrodiagnostic Testing (EMG)

As with CIDP, the diagnosis of MMN rests on the nerve conduction studies. When affected nerves are tested, severe or even complete block of electrical impulses is seen. Conduction velocity is severely slowed through that same segment of nerve. However, conduction velocity is completely normal along the rest of the nerve. Sensory nerve conduction studies are normal. These are important features that distinguish MMN from CIDP. In CIDP, there is more diffuse slowly of motor conduction velocity and sensory nerve conduction studies are usually abnormal.

Cerebrospinal Fluid (CSF) Examination

The CSF is normal in MMN, and spinal tap is not indicated unless there are very atypical features. Nerve Biopsy Since the sensory nerves are not involved in MMN and since it is unwise to biopsy motor nerves, nerve biopsy is not indicated in MMN. Laboratory Testing About half of all patients with MMN have very high levels of specific antibodies in their blood called anti-GM1 antibodies. They are directed against a specific component of the myelin sheath, the glycolipid. These antibodies can be measured in the blood. They do not need to be routinely measured unless there are unusual features and particularly if the patient appears clinically to have MMN, but does not have the expected abnormalities with the nerve conduction testing. There are no other useful laboratory tests.

What Causes MMN?

Like GBS and CIDP, MMN is an autoimmune disease. It is extremely rare, but the exact prevalence is not known. It affects men more than women. It is not known why only the motor nerves are affected. There is no recognised trigger for the disease, and there are no known associated diseases. The disease is more common in young people between 20 and 40 years of age, although children and the elderly are occasionally affected. Occasional periods of more rapid progression can be seen, but it is not clear that these are precipitated by any particular event.

How is MMN treated?

The only proven effective treatment for MMN is IVIg. Several studies have established the effectiveness of this treatment. However, IVIg, does not cure the disease and long-term, probably life-long, treatment is necessary. The effect of the treatment usually lasts a few weeks to, at most, a few months. Most patients need to have the treatment repeated every 2 to 6 weeks. Cyclophosphamide may also help, but the risks usually outweigh the benefits. Patients may deteriorate more rapidly if treated with steroids or with PLEX (plasmapheresis).

More details about Miller Fisher syndrome (MFS) is also known as:

  • [The] Miller Fisher variant [of GBS]
  • Fisher('s) syndrome
  • acute idiopathic ophthalmologic neuropathy

Related conditions are:

  • GBS with ophthalmoplegia
  • Bickerstaff's brainstem encephalopathy
  • acute ophthalmoparesis

In 1956, [Charles] Miller Fisher, a Canadian whose specialisation was stroke, described three patients with acute external ophthalmoplegia (eye paralysis), sluggish pupil reflexes, ataxia (lack of balance) and areflexia (absent tendon reflexes). Two patients had no weakness; the other had a facial palsy and possible weakness. All three recovered spontaneously.

Because some patients with GBS had ophthalmoplegia and there were other similarities, Dr Fisher concluded that these patients had suffered a disorder akin to GBS. [Fisher CM. Syndrome of ophthalmoplegia, ataxia and areflexia. N Engl J Med 1956;255:57-65]

Pure Miller Fisher syndrome (without generalised weakness) is rare. Electrodiagnostic abnormalities found in all patients are characteristic of an axonal neuropathy or a neuronopathy with predominant sensory nerve changes in the limbs and motor damage in the cranial nerves. [Fross RD, Daube JR. Neuropathy in the Miller Fisher syndrome: clinical and electrophysiologic findings. Neurology 1987 Sep;37(9):1493-1498]

Patients described as having Miller Fisher syndrome often have a neuropathy that overlaps with GBS and demonstrate generalised weakness, sometimes paralysis, as additional symptoms.

It was sometimes proposed the Miller Fisher syndrome was caused by brainstem encephalitis. It is true that the syndrome can be mimicked by a brainstem lesion, but typical cases of Miller Fisher syndrome rarely show any evidence of brainstem abnormalities either radiologically or during post-mortem examination. When clinical or radiological brainstem abnormalities are found, the condition may be referred to as Bickerstaff's syndrome or Bickerstaff's brainstem encephalopathy (or encephalitis) (BBE).

Research in recent years has concentrated in identifying the antibodies that are thought to be responsible for GBS etc. It has been confirmed clinically that MFS, GBS with ophthalmoplegia, BBE, and another condition called acute ophthalmoparesis* are closely related, forming a continuous range. This is supported by immunological findings with the antibody anti-GQ1b IgG being the common factor. [J Neurol Neurosurg Psychiatry 2001 Jan;70(1):50-55] This antibody is not found in other GBS patients so it is thought that it is responsible for the ophthalmoplegia.

*Acute ophthalmoparesis (AO) is characterised by acute onset of paresis of the extraocular muscles without ataxia or areflexia.

Although the efficacy has not been clinically proven, treatment of Miller Fisher syndrome is much the same as 'classic' GBS though the different symptoms require modified management with emphasis on the eyes. Intravenous immunoglobulin or plasma exchange treatment is likely in all but the mildest cases. The chances of recovery are good.