8 Minimal Response Syndrome
What is Minimal Response Syndrome?
An increasing number of severely brain-damaged patients survive as a result of improved technology, and face severe incapacitating disabilities . Over the past 30 years, epidemiological studies have shown an increase in the survival of patients with both traumatic and nontraumatic brain injuries . The numbers of patients who remain in an altered state of consciousness (ASC) — i. e., those in coma, in a vegetative or near-vegetative state, with postcomatose unawareness, with postcomatose cortical unresponsiveness, slow recovery, or those who are minimally responsive or with minimal activity — are therefore substantial . The existence of so many “similar” names for these conditions suggests two possibilities — firstly, that there is disagreement regarding the nomenclature, or secondly, that ASC is a “basket” term including a spectrum of diagnoses, rather than being a single definite condition .
This chapter is deals with aspects of the treatment of one specific subtype of ASC patients — those who are termed “minimally responsive” (in “postvegetative state” or in a “low-awareness state”). No one clear unique definition for this “vague” entity is found in the literature. The definition of “minimal response” includes objective issues such as “measurable” parameters, as well as subjective issues, such as the decision as to which response may be called “minimal”. Minimally conscious patients are those who can follow simple commands reliably, but are unable to follow complex commands .
Significance of the Syndrome
Few studies have been published concerning the clinical aspects of patients in the minimally responsive state. There have been many more reports on comatose patients and/or patients who succeed in recovering from coma to “active” life. Therapists get satisfaction and the recognition accompanying success when patients recover. The drama of treatment in the intensive-care unit, where the major emphasis is on saving the life of the patient, often ceases to interest the medical staff once the patient has gained “stability.” The quality of the life that has been saved may be largely ignored; in other words, minimally responsive patients draw a “minimal response” from the medical and scientific personal in turn.
There are, however, two main reasons why it is important to focus on this group of patients:
• Developments in medicine have enabled more people to survive severe brain damage and to remain in this state.
• Focusing investigations on the life of a person who is in the minimally responsive state can enrich our understanding about what the term “consciousness” actually means.
Implications for Health Policy
A policy on the care of this group of patients needs to be developed, and it should be based on the following considerations: what is the optimum way of assessing the response and what level of consciousness does it actually reflect ? The answers to these questions should form the basis of the rationale and guidelines used in practical clinical management.
To better understand the meaning of the syndrome of “minimal response” it may be useful to interpret firstly the meaning of its components . The response component is a measurable parameter, which means it has a quantitative value. To determine the meaning of “response” is not a purely medical and/or laboratory decision, but depends upon the “value” of the response (i. e., a qualitative statement). Thus, the decision that a response is minimal should not be taken only by the medical team. The response should be measurable and repeatable. Further questions then arise, for example: what kind of responses can be called meaningful ones? Who should decide this? How (using what tools) ? When and for how long? Since the answers to these questions are both qualitative and quantitative, they should be given by the medical team working together with other nonmedical personal such as “the family,” religious personnel, and/or a legal representative.
Practically, since we are dealing with patients who suffer from very severe neural damage, their “minimal response” is not a constant one, but instead may change depending on various self and nonself influences . The syndrome of minimal response therefore represents a wide range of conditions in patients and cannot be defined for some time after the initial neural insult (at least several months).
Diagnosis and Assessment Tools
Diagnosis is very much linked to definition. Coma is the extreme manifestation of severe brain insult. Loss of consciousness and coma are synonymous terms for the diagnosis of a patient who has no “connection” with his surroundings. “Coma is a profound or deep state of unconsciousness. The affected individual is alive, but is not able to react or respond to life around him/her. Coma may occur as an expected progression or complication of an underlying illness, or as a result of an event such as head trauma” . The use of a practical method of assessing coma, such as the Glasgow Coma Scale (GCS) , enables the medical team to deal with these patients using more concrete (regular) medical terminology. It does, however, emphasize the complexity of this diagnosis, since “coma” is no longer a vague concept, but a measurable entity — i. e., it has a quantitative value. Farber and Church-land  stated that it is more fruitful not to define consciousness, but to describe the various subcategories that are included in the concept. These subcategories are:
• Sensory awareness: this includes stimuli from the sensory organs, but also “modality-specific imagery.”
• Generalized awareness: this includes inner states with no clear link to any modality, such as “comfort.”
• Metacognitive awareness: “there are all sorts of things one can be aware of in the realm of one’s own cognition.”
These subcategories give some insight into the concept of consciousness, since it is not only synonymous with awareness, but also carries with it an implication of agency and control. Included in it is the more vague term of “soul.” Neural synchrony with a precision in the millisecond range may be crucial for conscious processing, and may be involved in arousal, perceptual integration, attention selection, and working memory . Consciousness is a complex concept that incorporates several issues, such as wakefulness, the experience of oneself and one’s surroundings, and the possession of intentions. Consciousness, in all its aspects, is a matter of degree.
Coma is a term for the acute phase after the insult. Jennett and Bond  developed an assessment for the postacute state in these patients. The Coma Outcome Scale consists of five global categories in an ordinal scale going from recovery, moderate disability, severe disability, and persistent vegetative state, to death. Jennett and Plum were among the first to introduce the concept of persistent vegetative state in describing the syndrome of wakeful unresponsiveness . In 1991, Sazbon and Groswasser suggested an alternative term, “postcomatose unawareness” . Glenn suggested a more direct term, “postcomatose cortical unresponsiveness” . These semantic nuances emphasizes the complexity of this issue. The state of “minimal responsiveness” includes patients who are unable to respond to commands and communicate reliably . “Minimal responsiveness” can be diagnosed under a general term, but it must be emphasized that this broad category may actually include different levels of brain functioning, both in terms of quality and quantity. The body of knowledge, precision of assessment, specificity of treatment, and effectiveness of communication might be improved if we had better tools for differentiating these particular patients [18,19]. Horn et al. , after presenting a review of the existing assessments for minimally responsive patients, concluded that their efficacy was based on short-term projects and that the tools required further validation in order to establish their usefulness in the long-term setting. The distinction between patients who are diagnosed as being in the vegetative state, as opposed to the minimally responsive state, depends not only on their functional status, but also on the tool by which they are evaluated . It is not surprising, therefore, that the diagnostic classification and assessment of patients who remain unconscious for prolonged periods and recover from coma only to demonstrate a very low level of response, has not yet been well developed [14–16].
Better tools for assessing, differentiating, monitoring treatment, and communicating about these particular patients should be developed [18, 19,21,22]. On the basis of multicenter data on patients with low-level brain injury (vegetative or near-vegetative), Berrol stated that there are substantial changes occurring that may not reflect the potential for functional improvement . He also added that it might well be that evolutionary changes continue to occur over long periods of time. Ansell and Keenan introduced the term “slow to recover,” which was used for patients who improve more slowly than most others with severe brain injury . These patients do not follow the “normal recovery pattern,” seen as the achievement of major functional improvement during the first 6 months after injury. Ansell and Keenan stated that these patients are considered ready for rehabilitation when they reach Ranchos level V , i.e. when “responses are prompt and consistent although not necessarily accurate or appropriate.” The few reports about long-term follow-up in this population indicate gradual improvement [15, 24,26].
Rosenberg and Ashwal  suggested the following distinctions between patients who are in coma, vegetative, or minimally responsive:
• Coma: patients have no self-awareness, are not aware of pain, do not have sleep-wake cycles or purposeful movements, and may have depressed respiratory functions. The coma diagnosis does not last longer than 4 weeks; the possible outcomes are death, vegetative state, minimal response, and recovery.
• Vegetative state: patients have no self-awareness, do not feel pain or have sleep-wake cycles, have no purposeful movements, but do have normal respiratory function.
• Minimal response: patients have limited self-awareness, do feel pain, and have sleep — wake cycles. They may also have severely limited movement, and respiratory function may be depressed .
Clinical evaluation of awareness may be divided to subgroups such as: visual, auditory, somatosensory, and motor activity. To avoid misdiagnosis, it is recommended that information be gathered from a variety of sources, including interviewing family members .
The differential diagnosis becomes more questionable when sophisticated tools for evaluation are used . Menon et al. used evoked a response of oddball (P300) study and a 15O positron emission tomography (PET) subtraction paradigm to assess the response to familiar faces that were presented. These tests were used to demonstrate responsiveness in a patient who was otherwise diagnosed as being in the vegetative state .
Incidence and Prevalence
There have so far been no epidemiological studies dedicated to these patients. As mentioned above, there is no absolute agreement on which patients should be labeled under this diagnosis. It is therefore impossible to give any reliable numbers for the incidence and prevalence of minimally responsive patients. This task is especially complicated, since there are two possible ways in which patients may enter the minimally responsive state — firstly, those who “recover” from the vegetative state, and secondly, those whose mental function has deteriorated to a minimal response (e. g., patients suffering from severe degenerative brain disease). Although these two groups of patients are similar from the point of function, it can be expected that their “brain status” will react differently, since one group is on a “recovery path,” while the other is on a “deteriorating path.” The focus in this section is mainly on the first group. The incidence of this subgroup can be estimated from data for patients who were comatose following insult and did not die. When information from a local district in Japan was generalized, there was an estimated figure of approximately one per 100 000 population for traumatic brain injury patients with a very severe outcome .
The next question concerns the prevalence — an even harder issue, since it incorporates data on the incidence as well as data about the expected length of life. As mentioned before, these patients are fully dependent, so the expected length of life has a direct relationship to the quality of care and therapy provided. It is reasonable to assume that the reduction in motor activity has a negative influence on the cardiorespiratory system. In recent years, there have been many studies on the didactic relationship between the immune system and central nervous system (CNS) activity, but it is impossible to predict from these data what quantitative effect it may have on changes in lifespan. It is reasonable to estimate that life in “semi-isolated surroundings” would have influence on physiological and psychological elements, but since there are so many factors involved, no one can predict the “end-point” of their effects. These patients are unable to travel, for example, so that they are safe from many dangers that others are exposed to in life. It is impossible to use data concerning small groups of patients who are treated in a specific community to deduce “hard” data concerning the expected length of life of these patients. In practical terms, this is a very important medicolegal issue, since data of this type are needed to estimate the amount of compensation for these patients. Certainly, individual parameters such as age, sex, and premorbid medical condition will have an effect on lifespan.
More specific epidemiological studies have been performed concerning the follow-up in severely brain-injured patients admitted to neurosurgical departments. On the basis of such data, a prediction “tree” has been developed . It is impossible to determine from these data any clear information concerning minimally responsive patients, since this group is usually included in the subgroup defined as “bad outcome.”
Practical Management Recommendations
By definition, these patients in the minimal responsive state are fully dependent for all their activities of daily living. Their cooperation is severely limited, as is their ability to ask for any specific needs or be involved in any decision-making concerning their life. The quality and quantity of their treatment will depend totally on their care-givers. Their lifespan is thus directly related to the quality of care.
Objectives of Treatment
There are three main aims of treatment for these patients:
• Care and management for basic maintenance (e.g., feeding, infection prevention, and preservation of general good health).
• Specialized therapeutic techniques aimed at improving quality of life. These may include a variety of stimulating techniques — motor, sensory, and communicative.
• Spiritual maintenance — e. g., the use of physical contact, such as massage, hydrotherapy, enhancement of the surroundings with art and music, human contact, and animal contact.
The separation between these aims of treatment (care and therapy) is not always so clear. The meaning of the word “recovery” can be interpreted two ways — either raising the level of responsiveness without changing the diagnosis, or achieving recovery to a point at which the patient can no longer be considered to be in the minimally responsive state.
Treatment Aimed at “Care”
Maintenance (Keeping the Patient Alive)
Nutritional intervention. Support all elements of nutrition under the guidance of a specialist in the field. The metabolic balance must be controlled so as to ensure that neither malnutrition nor obesity develops. All of these patients require feeding; this can be achieved either orally or via a feeding tube.
Hygienic care, including the bladder and bowel. Since none of these patients are expected to be able control their secretions, routine check-up and cleansing should be done. Care must be taken that there is no residual urine in the bladder and no difficulties in passing stool. Whenever there is any difficulty in controlling secretions, medical intervention should be involved, such as intermittent catheterization or administration stool softeners. These procedures should only be prescribed by a specialist and should be followed up with intensive monitoring.
Respiratory and skin care. These patients are very limited in self-movement, so their position should be changed every few hours, including during the night, to prevent skin lesions. The skin all over the body must be routinely checked and lubricated. Some of the patients breathe via tracheotomy tubes, and all are expected to have difficulty in expectoration. It is extremely important to position these patients in the sitting and/or standing position at least once daily. Some of these patients will require routine respiratory physiotherapy.
Pain control. The argument as to whether ASC patients have some conscious awareness at subcortical levels is as yet unresolved. There is therefore no reliable way of determining how much they can perceive pain and suffering . In many cases, it is only possible to suspect that the patient is indeed suffering only by observing mimic reactions, hearing wailing, and/or observing changes in autonomic activity on monitors. It is critically important first to look for a possible cause for the observed changes, which may be reversible — e. g., smoothing out the bedsheet or removing any internal blockage.
Sleep control. Every few months, the patient’s sleep-wake cycle should be monitored to test the quality of the sleep cycles. Treatment for sleep disturbances should be implemented whenever significantly abnormal sleep patterns are detected.
Prevention of Secondary Complications
Routine daily motor activity. Patients should spend part of the day sitting out of bed. Standing should be carried out whenever possible. Passive movements and stretching (under the direction of a physiotherapist) should also be performed daily, with the aim of preventing contractures developing due to muscle shortening or the development of new bone formation.
Continuous medical monitoring to prevent development of metabolic imbalance. Observation should ensure that any developing infection is noted as quickly as possible. Deep vein thrombosis or decubitus ulcers or osteoporosis should be prevented.
Pharmacological treatment should be provided, with anti-epileptic drugs to prevent seizures without the possible development of unwanted side effects.
Family support. The families of these patients can expect to have to live for many years with a relative who is “minimally responsive.” There is little or no communication with the patient as there was before the trauma. The patient’s absence from the family’s regular daily routines and the uncertainty of the future can all contribute to family distress.
Touch. The importance of touch in this group of patients cannot be measured objectively. Treatment should provide the patient with more than just the technical procedures required to maintain life. The families should be encouraged to touch and massage their loved one as much as possible.
Sexuality. Since this group of patients is frequently in the age group in which sexual relationships are an important aspect of life, this subject should be open to discussion with the families. If the patient’s partner demonstrates a desire to have an intimate relationship with him or her, this should be encouraged. However, possible medical side effects such as overstimulation of the autonomic system should be monitored. No one can say how much positive stimulation such a relationship may provide.
Treatment Aimed at “Therapy”
Cognitive malfunctions in these patients mainly involve arousal disturbances, attention, recognition, and memory disorders. There have been some attempts to improve these activities by therapy and/ or pharmacological intervention. Various methods of stimulation are employed , and various medications have been used, such as stimulant antidepressants .
To stimulate recovery, many rehabilitation professionals recommend placing minimally responsive individuals in stimulation-rich environments . They believe that exposure to frequent and varied sensory stimulation facilitates dendrite growth and improves synaptic conductivity in patients with traumatic brain injury (TBI). It is believed that these patients will gain improvement in their cognitive functions, environmental awareness, and interactions. There are two controversial ideas about the activation of the reticulolimbic system: the more widely accepted idea that external stimulation may stimulate recovery; or alternatively, that too much uncontrolled activation may actually interfere with the natural recovery processes.
In most rehabilitation facilities, it is now accepted that a certain degree of stimulation should be given. However, controversy persists as to the best method and the amount that is necessary .
Motor and Tonus Control
These patients may suffer from different types of motor control dysfunction. A specialist should follow any motor response, for use in communication. Basic reflexes should be stimulated to improve balance and body positioning. Abnormal muscle tonus is most likely to be in the form of spastic hypertonus. A multidisciplinary team, including medical, physiotherapy, and nursing personnel, should conduct the “battle” against these impairments. The therapy should include positioning the patient throughout the day. Specialized physical therapy includes techniques for reducing tonus manually, and the use of various modalities such as hydrotherapy, cryotherapy, and the introduction of neurolytic agents for muscle/nerve block.
As mentioned above, these patients suffer from very severe brain damage, and the prognosis is poor. Since conventional medicine is unable to offer miracle cures for these patients, the families often are drawn to seek alternative solutions in the form of complementary medicine — such as acupuncture, homeopathy, reflexology, etc. However, controlled studies are still needed before such therapies can be legitimized.
Spirituality, Feelings of Satisfaction
The patients are individuals who may live for many years, but are unable to initiate any enjoyable activities. An effort should be made to look for a way to make them feel positive — emotionally and spiritually. It may be using music, visual stimulation, taste and smell, or an opportunity to be at home for short periods. The link between desire, motivation, and awareness is an interesting issue that has not yet been fully investigated.
Clinical Treatment Providers
Who should provide the treatments and for how long? Since the treatment is expected to be given for many years, the cost-effectiveness of interventions needs to be taken into consideration. Since the goals are dynamic, it is recommended that an expert in the field should monitor the patient over a long period of time and take the decision as to which is the treatment of choice. The chance of recovery from this state decreases as time progresses, so therapy for stimulation should be more intensive in the earlier stages — i. e., in the first 2 years post insult.
As was mentioned earlier, the line between what is care and what is therapy is not always clear. Every form of contact with the patient has a combined influence of therapy and care. Care-givers and family members carry out the majority of contact care. It is extremely important that this contact (with nonmedical professionals and family members) should be controlled and monitored by a specialist in the field, such as the physiotherapist, occupational therapist, speech pathologist, etc. The guidance provided by the specialist is intended to prevent complications and enable modifications to be made whenever needed (and it is recommended that he or she be a member of the team).
In many of these patients, the quality and quantity of the response can demonstrate functional progress over many years of treatment, but they nevertheless remain at tragically low levels of function. Other patients may make minimal progress, although that, however, becomes very significant in subjective terms for them and their families in terms of quality of life. Most of these patients do not make any conventional functional independent progress (i. e., reducing the assistance needed) after many years of treatment in their communication, social, or emotional functions. The single case design model appears to be the intervention of choice, with its great flexibility and tailored approach to each individual case . “Recovery” from ASC does not appear to be a smooth, continuous process; those who remain in the vegetative state can show improvements and those who do recover from vegetative state may show little or no improvement, or even deterioration at times . The degree and rate of recovery within different modalities varies between individuals; it will usually occur first in the auditory, communication, motor, or olfactory modality, or in a combination of these responses; visual responses are only rarely the first sign .
Debate is continuing regarding whether ASC patients have some conscious awareness at subcortical levels or not. There is no reliable way of determining the extent to which they can perceive pain and suffering .
Since there is only limited research evidence as to the long-term benefits of sensory stimulation programs, the recommendations rely on “agreed opinions” rather than “hard data.” In order to prevent overstimulation, staff and relatives should use a consistent program of specific stimulation. A period of rest should be allowed before starting the specific controlled sensory input session.
Rehabilitation has been defined as “the development of a person to the fullest physical, psychological, social, vocational, avocation, and educational potential, consistent with his or her physiological or anatomical impairment and environmental limitations” . The application of this definition to severely injured patients, with a guarded prognosis for functional independence, raises interrelated ethical, social, practical, and financial questions. There are no clear criteria for appropriate use versus abuse of rehabilitation resources in such patients.
In order to improve communicative behaviors in minimally responsive patients, Shiel and Wilson  adapted a structured interview that was developed for children with mental delay. A single case report demonstrated that this system was useful in enabling a patient to obey commands consistently when they were within the patient’s ability and to interact with staff, primarily using facial expression. She was able to understand and retain simple information for a period of 10 min, but had no recall of this 2 h later .
Even at the “lowest” level of minimal response, if motor responses are evaluated and interpreted, then at least minimal degrees of movement can be observed . The role of repeatable meaningful responses to commands has been proposed as a distinguishing neurobehavioral characteristic of the minimally responsive state . Even these minimal movements can have huge importance, since they may serve as a communication tool. Extended observation can prevent misdiagnosis ; in their study of 49 vegetative patients, Childs et al.  found that 37 had been incorrectly diagnosed.
Policy and Ethics Related to the Minimally Responsive Patient
In a multicultural, pluralistic society, individuals may be members of several different cultures tied to ethnicity, religion, or business that share some values and differ in others. The rules of behavior for the providers of the rehabilitation services are based on three major cultural fields: the scientific, the humanistic, and the entrepreneurial .
Practical and ethical questions arise on a daily basis concerning the treatment of these patients, such as how long, how much, and in what way these patients should be treated [1,46,47]. Many articles have been written concerning the questions of legal and ethical aspects of patients in the vegetative state, usually concerning life and death and euthanasia . Very few articles have been concerned with the question of what is the “meaning” of treatment for the minimal responsive patient. In the end, however, the question of treatment efficacy remains a moral, rather than a scientific one. Resolving the question of “what is treatment effectiveness?” hinges on the definition of effectiveness. Many of these patients will successfully gain functional improvement over time with the application of conventional methods of rehabilitation and the novel use of pharmacological agents. Usually, it is only several months after the insult that they began to respond in a consistent way. This recovery process is slow and does not change the patients’ basic severe disabilities, as they are still fully dependent in all their activities of daily life. However, they may be able to communicate emotions and desires, and to become more involved in their family life.
The question of how long the treatment should be carried out is easier when the diagnosis is more definitive, as in the vegetative state, than in a group of patients whose abilities are much more diverse, as in the minimally responsive state. Based on reviews of clinical experience and scientific findings, the Multiple Task Force indicated that the odds of emergence from vegetative state are small after 1 year . It is impossible to make such a statement about minimally responsive patients, since the question is not one of quantity (such as a return to consciousness, or emergence from the vegetative state), but of quality (what are the changes in the level of consciousness?).
Questions that involve combined parameters of ethical and practical issues include what the outcome of rehabilitation will be, and what the expected prognosis is. The answers to such questions can be based on statistical and pathophysiological data – for example, a statement such as: “the least recovery of function was seen in anoxic patients who remained comatose for 4 weeks and more” . Comatose patients with traumatic brain injury recover over a period of months and even years after injury, whereas the period of recovery from anoxic brain damage was measured in weeks, with practically no functional gains after 4 months . These widely accepted statements about the time course of recovery, and by inference the appropriate time for treatment, are based on “macroscopic” assessment of functional activity using extremely simple ordinal rating scales with extremely broad and vague categories, such as the Disability Rating Scale . For a “minimally responsive patient,” this “conventional” and simplistic approach of evaluation may not always be valid, since in the view of the patient and family some “microscopic” functional improvement has a “huge” significance.
There are no clear criteria for appropriate use versus abuse of rehabilitation resources in such patients. Who has the responsibility for deciding how much and for how long the treatments should be provided ? Often a patient does not gain any conventional functional independence (i. e., reducing the assistance needed) after several years of treatment, yet on the other hand gains significant improvement in communication abilities and social and emotional functioning. Is the goal of the rehabilitation process to achieve functional ability, or to improve the quality of life within the confines of the disability? Any attempt at defining the quality of life and “worth” of questionable functional gains will imply moral and ethical judgments. Some patients may achieve some rehabilitation, but nevertheless remain at tragically low levels of function. Others may obtain minimal progress, although it is very significant in subjective terms to their quality of life. There is no way at present to predict accurately how much recovery will occur, or when the recovery will plateau. Ansell reported that about half of these patients (classed as “slow to recover”) reach a status of “rehabilitationready”, as defined, between 2 and 48 months after injury; two-thirds of these patients had reached this status of “rehabilitation-ready” 6 months after injury .
According to conventional prognostic criteria, a “minimally responsive” patient is doomed to a very poor rehabilitation outcome, as measured in terms of functional independence and simple, ordinary category scales. A “microanalytic” approach to change may reveal that the long-term rehabilitation process has a more positive impact. Although in the eyes of family members this rehabilitation process is absolutely worthwhile, the gains may only decrease the global costs to society if the families care for patients outside of expensive institutions. With “the era of unlimited medical care over” , the view that society as a whole will take of the costs arising from full professional care for these patients is not clear. No definite answers are available to difficult questions such as for how long, and how much, patients with “minimal activity” should be treated. Each group has to make its own decisions on these issues, depending on resources and ethics. These dilemmas need to be discussed in future medical planning and training programs.
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