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Miller Fisher Syndrome
Introduction
Polyneuropathies are dysfunction in multiple nerves and divided into 2 broad categories: axonal or demyelinating. Axonal neuropathies cause symptoms related to axon damage and loss and are caused by a broad number of systemic illnesses. Demyelinating neuropathies produce abnormalities because Schwann cells do not interact appropriately with axons. Schwann cells are glial cells that play an important role in the peripheral nervous system including saltatory conduction of nerve impulses along axons, nerve development and regeneration, modulation of neuromuscular synaptic activity, and presentation of antigens to T lymphocytes. Demyelinating neuropathies include toxic, hereditary, and immune-mediated etiologies; the latter can be further be classified as acute and chronic depending on the onset. Acute, immune-mediated demyelinating polyneuropathies (AIDP) are classified within the spectrum of Guillain-Barre syndrome (GBS), named after the French physicians who discovered it. The focus of our review will be the Miller Fisher syndrome (MFS), a rare variant of GBS. James Collier first discovered the variant in 1932 and described it as a triad of symptoms including ophthalmoplegia, ataxia, and areflexia. Miller Fisher later characterized it in 1956, classifying it as a unique entity within the GBS spectrum.[1][2][3][4][5][6][7][8]
Etiology
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Etiology
MFS and GBS are thought to result from an aberrant acute autoimmune response to a preceding infection (e.g., Campylobacter jejuni, Cytomegalovirus, Epstein-Barr virus, or human immunodeficiency virus (HIV). A cross-reaction between peripheral nerve antigens and microbial/viral components through molecular mimicry is thought to drive the inflammatory process of this illness. [9][10][11] Approximately two-thirds of cases are preceded by symptoms of upper respiratory tract infection or diarrhea, and about 50% develop following an infection. Researchers do not fully understand the precise mechanism of pathogenesis. The immune response can be directed toward the myelin or the axon of the peripheral nerve.[12][7]
MFS is associated mainly with dysfunction of the third, fourth, and sixth cranial nerves. Documented cases have been reported, however, for most of the other cranial nerves. Antibodies against the GQ1b ganglioside are a typical serological finding as described in the pathophysiology section of this article, but the absence of antibodies does not rule out the disease completely. Other risk factors associated with the disease include the use of certain drugs (heroin, suramin, streptokinase, and isotretinoin), use of TNF-alpha antagonist therapy, other concurrent autoimmune diseases (systemic lupus, Hodgkin disease, and sarcoidosis), surgery, epidural anesthesia, bone marrow transplant, and immunizations. [13][14][15][8][16]
Epidemiology
The worldwide incidence of GBS is approximately 1 to 2 in 100,000, with the MFS variant representing a tiny subset of the cases (1 to 2 in 1,000,000). It affects more men than women with an approximate gender ratio of 2:1 and a mean age of 43.6 years at the onset of disease.[17] It has a higher incidence in Asians, estimated between 15% to 25% of GBS in this population compared to 5% in the Western populations. A viral infection precedes the neurological symptoms in 72% of cases, with an average latent asymptomatic and incubation period of 10 days. A recent study that looked at patients admitted with GBS, MFS, and Bickerstaff brainstem encephalitis (BBE) in a tertiary hospital showed that recurrence of symptoms occurs at a higher rate in patients with MFS, and BBE, than GBS. [18] [19]
Pathophysiology
Molecular mimicry between peripheral nerve and microbial/viral antigens is thought to occur through the activation of the adaptive immune system. Humoral and cell-mediated lymphocyte mobilization is thought to play a major role. Gangliosides are important carbohydrate determinants for autoimmune activity. [20][21]Several studies have suggested that antibodies against gangliosides, the IgG anti-GQ1b antibody, are a specific feature of MFS. The presence of ophthalmoparesis in MFS is thought to result from a direct action of anti-GQ1b antibodies on the neuromuscular junction between the cranial nerves and ocular muscles. Other disorders including post-infectious acute ophthalmoplegia (AO), also named incomplete MFS lacking ataxia, Bickerstaff brainstem encephalitis (BBE, also named atypical MFS with central nervous system signs), and Guillain-Barre syndrome with ophthalmoplegia (GBS-OP) present with a positive GQ1b antibody. About 70% to 90% of patients will have positive results through an enzyme-linked immunosorbent assay (ELISA). A minority of patients (10% to 30%) of patients are still negative (GQ1b-seronegative), possibly related to the requirement of calcium-dependent ligands to be present for binding of the antibody, as shown in a study by Uchibori et al., 2016 in the Journal of Neuroimmunology. [22] [23] [24] [25] [26] [15] [27] [7] [28] [29] [30] [8]
Histopathology
The first neuropathological description of MFS was described in a case report by Phillips and Anderson in 1984. In this case, the brain of the patient, who died unexpectedly from bronchopneumonia, was prepared for histopathological analysis. Microscopic examination using solochrome cyanine staining (for myelin) showed patchy and extensive segmental demyelination associated with the invasion of foamy macrophages and lymphocytes. These changes affected both motor and sensory roots in the peripheral nervous system, as well as cranial nerves. The brain stem and spinal cord, among other regions of the central nervous system, are relatively spared. Electron microscopy confirmed the above findings and exquisitely showed complete demyelination of axons in Schwann cell cytoplasm with surrounding macrophages and lymphocytes.[31] [16]
History and Physical
The clinical hallmark of MFS is a triad presentation of acute ophthalmoplegia, areflexia, and ataxia in the setting of a preceding bacterial or viral illness. Distal paresthesia with or without weakness is also present. Symptoms on an average peak in four weeks or less, with supporting ancillary criteria as described by Brighton for GBS by Fokke C et al. in 2014. Other associated symptoms include diplopia or blurred vision, dysarthria, dizziness, and extremity tingling. Cranial nerve involvement is typical, resulting in facial, oculomotor, or bulbar weakness, which may extend to the limbs. Physical examination findings include typical findings for GBS like facial paresis, distal hyporeflexia without signs of upper motor neuron dysfunction, and loss of light and vibratory sensation in the distal extremities. Autonomic dysfunction such as hypertension, hypotension, or cardiac arrhythmia presents in advanced untreated GBS/MFS. Interestingly, the corneal reflex can be impaired. [32] [33] [7] [8]
Evaluation
If there is clinical suspicion for MFS and/or GBS, a lumbar puncture with appropriate cerebrospinal fluid (CSF) studies is warranted to narrow the differential diagnosis further. A hallmark of GBS and MFS, if present, is an albuminocytologic dissociation, or a combination of normal cell count and raised protein level in the CSF found in approximately 90% of patients at peak disease. There are, however, certain caveats: only half of the patients have albuminocytologic dissociation on initial analysis, and a normal protein level, especially early in the disease, does not exclude the diagnosis. Approximately 10% of patients with GBS have normal CSF studies. Approximately 15% to 20% have a mild increase in cerebrospinal fluid cell count (5 to 50 cells/microliter). Furthermore, nerve conduction studies can support the diagnosis and provide prognostic information.[34][35][36] [37]
For MFS, electrodiagnostic studies may show reduced or absent sensory responses without slowing of sensory conduction studies.[38] CT/MRI scans of the spine may show thickening and enhancement of the intrathecal spinal nerve roots and cauda equina, along with some spinal nerve roots enhancement. The literature has described abnormalities of the spinal cord posterior columns, and brain oculomotor, abducens, and facial nerves. [8]
The Brighton criteria are a validated, quantitative tool that uses clinical history, physical exam, laboratory, and imaging findings to diagnose GBS and its variants, including MFS. The scoring system is based on the following features:
- Bilateral and flaccid weakness of limbs (100% of patients)
- Decreased or absence of deep tendon reflex in distal extremities
- Monophasic course and time between onset and nadir is 12 hours to 28 days (97% of patients)
- Decreased or absent deep tendon reflexes in weak limbs (91% of patients)
- Cerebrospinal fluid cell count fewer than 50/microliter (100% of patients)
- Cerebrospinal fluid protein concentration greater than reference range (49% of patients initially, 88% at 3 weeks
- Nerve conduction study results consistent with 1 of the Guillain-Barré syndrome subtypes (99% of patients)
- Lack of an alternative diagnosis for weakness
The Brighton criteria range from level 1 (highest level of diagnostic certainty) to level 4 (Guillain-Barre syndrome diagnosis of exclusion, alternative possible).
Treatment / Management
MFS is mainly treated with adequate supportive care, pain control, respiratory support as needed, and immunotherapy. Although used in the past, oral or intravenous (IV) steroids are no longer recommended in the treatment of GBS or MFS because they are ineffective. Corticosteroids may slow recovery from GBS they are recommended only in the setting of neuropathic or radicular pain. IV immunoglobulin (IVIg) and plasma exchange are both effective treatments for GBS and severe cases of MFS. No difference exists between the primary outcomes of mortality, disability, and length of intubation between IVIG and plasmapheresis. Patients with MFS usually do not require immunotherapy, presumably because they have a good prognosis and spontaneous recovery. IVIG should be considered in patients with severe Miller Fisher syndrome who have swallowing and respiratory difficulties, despite lack of supporting evidence of benefit. Overall, IVIG is preferred over exchange due to convenience, availability, and minimal adverse effects, however; the cost can be prohibitive for some low income or underinsured patients.[39][40][41] [42] [43] [44](A1)
Before IV immunoglobulin therapy, clinicians should check serum IgA levels because patients with IgA deficiency are at higher risk of anaphylaxis. The usual IVIg dose is 2 g/kg divided over 2 to 5 days. A second treatment course may be necessary for some patients. In children and adolescents, a dose of 1 g/kg per dose IV daily for 2 days is given. Alternatively, 400 mg/kg per dose IV daily for 5 days has been used. For patients with renal impairment, clinicians should use approximately 50% of the usual dose. Plasma exchange is effective when given within 2 weeks of illness onset in patients who are unable to walk, reaching highest effectiveness within seven days of weakness onset. Plasma exchange sessions (2 to 3 L of plasma/body weight) over 2 weeks is the standard course for patients who are unable to walk without assistance. Mildly affected patients with low disability score still benefit from 2 plasma exchanges of 1.5 plasma volumes. Contraindications for plasma exchange include the recent prior use of IV immunoglobulin infusion therapy, hemodynamic instability, pregnancy, sepsis, and hypocalcemia. [45] [46] [47] [44](A1)
Pain relief is an important consideration and a barrier to rehabilitation in the hospital. In a study of pain intervention in patients with GBS, 75% of patients required oral or parenteral opioids for pain management and 30% of patients required IV opiates. Therefore, an optimal pain regimen early in the course of the disease is important to accelerate recovery. A combination of medications is often needed as because of the mixed nature of the pain. Indicated medications include gabapentin, pregabalin, carbamazepine, and amitriptyline. Corticosteroids can be used to address neuropathic or radicular pain. Oral or intravenous opioids, for example, IV morphine 1 to 7 mg per hour, should be used with extreme care due to the suppressing effect on respiratory drive, and autonomic system side effects like urinary retention. [48](A1)
Deep vein thrombosis (DVT) prophylactic therapy should be started promptly to reduce the risk of pulmonary embolism. Administration of prophylactic doses of subcutaneous heparin or enoxaparin is appropiate. Alternatively, mechanical compression stockings can be used in adult patients unable to walk. If autonomic dysfunction is present, additional supportive treatment may be necessary. If the patient is moderate to severely bradycardic and at risk of asystole, the patient may require a cardiac pacemaker. If dysphagia is present, a nasogastric tube may be necessary for feeding and nutrition. Bladder catheterization can relieve patients with urinary retention. A bowel regimen will be indicated to help with constipation. Early physical therapy during the illness and early rehabilitation is pivotal once patient clinically improves. [41][49]
Inpatient and intensive care unit (ICU) disposition is an important consideration for a patient with acute GBS and its variant MFS. This is based on symptoms severity, and, most importantly, respiratory status. Mechanical ventilation is required for the 20% to 30% of patients who develop respiratory failure; endotracheal intubation and even a tracheostomy may be necessary. Signs of respiratory muscle fatigue include tachycardia, tachypnea, asynchronous chest/abdomen movement, and evident use of accessory muscles. All patients with acute debilitating symptoms, as mentioned, are admitted inpatient for supportive care. ICU admission and mechanical ventilation are recommended in patients with at least 1 major criterion or 2 minor criteria. Major criteria include hypercapnia PaCO2 greater than 48 mm Hg, hypoxemia PaO2 less than 56 mm Hg at room air, vital capacity less than 15 mL/kg of body weight, and negative inspiratory force less than -30 cm H2O. Minor criteria include an inefficient/weak cough, dysphagia, and atelectasis as evidenced in a chest x-ray. [50] [51] [7] [8] [16]
Differential Diagnosis
MFS can be mistaken with similar disorders with overlapping clinical features. The most common differential is brainstem (Bickerstaff) encephalitis and a pharyngeal-cervical-brachial weakness GBS variant. Distinguishing features of brainstem encephalitis are the presence of hyperreflexia and encephalopathy. The pharyngeal-cervical-brachial variant of GBS is clinically characterized by acute weakness of the oropharyngeal, neck, and shoulder muscles, dysphagia, and facial paresis with preserved reflexes and strength in the lower extremities. These 3 disorders have in common the presence of anti-ganglioside antibodies in CSF. The gradual onset of MFS is a key factor in distinguishing it from acute brainstem stroke. Other differential diagnoses to consider include Wernicke encephalopathy, ocular myasthenia gravis, Lambert Eaton syndrome, multiple sclerosis, and sarcoidosis, among other autoimmune disorders. Neuroimaging (CT/MRI or MRA) and electrodiagnostic (EMG, nerve conduction, or evoked potential), among other ancillary tests in the central and peripheral nervous system can be helpful to exclude these alternative diagnoses. Of note, under an uncertain GBS variant besides MFS and/or suspicion of brainstem encephalitis that is severely debilitating, the treatment regimen remains unchanged: IVIG or plasma exchange. [8] [52] [53] [16]
Prognosis
The outcome of MFS is usually good with a case fatality of less than 5%. The mean recovery times range between 8 to 12 weeks. Residual symptoms may be present in some patients, and recurrence has been reported in the literature. In GBS, however, hyponatremia is predictive of poor outcomes with the development of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). About 21 to 48% of GBS patients can suffer from hyponatremia. Hyponatremia is an independent predictive factor for mortality that has been called into question in newer studies, making respiratory status and complications in the ICU as the top predictors of mortality and morbidity.[54]
Complications
The most common complication is generalized fatigue, reported in three-fourths of patients with GBS and MFS. Recovery tends to be better in patients with MFS. About one-third of all patients still experience pain one year after onset. Severe complications are more likely in patients with an extended ICU stay. These include sepsis, pneumonia, pulmonary embolism from a deep vein thrombosis (e.g., immobilization), and gastrointestinal bleeding. Other complications may arise from patients suffering from autonomic dysfunction including arrhythmias, and ileus. Respiratory muscle fatigue is a feared complication in ICU patients older than 50 years, due to the risk of mortality from respiratory failure. Among severely affected patients, 20 to 33% may be unable to walk for more than 6 months after symptom onset, especially if infected with C. jejuni. Patients may also suffer from chronic psychiatric illness due to persistent pain and disability. [55] [16]
Postoperative and Rehabilitation Care
A patient discharged with GBS or MFS may need a lengthy and intense program of physiotherapy to recover function. Complete recovery is dependent on many factors, including the severity of neurological deficits at onset, the age of the patient, complications, motivation, and goals of the patient, among others. A thorough physical and occupational therapy assessment in the hospital is essential to identify the patient’s needs and goals of therapy. Patients with GBS and MFS frequently begin acute care and PT/OT therapy in the intensive care unit, then progress to a sub-acute setting in a rehabilitation department or outside nursing/rehab facility and eventually translate to home-based or outpatient therapy. The assessment includes a patient/caregiver interview, sensory function, skin inspection, testing joint range motion, manual muscle testing, functional testing (e.g., ADL/IADL pre and post-illness), mobility, respiration (e.g., vital capacity and inspiratory force), autonomic dysfunction, and endurance.
The principal goals of therapy include achieve optimal muscle use as tolerated by pain and use supportive equipment to help the patient resume functional activity as close to baseline as possible. Activities are increased gradually as tolerated, with increased muscle repetitions at low resistance to avoid injuries, teaching energy conservation, and training caregivers in transferring technique and mobilization of the patient at home. In summary, PT/OT are integral parts of the recovery and management of MFS. An appropriate plan of care can help a patient minimize pain, increase strength and endurance, and prevent secondary complications including overuse damage to muscles and joints while improving balance, mobility, and restoring functional activity. [56] [57]
Consultations
Neurology and possibly neuromuscular subspecialty consultations, if possible, should be considered for GBS or MFS cases. If needed, a critical care intensivist may need to be consulted for ICU admission and management.
Deterrence and Patient Education
What are Miller Fisher and Guillain-Barre syndrome?
Miller Fisher Syndrome (MFS) is one of the rare forms of a spectrum of Guillain-Barré syndrome (GBS). It is a neurological condition that causes mild to severe muscle weakness. It is caused by an immune system reaction against certain proteins in our nerves important for movement, sensation, and function. This syndrome can begin after certain bacterial or viral infections found in our food, or the environment infects us. The body confuses the nerves with the bacterial or viral proteins leading to nerve damage, resulting in symptoms observed. The most common bacterial trigger for GBS and MFS is Campylobacter jejuni which can cause abdominal pain and diarrhea. Viruses that may cause MFS and GBS include HIV infection, Epstein-Barr (mononucleosis), and Zika virus.
What are the symptoms of Miller Fisher syndrome?
Miller Fisher syndrome causes eye and muscle weakness on both sides of the body. It may cause trouble walking and balance problems. It can start in the legs and slowly spread to the arms and face. Some people lose the ability to move their legs, arms, or face. Some people may have trouble breathing because it affects their respiratory muscles. Other symptoms of MFS can include:
- Tingling or numbness in the hands or feet
- Pain in the back, legs, or arms
- Problems with eye movement and/or blurry vision
- Loss of coordination in the arms and legs
What are the tests for Miller Fisher syndrome?
The doctor or nurse will ask about symptoms and do an exam. He or she will also do tests to be sure you have MFS and differentiate from other possible illnesses. Tests can include:
- A lumbar puncture (spinal tap): A procedure where the doctor puts a thin needle in the lower back and removes a small amount of spinal fluid. Spinal fluid is the fluid that surrounds the brain and spinal cord. That fluid is sent for further testing.
- Antibody testing: The doctor may send a blood test to determine whether the patient has MFS. There are specific sugar chains in the nerve called a ganglioside that the body attacks. This antibody is present in most, but not all, patients.
- Nerve conduction studies: This test can show whether the nerves are carrying electrical signals the correct way.
- Electromyography (EMG): This test shows whether the muscles are responding to the electrical signals from the nerves in the correct way.
- Neuroimaging CT/MRI of the spine: This test can show whether the body is attacking the nerves cells in the spinal cord. It would light up if it is positive.
- Other blood tests to rule out other illnesses
How is Miller Fisher syndrome treated?
Treatment for Miller Fisher syndrome is the same as GBS and involves different components depending on severity:
- Treatments for problems caused by the MFS: People with MFS are usually treated in the hospital to rule out a more life-threatening version of GBS. In the hospital, the doctor will monitor a heartbeat, breathing, and general health. If breathing problems are present and begin to get worse, you may need a breathing tube. A breathing tube goes down the throat and into the lungs and provides oxygen to your body.
- Treatment for pain: Doctors can use different medicines to treat pain, always watching that they do not use medication that could make breathing harder
- Treatment for the condition itself: There is no immediate cure for MFS and GBS. However, there safe and effective treatments that can help the body improve in a shorter time. These treatments are immunoglobulins (IVIG) and plasma exchange. IVIG is a medicine that helps the body rid itself of the proteins (antibodies) that damage the nerves. Plasma exchange is an alternative procedure where a machine pumps blood from the body and removes the proteins attacking the nervous system. Then the machine returns the blood to the body clean.
- Physical rehabilitation of affected muscles: People whose muscles get very weak may need to go to a facility for physical and neurological rehabilitation. It usually consists of 1 to 2 weeks of intense rehabilitation with a comprehensive team of health professionals. Their goal is to strengthen the body’s muscles as close to the previous function as possible.
How long does Miller Fisher syndrome last?
Acute MFS usually lasts a few weeks and can be shortened with appropriate treatment. Complete resolution of symptoms lasts several weeks to few months depending on the severity of presentation. The good news is that MFS tends to have a more benign course compared to other forms of GBS. Therefore, most people will recover completely and have no long-term muscle weakness. Very few people have muscle weakness that lasts years.
What can I do to prevent Miller Fisher Syndrome?
Certain bacterial and viral infections can cause these disorders. Some measures can be followed to reduce contact with eliciting agents including:
- Improve sanitation: Washing hands thoroughly with soap and water before and after handling poultry and generally when touching raw meat
- Cooking poultry products thoroughly
- Disinfecting water supply
- Avoiding raw milk consumption
- Safe sex practices
- Immunocompromised patients must adhere to medication regimen to avoid certain viral infections
Pearls and Other Issues
- MFS and GBS are thought to result from an aberrant acute autoimmune response to a preceding infection (e.g. Campylobacter jejuni, Cytomegalovirus, Epstein-Barr virus, or Human immunodeficiency virus (HIV) through a molecular mimicry mechanism that leads to the destruction of myelinating components of the central and peripheral nervous system.
- MFS variant represents 1 to 2 in 1,000,000, with average occurrence during mid-adulthood, affecting more men than women 2:1, and disproportionate incidence in Asian communities.
- The clinical hallmark of MFS is a triad presentation of acute ophthalmoplegia, areflexia, and ataxia in the setting of a preceding bacterial or viral illness. Associated symptoms also include diplopia or blurred vision, dysarthria, dizziness, and extremity tingling with or without cranial nerve involvement.
- Physical exam findings include facial paresis, distal hyporeflexia without signs of upper motor neuron dysfunction, and loss of light and vibratory sensation in the distal extremities. Autonomic dysfunction although possible is less likely to occur in MFS.
- Although the diagnosis of MFS is mostly clinical, supportive testing can help differentiate from other diseases or variants of GBS, including a lumbar puncture with CSF studies, anti-ganglioside antibody testing, nerve conduction studies, electromyography, CT/MRI imaging, among other ancillary testing.
- Differential diagnoses include brainstem (Bickerstaff) encephalitis, pharyngeal-cervical-brachial weakness GBS variant, and other neuromuscular autoimmune disorders. MFS and these 2 variants have in common the presence of anti-ganglioside antibodies in CSF.
- MFS is mainly treated with adequate supportive care, pain control, and respiratory support as needed, and immunotherapy. IVIG or plasmapheresis are the mainstays of therapy. Corticosteroids are no longer recommended and are ineffective in the majority of cases.
- The prognosis of MFS is usually good with a case fatality of less than 5%. The mean recovery times range between 8 to 12 weeks. Although recurrence may occur, it is uncommon.
- The most common complication is generalized fatigue. About one-third of all patients still experience pain one year after onset. Severe complications are more likely in patients with an extended ICU course.
- ICU transfer from the emergency department is reserved for the sickest patients who meet certain criteria including impending respiratory failure. Major criteria include hypercapnia PaCO2 greater than 48 mm Hg, hypoxemia PaO2 less than 56 mm Hg at room air, vital capacity less than 15 mL/kg of body weight, and negative inspiratory force less than -30 cm H2O. Minor criteria include an inefficient/weak cough, dysphagia, and atelectasis as evidenced in a chest x-ray.
- Early physical and occupational therapy can lead to a faster recovery in patients with any form of GBS, including MFS. The goals of therapy should be individualized according to the patient's wishes, it includes achieving optimal muscle use as tolerated by pain, and use supportive equipment to help the patient resume functional activity as close to the pre-hospitalization baseline as possible.
Enhancing Healthcare Team Outcomes
The diagnosis and management of MFS are complex and best done with an interprofessional team that includes the neurologist, internist, intensivist, pulmonologist, physical therapist, ophthalmologist, psychiatrist, infectious disease expert, and ICU nurses. MFS is mainly treated with adequate supportive care, pain control, and respiratory support as needed, and immunotherapy. IVIG or plasmapheresis are the mainstays of therapy. Corticosteroids are no longer recommended and are ineffective in the majority of cases. Most patients require a prolonged stay in the hospital. The prognosis of MFS is usually good with a case fatality of less than 5%. The mean recovery times range from 8 to 12 weeks. Although recurrence may occur, it is uncommon.
After discharge, fatigue remains a common complaint and physical therapy is highly recommended. Pain and limited range of motion will persist in a significant number of patients.[58][59] [Level III] An interprofessional team approach will result in the best outcomes. [Level 5]
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