Acute immune related neuropathies are acute monophasic illnesses often preceded by infection that classically feature rapidly progressive, relatively symmetric, muscle weakness leading to flaccid paralysis with absent or depressed deep tendon reflexes1. These neuropathies are also known as Guillain-Barré Syndrome (GBS) and its variants, including the Miller-Fisher variant.
GBS is triggered by the immune response to a preceding infection2. GBS is associated with Campylobacter jejuni, human immunodeficiency virus (HIV), cytomegalovirus (CMV), and Epstein-Barr virus. Two-thirds of patients report a preceding gastrointestinal or respiratory illness2. There have been reports of GBS following certain vaccinations without preceding illness, such as the inactivated polio vaccine and influenza vaccine. Cases of GBS induced by medications like Pembrolizumab and adalimumab have also been reported in recent years3,4. Rare cases of GBS have been described to be associated with bone marrow transplantation, pulmonary tuberculosis, Zika virus, cerebral hemorrhage, and ulcerative colitis.
Epidemiology including risk factors and primary prevention
GBS has a global incidence of 1-2 in 100,000 annually in all age groups5. The average age of patients with GBS is around 40 years, but the incidence increases by twenty percent for every ten years after the first decade of life. Additionally, males have a greater incidence rate of GBS than women6. GBS variants occur at different rates globally The most common type in North America and Europe is acute inflammatory demyelinating polyradiculoneuropathy (AIDP). Other variants, like acute motor axonal neuropathy (AMAN) and Miller Fisher syndrome, are more common in Asian countries7. The pretest probability is higher for individuals who have recently been diagnosed with Campylobacter jejuni, CMV or EBV infection. Those with a known HIV infection are also at higher risk. Some individuals may have genetic variations that are associated with an increased risk of developing GBS. Patients who meet these criteria should be more thoroughly worked up when presenting with ascending weakness.
There are two pathophysiological forms of GBS: demyelinating and axonal. Demyelinating GBS is characterized by inflammatory infiltrates, consisting of T cells and macrophages, and areas of segmental demyelination found in spinal roots and large and small motor and sensory nerves. There is often secondary axonal degeneration. The antibody immune response to various infectious agents cross-reacts with peripheral nerve components secondary to shared epitopes, a concept known as molecular mimicry. Autoantibodies against gangliosides bind to myelin antigens resulting in complement activation followed by membrane-attack complex (MAC) formation. This initiates vesicular degeneration of Schwann cells. Axonal GBS variants are characterized by IgG and complement mediated attack on the cell membrane of axons. The particular ganglioside targeted by autoantibodies determines the phenotype, classical GBS versus a variant such as Miller-Fisher1. The extent of T cell involvement in the induction phase remains unclear. Additionally, studies have shown that the progressive phase of nerve injury in GBS is humorally-mediated rather than T-cell-mediated8.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
From the onset of illness, the severity of symptoms for most patients progresses for up to two weeks, followed by a plateau for two to four weeks. Progression of symptoms can last up to 6 weeks in some cases8. On average, the time to nadir is four weeks post onset without any medical intervention9. Approximately 20-30% of patients develop respiratory failure during the progressive phase of GBS and require ventilation in an ICU10. After initiation of IVIG or plasma exchange therapy, a small percentage of patients’ conditions may deteriorate8. However, the use of plasma exchange or IVIG has decreased the time to onset of recovery by forty to fifty percent11. Severity and duration of this condition can vary significantly in each patient. Some may have mild, reversible weakness while others may become quadriplegic without signs of improvement. While most patients with GBS have a good prognosis with varying recovery time, up to twenty percent of patients remain severely disabled and five percent die despite immunotherapy12.
Specific secondary or associated conditions and complications
There are numerous secondary consequences of GBS that require supportive care. The most significant of these are respiratory failure and autonomic dysfunction, requiring intensive care unit (ICU) monitoring. Patients with GBS are at high risk for autonomic dysfunction, pressure ulcers, pulmonary infections, deep vein thrombosis, often require bowel and bladder care, psychological support, and pain control.
Essentials of Assessment
Patients present with relatively symmetric weakness, with nearly 75% of GBS cases being preceded by a gastrointestinal or respiratory illness within 6 weeks before onset of symptoms13. Weakness begins in the legs 90% of the time with accompanying paresthesias in the hands and feet 80% of the time. Sixty-six percent of patients report pain, particularly in the back and extremities14.
Key features on physical examination include:
- Relatively symmetric muscle weakness, leading to anywhere from mild difficulty walking to complete paralysis of all extremity, facial, respiratory and bulbar muscles
- Absent or depressed deep tendon reflexes
- No or mild sensory abnormalities
- Autonomic dysfunction, with tachycardia, urinary retention, hyper- and hypotension, orthostatic hypotension, bradycardia, ileus, and hypohydrosis15
Presentation can vary depending on variant type and severity. For example, some patients may have hyperreflexia that then progresses to diminished reflexes – which is more likely to be seen in Bickerstaff encephalitis. Less common features include papilledema, facial myokymia, hearing loss, meningeal signs, vocal cord paralysis, mental status changes, ophthalmoplegia, and syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Clinical functional assessment: mobility, self-care cognition/behavior/affective state
Functional motor gain and recovery are measured using the traditional Functional Independence Measure (FIM) motor scores at admission and discharge. FIM is a sensitive tool that can assess disability and changes during rehabilitation in GBS patients32. Given the high variability in presentation of each patient with GBS, it is best to develop additional personalized goals after discussion with the patient.
Cerebrospinal fluid (CSF) shows albuminocytologic dissociation, elevated CSF protein with a normal white blood cell count, typically one week after the onset of symptoms in up to two-thirds of patients with GBS1. Electromyography and nerve conduction studies show an acute polyneuropathy with demyelination, although some variants can have axonal features. Diagnosis can also be confirmed with Anti-ganglioside antibodies, including GQ1b, GM1, GD1a, and GT1b. Other laboratory studies include serology for HIV, EBC, CMV, and other infectious or autoimmune etiologies to determine cause of GBS7.
While imaging is not necessary to make a diagnosis of GBS, there are findings that could be useful in confirming the diagnosis. A small study showed that ultrasound reveals significant enlargement of peripheral nerves in patients with EMG-confirmed GBS, particularly in the median nerve. Vagal nerve enlargement correlated with autonomic dysfunction while C6 root enlargement correlated with CSF protein levels16. Additionally, spinal nerve root enhancement, particularly in the thoracolumbar distribution, has been seen on MRI in the pediatric and adult population17,18. MRI is not typically used for diagnosis of GBS as enhancement of the nerve roots may not be present at onset of symptom. These imaging modalities could be useful in situations where diagnosis remains unclear or electrodiagnostic confirmation is not available.
Supplemental assessment tools
The Medical Research Council (MRC) Scale for Muscle Strength is also used for assessment, which is based on both the patient’s effort as well as clinical functional assessment. Additional assessment tools used commonly with GBS include the Perceived Impact of Problem Profile (PIPP) and Depression Anxiety Stress Scale (DASS). The PIPP focuses on the impact and distress of health conditions from the patient’s perspective. Meanwhile, the DASS is used to isolate and identify aspects of emotional disturbance that might not be apparent to the patient.
Early prediction of outcomes
Poor prognostic factors:
- Older age
- Quick onset of symptoms, particularly if <7 days
- Severe muscle weakness at presentation
- Need for ventilatory support
- Preceding diarrheal illness
- Average distal motor response <20 percent of normal in nerve conduction studies
- Small rise in serum IgG after administration of IVIG
Approximately twenty percent of patients who suffer from GBS will have some residual physical deficits1. This deficit can range from minor weakness to complete wheelchair dependence. Changes in the home and workplace may be necessary to maintain previous functionality.
Social role and social support system
Patients with GBS often have significant anxiety and affective lability due to the sudden and severe nature of the illness. About 30% patients will have to make significant changes in their daily lives due to resultant disability or impairment19. Close relatives of patients with GBS also face psychological changes like anxiety or depression in the first months after onset of symptoms20. Thus, rehabilitation plans should use a family approach. Not only is it important for patients to have the support of their family, friends and care team, but they often benefit from selective serotonin reuptake inhibitors (SSRIs) and/or anticonvulsants21.
Physiatrists should advocate for aggressive treatment and implementation of therapies early in the illness course. As there is a large gradient of disability among patients with GBS (full recovery to vent dependent), it is essential to define individualized treatment goals soon after diagnosis.
Rehabilitation Management and Treatments
Available or current treatment guidelines
Due to the clinical heterogeneity of GBS, rehabilitation plans must be custom tailored to a particular patient’s deficits. Approximately 40% of patients with GBS require inpatient rehabilitation22. Ideally, rehabilitation begins in the acute stages with contracture prevention, a bowel and bladder regimen, pressure ulcer prevention and pain management. Once the illness has hit its nadir, attention switches to regaining strength and gait training.
At different disease stages
Initial Onset/Acute Illness
In the acute phase of GBS, patients may not be able to perform active movements. Initial management of GBS patients should focus on prevention of contracture, nerve compression and pressure ulcer formation secondary to paralysis. This can be accomplished with range of motion exercises and positioning with static splinting. Patient positioning should be changed routinely during hospitalization to prevent pressure ulcers23. DVT prophylaxis should be considered for all patients with significant paralysis. In addition, both musculoskeletal and neuropathic pain can be a significant problem for some patients. Oral and intravenous pharmacological management as well as topical capsaicin and transcutaneous electrical stimulation for localized pain have proven beneficial14. Patients with GBS typically present with lower motor neuron dysfunction of bowel and bladder and will require a scheduled program. Some patients may benefit from nasal intermittent positive pressure ventilation early in GBS. Small studies have shown that it can decrease ICU length of stay, mortality, and the need for mechanical ventilation24.
Once out of the acute phase of GBS, focus should turn to strengthening with high repetitions and low weight to avoid overworking muscles, which could lead to paradoxical weakening. Gentle strengthening with isometric, isotonic, isokinetic, manual-resistive, and progressive resistive exercises should be incorporated to fit the patient’s condition. Some patients will also need to progress to gait training with use of the tilt table due to prolonged bed rest and dysautonomia. Others may benefit from partial body weight support systems during gait. Hydrotherapy can be used to promote mobility and muscle strengthening as well. A small contingent of patients develops dysfunctional vibratory sensation and proprioception. These patients require sensory reintegration and repetitive exercises to redevelop coordination. Neurogenic bladder and bowel can be addressed with pelvic floor muscle training and biofeedback23.
Coordination of care
Rehabilitation of a patient with GBS requires a team-based approach, ideally with a physiatrist as the team leader. Physical, occupational, respiratory and possibly speech therapists are essential. Rehabilitation psychologists also play a valuable role in recovery. Multidisciplinary care for GBS patients has been proven effective in inpatient rehabilitation25.
Patient & family education
Educating the patient, family, and additional caregivers on GBS and its recovery pattern is essential. The patient will face new disabilities, some of which could be permanent, and will need assistance in making adaptations in his/her life. It should be emphasized that full recovery can take up to two years.
Measurement of Treatment Outcomes including those that are impairment-based, activity participation-based and environmentally based.
Measurement of treatment outcomes is determined by comparing scores on the FIM, MRC, PIPP, and/or DASS scales at admission, discharge and at outpatient follow-up.
Translation into Practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
- Begin the rehabilitation process early in the ICU
- Initially focus on maintaining range of motion by preventing contracture
- Once the illness has hit its nadir, switch gears to work on gentle strengthening, with particular focus on gait and sensory abnormalities that will affect mobility
- Pain management is important throughout rehabilitation for patient comfort and to maximize gains through therapy
- Recovery from GBS can take up to two years, therefore continued therapy as an outpatient and independently at home is essential for maximal recovery
Cutting Edge/Emerging and Unique Concepts and Practice
- The addition of yogic relaxation, pranayama, and meditation to the treatment plans of patients with GBS significantly improves sleep quality but does not reduce disability26.
- The use of a virtual motor rehabilitation system improves clinical outcomes in patients with GBS while entertaining patients27.
- Higher intensity rehabilitation, compared with traditional less intense interventions, reduce disability in patients with GBS when implemented in the later stages of recovery28.
- Neuromuscular electrical stimulation in the early phase of GBS has been shown to be safe and feasible, though further research is required to determine its effect on muscle function29.
- Use of electroacupuncture at shu-points of the five zang organs has been reported to treat GBS with significant improvement in motor function30.
Gaps in the Evidence-Based Knowledge
Given the heterogeneity of GBS, there is lack of agreement on the appropriate clinical approach and most effective forms of intervention. As a result, there is a lack of high-quality evidence for the overall effectiveness of rehabilitation for GBS31.
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Amy Kanallakan, MD, Sruthi Pandipati Thomas MD, PhD. Acute Immune Related Neuropathies. 4/4/2016
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