28 - Skin symptoms

Editors: Goldman, Ann; Hain, Richard; Liben, Stephen

Title: Oxford Textbook of Palliative Care for Children, 1st Edition

Copyright 2006 Oxford University Press, 2006 (Chapter 34: Danai Papadatou)

> Table of Contents > Section 3 - Symptom care > 26 - Neurological and neuromuscular symptoms

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26

Neurological and neuromuscular symptoms

Kate W Faulkner

Paul B Thayer

David L Coulter

Introduction

Caring for children with life-threatening neurological or neuromuscular symptoms and conditions involves the art of palliative care much more than the science. For example, consider the challenge of pain assessment in non-verbal children whose development is regressing. Here, a working partnership with families is paramount, because often, it is the subtle deviation from children's baseline status that leads parents, and then practitioners, to the recognition of the presence of pain [1]. After a symptom is identified, the diagnostic art continues as caregivers attempt to identify the etiology, be it something physical (related or unrelated to the primary diagnosis), something in the environment, or even a side-effect of previous therapies. Again, since children with neurological impairments or symptoms often have a limited repertoire of responses, a symptom such as increased irritability could have a dizzying array of etiologies, each best approached in a different fashion.

Palliative care and hospice teams are unfortunately most often familiar with children in their last stages of life, when symptoms are rapidly progressive and usually require drug therapy to control. However, children may well live with prominent neurological and neuromuscular symptoms progressing slowly over a number of years. Though medication therapy might still be indicated, often there are other forms of treatment to consider, including surgery, physical and occupational therapy, integrative therapies, environmental interventions, and dietary manipulation. The palliative care team may help the family become aware of these options, serving an important educational and coordinating role. Even if drug therapy is indicated, the practitioner should be aware that few of the recommended drugs have been tested for safety or effectiveness in children. Again emanating from the art rather than the science of medicine, informal networking among physicians and pharmacists has led to a consensus about drugs, doses, effectiveness, and potential side-effects [2].

Chapter outline

This chapter addresses three aspects of palliative care for neurological and neuromuscular symptoms. The first section includes brief summaries of major life-limiting conditions, including synopses of their incidence, etiology if known, clinical presentation, prominent symptoms, general prognostic guidelines, current treatment options, and an indication of sources for more detailed information. This section should help the team provide a roadmap of possible illness trajectories, future symptoms, and therapeutic options to affected children and their families.

The second section reviews the most common or problematic neurological and neuromuscular symptoms palliative

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care practitioners may encounter, along with a discussion of etiology (where known) and the range of therapeutic approaches to ameliorate the symptoms.

The third and final section highlights the global impact of these symptoms on children and their families. Several families have been willing to share their stories, so that the palliative care team might come to better appreciate the experience of living with these conditions and symptoms.

Neurological and neuromuscular conditions

Dramatic changes in the incidence and etiology of childhood death have occurred over the last century in developed countries, as better public health policies have led to improvement in infection prevention and control. After the first year of life, the current greatest threats to children's lives in these countries are unintentional and intentional injuries [3, 4]. Yet, substantial numbers of children still die of complex chronic conditions or diseases, including malignancies.

More deaths occur in the first year of life than all other years of childhood combined, and two-thirds of these deaths occur in the first month of life [6]. The leading cause of infant mortality in the United States in 1999 was congenital anomalies , which include malformations, deformations, and chromosomal abnormalities. A review of two decades of mortality data in the United States showed that malignancies accounted for 2% of infant deaths, neuromuscular diseases for 15%, genetic conditions for 22%, and metabolic defects for 1% [5]. The overall steady decline in infant mortality in most developed countries has traditionally been linked to improved pre- and perinatal care [7]. However, increased use of prenatal testing, and diagnosis of lethal anomalies, leading to elective pregnancy termination prior to the birth of the affected infant, may also be contributing to the decreased number of deaths due to congenital anomalies [8].

During the middle years of childhood, a little over one-third as many deaths occur from life-limiting conditions, as occur in infancy. From one to nine years of age, malignancies account for 36% of deaths, neuromuscular for 21%, genetic for 5%, and metabolic for 3% of all life-threatening illnesses [5]. This proportion changes again in a modest way for 10- to 24-year-old adolescents and young adults. Cancer accounts for 48% of deaths from complex chronic conditions, neuromuscular for 17%, genetic for 13%, and metabolic for 1%. The total number of deaths in this age group work out to about 60% of the total number of deaths that occur in the first year of life.

These statistics are helpful in predicting where palliative care interventions are likely to be most needed and beneficial. Certainly, the team should have a large focus on infants who are newly diagnosed, very symptomatic, and having a prognosis of days to weeks. But at the other end of the spectrum, care is needed for children with neurological and neuromuscular symptoms, and disorders whose course may last for years. Some of these children may have a steady downward course, while others may have waxing and waning of their symptoms [9]. The challenges of supporting this diverse group of children require ongoing assessment and flexibility on the part of parents and professionals alike.

Synopses of major life-threatening conditions with prominent neurological or neuromuscular symptoms follow. Their representation in any given palliative care census may well depend more on the relationship of the team with different referrers, than on the absolute number of children afflicted.

Malformations of the central nervous system

Neural tube defects account for most congenital anomalies of the central nervous system, and result from the failure of the neural tube to close spontaneously between the third and fourth week of gestation [10]. Both genetic predisposition and environmental insults may be responsible for these conditions, including a variety of drugs, infections, maternal diabetes, folic acid deficiency, and irradiation [11]. The most devastating of these disorders is anencephaly. The incidence of this universally fatal condition varies in different populations, but occurs in approximately one in 1,000 live births [12]. In the United States, mandatory folic acid fortification of all enriched cereal grain products since 1996 has led to a 21% decline in the incidence of anencephaly [13]. Increased prenatal surveillance, with elective termination of pregnancy, has also led to a decreased incidence in developed countries [14].

A number of elements contribute to the lethality of the condition. Failure of the cephalic neural folds to fuse into a tube exposes brain cells to the degenerative effects of amniotic fluid. Additionally, mutual induction of the three primary germ layers of ectoderm, endoderm, and mesoderm fails, resulting in deformities of both nervous tissue and supporting axial bone. Clinically, therefore, the calvarium of the anancephalic infant fails to develop, forebrain germinal cells degenerate so no cortex exists, and descending spinal cord tracts as well as the pituitary and optic nerves are absent [11].

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Anencephalic babies almost never survive infancy. During the days to weeks that they live, they exibit slow, stereotyped movements, and frequent decerebrate posturing. These movements can occur spontaneously, or in response to pain. Seizures sometimes occur. Brainstem reflexes, such as sucking and rooting, can be more prominent than in normal infants [11]. Palliative supportive care is generally indicated, though there may also be difficult ethical considerations of organ harvesting and extraordinary life support measures. Since anencephaly is difficult to diagnose histopathologically because of the presence of both primary and secondary destructive processes, it is hard to gauge the importance of the rare reports of survival for several years in a few cases of hydranencephaly [15].

Spina bifida in its many presentations is the second most prevalent neural tube defect. It represents a fusion failure of the posterior vertebral arches, sometimes with accompanying herniation of just the meninges (meningocele), or of the meninges and spinal cord parenchyma and nerve roots (myelomeningocele). In rachischisis, the most severe variant, an extensive defect of the cranio-vertebral bone exposes the brain, spinal cord and meninges. Although the etiology of the disorder is incompletely understood, it is influenced by socioeconomic status, gender, ethnicity, prior offspring with neural tube defects, and maternal age and parity [16]. The overall incidence of all forms approaches one in 1000 births [12].

Historically, nearly half of the infants with meyelomeningoceles who were not treated surgically died within the first year of life, as a consequence of hydrocephalus or central nervous system (CNS) infections [17]. Medical and surgical advances have reduced the mortality rate to 10 15%, with most of these children dying before entering school, of urinary tract infection leading to sepsis and renal failure [12, 18]. However, considerable morbidity exists in survivors that may be improved with palliative support. By adolescence, two-thirds will be wheelchair bound, incontinent of bowel and bladder, and have visual defects. Nearly half will have IQs below 80, and a quarter will have seizure disorders and develop precocious puberty. Nearly all will experience pressure sores and fractures [19].

The other major category of devastating CNS disorders likely to be encountered by the palliative care practitioner is defects of cell migration, including lissencephaly, schizencephaly, and porencephaly. Migratory disorders develop when neuroblasts of the germinal matrix, which forms the wall of the lateral ventricles, fail to reach their intended destination in the cerebral cortex [20]. This results in focal or generalized structural deformities of the cerebral hemispheres. Neuronal migration disorders are associated with a variety of other conditions, including metabolic diseases, chromosomal anomalies, neuromuscular conditions, and neurocutaneous syndromes. A variety of prenatal insults can lead to these disorders, only a few of which, including cytomegalovirus infection, fetal exposure to alcohol, carbon monoxide, radiation, mercury, and isoretinoic acid, have been identified [20].

The clinical presentation varies with the underlying abnormalities, but usually includes massive seizures, hypotonia, microcephaly, optic atrophy, a characteristic facies, spastic quadriparesis or hemiparesis, and profound developmental delay [21]. No treatment of the underlying brain development disorder is possible. This group of disorders is life-limiting, but prognostic variation is great, depending on the extent of the migratory defect and complications that arise.

Chromosomal anomalies

Human diploid cells contain 22 chromosome pairs called autosomes, and one pair of sex chromosomes. Genes, consisting of DNA coding sequences, are arranged in linear order on the chromosome, and contain most of the genetic information that is passed from one generation to the next. Maternal mitochondria also contribute DNA that transmits genetic information [22]. Constitutional chromosomal anomalies generally occur early in embryo-genesis, affecting all or most of children's cells. These mistakes occur more commonly with advancing maternal age [23].

Approximately one-third of recognized genetic disease shows phenotypic expression in the nervous system, reflecting the fact that more than 30,000 genes are expressed in children's brains [24, 25]. This section will consider conditions caused by duplication of an entire chromosome; the subsequent section on metabolic conditions reviews those caused by gene or mitochondrial DNA point mutations.

Studies have shown that major duplications or deficiencies in autosomes tend to be lethal, with death occurring either in utero or soon after birth [26]. Of the autosomal trisomies, only trisomy 21 (Down syndrome) is compatible with a survival of years. Even then, a review of spontaneous abortions reveals that less than a quarter of trisomy 21 cases are live born. No children with the most common trisomy, chromosome 16, are live born; only 2.8% of trisomy 13 cases, and 5.4% of trisomy 18 cases, are live born [27]. Overall, chromosomal anomalies occur in 0.4% of live births [23].

Trisomy 18 (Edwards syndrome) is the most common fatal anomaly, with an incidence of one out of 6,000 births [23]. Affected females are four times more common than males. The clinical presentation is that of a low-birth-weight infant, with a long, narrow skull and prominent occiput, low-set, malformed ears, closed fist with overlapping fingers,

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and rocker-bottom feet. Often, there are co-existing cardiac and renal defects. Neurological manifestations include a small brain and profound developmental delay [23, 28]. Although the vast majority of children will die in the perinatal period, survival beyond the first year of life is possible. A recent mortality review, using United States death certificates from 1979 through 1997, noted that median survival time was 10 days, but 5.6% of children lived longer than one year. Median ages were higher among females and children of African-American origin. The age at death was unaffected by the presence of concurrent cardiac malformation [29].

Trisomy 13 (Patau syndrome) occurs in one out of 10,000 births [23]. Median facial anomalies are prominent in this condition, including cleft lip and palate, and micrognathia. Ears are low-set and malformed, with many infants being deaf. Polydactyly and flexion deformities of the fingers are common. Cardiac abnormalities are frequent, as are polycystic kidneys, omphaloceles, and neural tube defects. The majority of children have small brains, small eyes, and profound neuro-developmental delays. Their clinical course is characterized by feeding difficulties and apneic spells [28]. The median age at time of death is also 10 days; however, slightly over 5% of children survive longer than one year. Race, gender, and the presence of a cardiac defect do not affect survival [29].

Numerous other chromosomal trisomies and deletions have been described and clinically characterized, though not all of them are certain to cause death in childhood [30]. There have been recent, encouraging examples of involvement of the hospice team in the care of these infants and families [31].

Metabolic diseases of the nervous system

Inborn errors of metabolism may be static, chronic and non-progressive (such as many disorders of amino acid metabolism), or they may be progressive and degenerative (such as most lysosomal enzyme disorders). Progressive metabolic disorders generally arise from a mutation (or set of mutations) in a single gene coding for an enzymatic protein that is usually involved in a catabolic pathway. Over 500 of these disorders have been described, most with an autosomal recessive pattern of inheritance. The overall incidence is approximately one in 5,000 live births. The mechanism by which inborn errors of metabolism produce brain dysfunction remains incompletely understood; however, it may be that products upstream of the enzymatic defect accumulate after birth in toxic amounts in brain tissue. Additionally, there may be a decrease in critical components downstream of the defect, so that appropriate neuro-development is not possible. The neuro-degenerative process can involve primarily the gray matter of the brain cortex itself, or the white matter of myelination [32].

Common neonatal symptoms of metabolic disorders include poor feeding, hypotonia, lethargy, respiratory difficulties, failure to thrive, psychomotor delay, seizures, and prominent vomiting. Rapid progression to death is the rule, unless prompt diagnosis and treatment are available [33]. Table 26.1 summarizes the symptoms for a select group of lethal point mutations. Diagnosis usually depends on specific enzyme assays, or on molecular genetic analysis [34]. Many nations have instituted newborn screening programs to detect more prevalent, treatable conditions. The recent introduction of tandem mass spectrometry has allowed rapid and inexpensive screening for a number of very rare disorders, but the yield and clinical utility of the procedure is still being defined [35].

In older infants and children, metabolic disorders present with chronic encephalopathy and the progressive loss of previously acquired abilities in mental and neurological function. Hallmarks include loss of developmental milestones, vomiting, irritability, seizures, myoclonus, tremors and either spasticity or hypotonia. Depending on the metabolic error, there may be changes in hair color and texture, skin dryness and texture, the development of coarse facial features, and a distinctive body odor. Again, without specific diagnosis and therapeutic intervention if available, many of these conditions will result in death in childhood. Besides assays, biopsies of liver or muscle may be helpful, as are neuro-imaging studies and genetic analysis [36].

Careful, specific diagnosis can lead to genetic counseling at a minimum, and treatment of the disorder, if treatment is available. Therapies are limited, and have as their goals correction of the metabolic abnormalities, removal of toxic metabolites, and treatment of other life-threatening conditions, such as cardiac arrythmias. For example, in the disorder phenylketouria (PKU), life-long dietary reduction of phenylalanine intake prevents neurological decline. A more definitive therapeutic approach to correcting genetic disease has been to transplant bone marrow or liver from a normal donor into affected children. Transplantation is effective only if the defective enzyme is normally expressed and active in the transplanted tissue, as stem cells are for several storage diseases [37]. Another possible therapy involves the periodic infusion of fully functional enzyme into children, if it can be identified, purified, and made affordable for a lifetime of therapy [38]. Finally, efforts to develop human protein drugs by cell culture or production in milk of transgenic animals are ongoing [39].

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Table 26.1 Selected incurable point mutation disorders Selected incurable point mutation disorders

Source: Derived from Rosenberg, R.N., Prusiner, S.B., Di Mauro, S., and Barchi, eds. Clinical Companion to the Molecular and Genetic Basis of Neurological Disease (Second edition). Boston: Butterworth Heinemann, 1998 and Menkes, J.H., Sarnat, H.B., eds. Child Neurology. Philadelphia, PA: Lippincott Williams & Wilkins, 2000.

Aminoacid disorders

NKH nonketotic hyperglycinemia (Glycine encephalopathy)

presents in the neonatal period;

intractable seizures/profound hypotonia;

frequent hiccups;

progressive obtundation with coma;

apnea/respiratory arrest in the neonatal period.

Ataxia disorders

Ataxia-telangiectasia

presents in infancy/early childhood with ataxia;

telangiectases bridge of nose/ears/neck/elbows/conjunctiva;

choreoathetosis/eye apraxia/nystagmus;

high incidence of leukemia/lymphoma;

diabetes in adolescence;

death variable from bronchopulmonary infection/cancer.

Carbohydrate disorders

Pompe's disease-infantile (Infantile acid maltase deficiency)

presents in first weeks/months;

diffuse hypotonia/weakness;

macroglossia/increased muscle bulk;

cardiomegaly/heart failure;

respiratory insufficiency leading to death by age 1 2 years.

Degenerative disorders

Canavan's disease (Spongy degeneration of the cerebral white matter)

presents at 2 4 months of age;

developmental arrest/macrocephaly;

optic atrophy/blindness/nystagmus;

hypotonia/spasticity;

irritability/sleep disturbance/seizures;

intermittent fevers;

gastroesophageal reflux/bulbar weakness;

death often in first decade.

Genetic epilepsies

Batten's disease (Neuronal ceroid lipofuscinoses)

presents at 9 19 months of age;

developmental regression/microcephaly;

generalized, persistent seizures;

optic atrophy/blindness/brown macular pigmentation;

death variable.

Lysosomal disorders

Hurler's syndrome (Mucopolysaccharidosis type I)

normal at birth/coarse facial features develop after

6 months;

chronic rhinorrhea/recurrent infections;

organomegaly/hernias;

bony changes (dystosis multiplex)/kyphosis;

mental regression to vegetative state;

death from airway obstruction/bronchopneumonia

mid-childhood.

Sanfilippo's syndrome (Mucopolysacchaidosis type III)

normal at birth/delayed development between 2 5 years

of age;

neurologic regression/ataxia/tremor/spasticity/bulbar palsy;

coarse facial features/mild hepatosplenomegaly;

loss of extension of the interphalangeal joints;

hydrocephalus; death in adolescence.

Niemann-Pick disease type A (Sphingomyelin lipidosis)

presents in first year of life;

massive hepatosplenomegaly/diarrhea;

persistent neonatal jaundice with brown/yellow skin;

generalized lymphadenopathy/pulmonary infiltrates;

macular degeneration with cherry-red spot;

cognitive regression;

death by 5 years of age.

Krabbe disease-infantile (Globoid cell leukodystrophy)

presents at 4 6 months of age;

restlessness/irritability/progressive stiffness;

increased muscle tone/tonic spasms/seizures;

fever without infection; mental/motor regression;

death by 15 months with terminal flaccidity/bulbar signs.

Tay Sachs disease (GM2 gangliosidosis)

presents at 4 6 months of age;

listlessness/irritability/hearing loss;

developmental regression/lethargy/immobility;

spasticity/myoclonus/generalized seizures/opisthotonus;

progressive enlargement of the head;

macular degeneration with cherry-red spot;

death by 2 5 years of age.

Metal metabolism disorders

KHD Kinky hair disease (Menkes disease)

presents most often in neonatal period;

hypothermia/hypoglycemia/poor feeding/poor weight gain;

marked hypotonia/neurological deterioration/seizures;

facies cherubic appearance/hair colorless and friable;

radiographic abnormalities/hydronephrosis;

enlargement intracranial vessels/subdural hematomas;

course variable/death during childhood most often.

Mitochondrial disorders

Leigh syndrome (Subacute necrotizing encephalomyelitis)

maternal transmission with presents in infancy/childhood;

variable course/some survive to adulthood;

psychomotor regression/somnolence;

myopathy/hypotonia;

optic atrophy with blindness/ophthalmoplegia;

movement disorders/ataxia/peripheral neuropathies;

disturbances of respiration.

Peroxisomal disorders

Zellweger syndrome (Peroxisomal assembly deficiency)

intrauterine growth retardation/typical high, flat facies;

profound weakness/hypotonia;

optic atrophy/cataracts, chorioretinities;

hepatomelagy/cirrhosis/renal cysts;

death by 1 year of age.

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Neuromuscular disorders

Neuromuscular diseases affect the motor neuron unit in one of four places: the motor neuron, its axon, the neuromuscular junction, or the muscle fibers innervated by the neuron. These conditions have a limited clinical expression with considerable overlap of signs and symptoms, making definitive diagnosis challenging. Diagnostic tools include muscle enzyme assay, electromyography, nerve conduction studies, and muscle biopsy [40]. Since the identification of the specific gene responsible for Duchenne muscular dystrophy was made 15 years ago, research on the molecular pathogenesis has revealed a number of closely connected disorders, allowing for genetic counseling and the potential for replacement gene therapy [41].

The most common and clearly defined of the muscular dystrophies is Duchenne muscular dystrophy, an x-linked recessive disease with a prevalence of one in 25,000. The disease becomes apparent in early childhood, when affected boys exhibit pelvic muscle weakness, resulting in lordotic posture, and experience difficulty in climbing stairs or in getting up from the ground. Striking enlargement of the calf muscles occurs, as collagen and fat accumulate between muscle cells. Hamstring contractures are common. Confinement to a wheelchair generally occurs by the teenage years, accompanied by rapidly progressive scoliosis. Death tends to occur in young adulthood, either from respiratory failure or from cardiac myopathy. Supportive care from a physical medicine and rehabilitation team can prolong functional survival. Palliative therapies include orthotic bracing, physiotherapy, and surgery to release contracted tendons [42].

Non-invasive oral and nasal intermittent positive-pressure ventilation, in conjunction with mechanically assisted coughing, has led to a steady improvement in life expectancy in the muscular dystrophies [43]. Over half of those adolescents using nocturnal home external ventilation since the 1990's have achieved a mean age of over 25 years [44]. Although assisted ventilation can lead to better clinical status in terms of sleep improvement, energy levels, and headaches, some patients find it physically or psychologically objectionable. It does not prevent the development of fatal cardiomyopathy, so its use is truly palliative. Both patient and family will benefit from anticipatory information and support from the team, in making the decision on adopting non-invasive ventilation.

As in all diseases with a single gene defect, considerable effort is being devoted to develop gene therapies. Different researchers are attempting cell transfer therapy using viral vectors, drugs designed to up-regulate compensatory muscle proteins, and strategies to repair the mutation in vivo. As yet, none of these approaches have entered the phase of human testing [45, 46].

The second most common group of hereditary neuro-muscular disorders is the spinal muscular atrophies (SMA's). These are transmitted by an autosomal recessive gene with an overall incidence of one in 10,000 to 25,000. The type 1 infantile form of SMA, commonly known as Werdnig-Hoffmann disease, generally presents before the age of 6 months with severe hypotonia, generalized weakness, muscle atrophy, absent tendon reflexes, and fasciculation of the tongue. Cardiac and smooth muscle remain unaffected, as does sphincter control. Children generally are unable to feed; over two-thirds die of respiratory involvement before two years of age [47].

Non-invasive nocturnal ventilation can confer numerous benefits, not only by prolonging life, but also by improving the quality. Symptoms related to hypoventilation, such as early morning drowsiness, headaches and feelings of heaviness can all be relieved by non-invasive ventilation. However, for many families this represents a burden they are not prepared to consider. Patients may find the mask intolerable. Many families do not want hospital technology to invade their home. Palliative care paediatricians may find themselves paradoxically advocating against this palliative intervention, on behalf of the patient [48, 49].

Lastly, it is important to remember that many patients who are offered interventions such as non-invasive ventilation, are old enough or mature enough to give or withhold consent for them. Boys with Duchenne muscular dystrophy, in particular, are often offered non-invasive nocturnal ventilation as they reach late teenage. It is important to consider the legalities of overriding the expressed wishes of these older children.

Cerebral palsy

Cerebral palsy (CP) is a neurological syndrome, rather than a specific disease entity. It is characterized by a group of motor syndromes resulting from disorders of early brain development. It is the most common form of chronic motor disability that begins in childhood. CP is often associated with epilepsy and abnormalities of speech, vision, and intellect [50]. Causes of CP include perinatal hypoxic-ischemic encephalopathy, intra- or periventricular hemorrhage, cerebral dysgenesis, and intracranial infection. The prevalence ranges from 1.5 to 2.5 per 1,000 live births, with the risk highest among very pre-term and low-birth-weight babies [51]. The clinical feature common to all CP syndromes is the presence of pyramidal or extra-pyramidal signs. The syndromes may be classified by the predominant type of motor disturbance, for example, quadriplegia (four affected extremities), diplegia (legs more than arms), hemiplegia (one side), ataxic (incoordination of voluntary movement), or dyskinetic (involuntary movements).

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The clinical presentation is one of a gradual change from generalized hypotonia of the newborn period to spasticity in childhood, along with an abnormal evolution of postural reflexes. Over time, the increased tone leads to contractures, with resultant limb deformities such as scissoring, and scoliosis [52]. In children with ataxic and dyskinetic forms of CP, however, the hypotonia of infancy persists. Once the diagnosis of CP is made on the basis of the clinical picture, a complete investigation of possible etiologies should be undertaken. Sometimes, underlying disorders have made children more susceptible to the effects of perinatal trauma and asphyxia. Many neurological, neuromuscular, and metabolic disorders cause increased vulnerability to the stresses of delivery and extra-uterine life [51].

Although CP has no cure, many palliative measures are available to aid children in becoming as highly functional as possible. Depending on the clinical presentation, these may include communication devices, physiotherapy, bracing, speech therapy, and involvement of other team members. The various treatments available for spasticity will be discussed in the next section.

Palliative care practitioners should be particularly familiar with spastic quadriplegia, the most severe form of CP. This syndrome, which accounts for about 20% of all CP cases, is characterized by marked motor impairment of all extremities and a high incidence of mental retardation and seizures. Swallowing difficulties are common, owing to supranuclear bulbar palsies, and often lead to aspiration pneumonia [50]. Nearly all deaths from CP during childhood will occur in this most severe group, with pneumonia frequently being the immediate cause of death [53, 54].

Central nervous system cancer

After the first year of life, cancer is the leading cause of disease-related mortality in childhood [55]. Cancers of the brain and central nervous system are the most common type of solid tumor in childhood, and are second only to leukemia in overall incidence. They account for approximately 20% of all pediatric cancers [56]. Leukemia and CNS cancer are also the most frequent cause of cancer deaths in children and adolescents. Although overall survival rates for most childhood cancers have improved dramatically since 1975, as reflected in the 44% drop in age-adjusted mortality, the improvement in prognosis for brain tumor patients is less dramatic, at 24% [55].

The overall annual incidence of tumors of the central nervous system is approximately three cases per 100,000 children. The incidence peaks in the first decade of life, then declines steadily through adolescence. About 10% of children with a brain tumor have a syndrome that has placed them at increased risk, such as neurofibromatosis or tuberous sclerosis. Other known pre-disposing factors include radiation, immuno-suppressive disorders, rare familial clusters, and previous cancer [56].

Different types of tumors predominate at different ages. In the first two years of life, cerebral cancer occurs more commonly, including low-grade gliomas, primitive neuroectodermal tumors (PNET), and choroids-plexus tumors. In older children, posterior fossa lesions predominate, including diagnoses such as medulloblastoma, cerebellar and brainstem astrocytomas, ependymoma, and brainstem glioma [57]. It is this predominance of midline tumors of the posterior fossa that makes the clinical presentation of brain tumors in children so different from those in adults. In addition to focal neurological deficits, children often present with protean manifestations of increased intercranial pressure. Major clinical symptoms are presented in Table 26.2.

Treatment of pediatric brain tumors involves varying combinations of surgery, radiation, and chemotherapy, depending on the age of the child and the type of tumor [58]. The value of extensive tumor resection has been established in a number of childhood CNS tumors as a means of cytoreduction of the cancer, prior to other forms of therapy. Advances in microsurgical technique have made more extensive surgery possible, without increased morbidity. Several of the most common brain cancers respond well to radiotherapy, but radiation of the growing brain and spine carries more risk of negative side-effects, including decreased intelligence, short stature, and secondary bone cancers. For this reason, radiation is normally not administered to infants and very young children, except as a last resort. Pediatric brain tumors tend to be more responsive to chemotherapy than do adult tumors, with various regimens being studied in efforts to improve survival [56, 58]. Considerable long-term sequelae of both cancer and cancer treatment are reported in survivors, including visual impairment, epilepsy, and cognitive and motor impairment [59].

In addition to primary brain cancer, neurological symptoms arise when other pediatric tumors metastasize to the brain or spinal fluid. Without specific chemotherapeutic or radiation therapy to prevent tumor spread, both leukemia and lymphoma have a high incidence of seeding the cerebral spinal fluid [60]. Neurological complications can occur in almost one-third of solid tumors as well, most often in association with neuroblastomas and sarcomas. Complications include brain space-occupying lesions, spinal cord compression, peripheral or cranial neuropathies, and seizures [61].

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Table 26.2 Clinical manifestations of pediatric brain tumors

Signs and symptoms

(Adapted with permission from (2000) Wong D.L. and Hess C.S., eds. Clinical manual of pediatric nursing, fifth edition, p. 498. Mosby, St. Louis).

Headache

recurrent and progressive;

in frontal or occipital areas;

usually dull and throbbing;

worse on arising, less during day;

intensified by lowering head and straining, such as during bowel movement;

coughing, sneezing.

Vomiting

with or without nausea or feeding;

progressively more projectile;

more severe in morning;

relieved by moving about and changing position.

Neuromuscular changes

incoordination or clumsiness,

loss of balance (use of wide-based stance, falling, tripping, banging into objects);

poor fine motor control;

weakness;

hyporeflexia or hyperreflexia;

positive Babinski sign;

spasticity;

paralysis;

Behavioral changes

irritability;

decreased appetite;

failure to thrive;

fatigue (frequent naps);

lethargy;

coma;

bizarre behavior (staring, automatic movements).

Cranial nerve neuropathy varies by tumor location, but can include

head tilt;

visual defects (nystagmus, diplopia, strabismus, episodic graying out of vision visual field defects).

Vital sign disturbances

decreased pulse and respiration;

increased blood pressure;

decreased pulse pressure;

hypothermia or hyperthermia.

Other signs

seizures;

cranial enlargement (before sutures close);

tense, bulging fontanel at rest (in infants);

nuchal rigidity; papilledema.

Coma and the vegetative state

Unintentional injuries remain the leading cause of death in childhood after the first year of life [55]. Traumatic brain injury accounts for 70% to 80% of these deaths, with a particularly high incidence among adolescent males [62]. Many survivors have life-long disability. The most common cause of accidents in children is involvement in motor vehicle crashes. Other leading causes of traumatic brain injury include pedestrian accidents, bicycle accidents, and drowning [63].

While the most effective resuscitative techniques in the field and emergency room for a child with severe head trauma or anoxia have been debated for decades, attention has only recently turned to considering optimal palliative care for injured children and their families [64, 65]. Teams can be effective in complementing the medical care by sensitive and effective communication with families, interpretation of diagnostic procedures, identification and coordination of the health care providers, and anticipatory guidance with families facing decisions about the course of further treatment.

Ongoing efforts to effectively prognosticate in children with severe traumatic brain injury involve refinement in clinical assessment and rating, with scales such as the Glasgow Coma Scale and Outcome Scale-Extended, and the use of tests such as the electroencephalogram (EEG) and somatosensory-evoked potentials (SEPs) [66, 67]. Both medical and neurosurgical treatment advances have improved survival by careful attention to airway maintenance, circulation, fluid and electrolyte imbalances, increased intercranial pressure, coagulapothies, and seizures. Treatment often involves prolonged stays in pediatric intensive care units. In general, children with comparable injuries have better outcomes than do infants or adults [68].

Children who survive acute injuries sometimes lapse into what has been called a vegetative state, as in the eighteenth century Oxford English dictionary definition, to live a merely physical life, devoid of intellectual activity or social intercourse [69]. ' The vegetative state is characterized by the combination of periods of wakeful eye opening, without any evidence of a working mind either receiving or projecting information, so there is a dissociation between arousal and awareness. After acute CNS insults, the eyes open spontaneously, after a period that varies according to the mechanism of the insult. In concussive head injury, it usually takes two to three weeks, and sometimes, as long as 12 weeks, before the eyes open and coma ends. The interval is much shorter in non-traumatic head injury. Some children can eventually regain a wide repertoire of reflex responsiveness without any evidence of awareness, while others regain some degree of recognizable consciousness. The term minimally responsive state has been used to differentiate this condition [70].

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The Multi-Society Task Force of adult and pediatric neurologists and neurosurgeons in the United States has summarized extensive outcome data on the vegetative state, and concluded that it could reasonably be declared permanent three months after non-traumatic injury, and 12 months after traumatic head injury in children. Out of children in a vegetative state one month after traumatic head injury, 9% were dead after one year, 27% were independent, with good recovery to moderate disability, and the rest were in a vegetative or minimally conscious state. For those with non-traumatic CNS injury, 22% had died after one year, and 6% were independent. The main causes of death were pulmonary or urinary tract infections, and systemic failure [71]. The type of palliative care that children receive, and the location of that care, also has some effect on survival [72].

There is no known cure for coma or the vegetative state, however, a wide range of palliative options, including feeding, physical therapy, environmental stimulation, and skin care are possible. Palliative care practitioners may become involved in the discussion of to what extent, and for how long, these supportive measures should be continued. Ongoing efforts to improve functional survival include the administration of bromocriptine, systematic neuropsychological testing, sensory stimulation, and comprehensive rehabilitation, with physical therapy, occupational therapy, and speech therapy [73].

Other life-threatening conditions with a neurological component

Neurological symptoms may complicate the process of other systemic life-threatening conditions. Although the brain and nervous system are not the initial targets, sometimes their involvement drives decisions to concentrate on comfort care, rather than further curative efforts. Several of these conditions are mentioned below.

Extreme prematurity

In the past decades, advances in the care of extremely premature infants (those born at 20 25 weeks of gestation, weighing 500 1000 g) have led to steady improvement in survival. However, neuro-developmental morbidity has been high, and includes impaired health, recurrent hospitalizations, educational problems, and adverse effects on the family [74]. Approximately 30% to 50% of surviving children who weigh less than 750 g at birth, or whose gestational age was less than 25 weeks, had moderate or severe disability, including blindness, deafness, and cerebral palsy [75, 76].

No consensus exists at present in developed countries, as to which babies might be candidates for palliative care rather than intensive care. Nor is there agreement on whether the final decision should come from the physician or the family. Physicians' attitudes tend to reflect those of the country and culture in which they live [77]. Parents tend to be more reluctant than physicians or nurses to withdraw life support from their extremely pre-term infants, even if the babies are likely to have moderate disabilities [74]. A palliative care consultation service in the neonatal intensive care setting can help facilitate the process of shared decision-making, and have a positive impact on the quality of ICU life for the infants who die [78].

Complex congenital heart disease

The interrelationship of neurological and cardiac disease occurs in at least two forms. The first is that some children are born with, or develop, both disorders as part of their disease process. In a recent review of cardiomyopathies, for instance, a number of co-existing conditions were identified, including inborn errors of metabolism, malformation syndromes and chromosomal defects, and neuro-muscular disorders [79]. Estimates are that about a third of the neurological complications associated with heart disease fall into this category. However, the other two-thirds occur following cardiovascular surgery. The majority of these were motor handicaps, that is, hemiplegia, tetraplegia, and paraplegia [80].

Even with improvements in surgical and medical care, children who have undergone repair or palliation of congenital heart defects have lower IQ scores and achievement tests, delays in reaching motor milestones, and higher frequencies of learning disabilities and use of special services, as well as speech, language, and behavioral abnormalities [81]. Helping families become aware of the prognosis and future course may assist them in making decisions about treatment [82].

Human immunodeficiency virus

The HIV virus is known to enter and replicate within the central nervous system shortly after initial systemic infection. Perinatally acquired HIV infection has a high association with neurological abnormalities, which seem to be associated with the release of various toxic factors by macrophages and microglia, or certain viral proteins, rather than through direct infection of neurons by HIV [83].

A wide range of CNS manifestations of HIV disease have been reported, including developmental decline in both fine and gross motor skills, cognitive delay or deterioration, language deficits, and delayed psychomotor speed [84]. The most severe and pervasive neurological problems occur in those children who have early serious HIV clinical disease [85]. Effective anti-viral treatment shows promise in delaying and improving the neurological complications of HIV infection [83]. This should

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allow for better quality of life, as children can lead a more normal existence in school and with their peers.

Neurological and neuromuscular symptoms

Pediatric palliative care practitioners will encounter a wide variety of neurological and neuromuscular symptoms in their practice. The constellation of symptoms seen will depend on the underlying diagnoses of referred children, and their positions in the trajectory of their disease. This section of the chapter will explore the most common or urgent of these symptoms, examining possible etiologies, diagnostic approaches, and a range of therapeutic options.

Incidence of symptoms

The most important determinant of the prevalence and type of neurological symptoms is the underlying diagnosis. To illustrate this, it is useful to look at the epidemiology of neurological and neuromuscular symptoms in children with neuro-degenerative disorders, compared to that of children with cancer. The largest published series of the former is that of Helen House, an English pediatric hospice [86]. Over 40% of the children admitted in an 11-year period suffered from neuro-degenerative conditions, chiefly inherited metabolic diseases. Examining the clinical course of the 45 children admitted in the last study year, communication disorders and feeding problems were found in over 70% of the children. Respiratory infections and dyspnea were recorded in 38% of the children, exacerbated by limited mobility, swallowing difficulty, muscular weakness, and kyphoscoliosis. A third had problems swallowing their own secretions. Seizures occurred in 60% of the children. Constipation was an ongoing symptom in 44% of the children. A little over a third of the children were identified as experiencing pain, with the most common etiology being muscle spasm. Other causes included constipation, gastritis, and esophagitis from reflux. Only three children, out of those having pain, required an opioid for relief. Movement disorders, including ataxia, dystonic posturing, and jerky uncontrolled movements, were found in over a third of the children. About the same number of children, particularly those with mucopolysaccharidoses, experienced sleep disorders. Though the great majority of the children were immobile, requiring assistance to turn or get up, and were incontinent of bladder and bowel, none developed skin breakdown.

The most important group of children with cancer who experience neurological symptoms, is those with tumors of the central nervous system. Weakness, immobility, motor and sensory loss, pain and seizures are the commonest neurological symptoms.

Neurological symptoms are not, however, restricted to children with brain tumors [87]. On reviewing the consult histories of over 150 children, headache and seizures were found to be the most frequent symptoms prompting consultation. Structural lesions were found in over 84% of the children with headaches, and in 37% of the children with seizures. There was an approximately equal distribution between lesions attributable to the cancer, to the treatment for the cancer, or from an cause unidentified. Leukemias and lymphomas were represented most often, followed by neuroblastoma, Ewing's sarcoma, and rhabdomyosarcoma. In following a more recent group prospectively, headache was still seen to be the most common complaint, followed by altered mental status, and back pain [88, 89].

Headache was more often reported by children with leukemia and lymphoma, and back pain by children with solid tumors. Iatrogenic complications, related to chemotherapy, accounted for over a quarter of the identifiable etiologies. Again, a high percentage of the neuroradiologic examinations were abnormal, and helped to identify the etiology of the symptom. A recent review limited to children with solid tumors showed that 31% presented with, or developed, neurological symptoms, including brain metastases, spinal cord compression, peripheral or cranial neuropathies, and seizures [61]. Children with neuroblastoma and sarcomas had the highest incidence of symptoms.

Neurological complications of chemotherapy have been examined in detail, and include acute alterations in consciousness, leukoencephalopathy, seizures, cerebral infarctions, paralysis, neuropathy, and ototoxicity [90]. Complications have been most often attributed to methotrexate, cyclosporin (ciclosporin), and platinum compounds. Radiation therapy on the central nervous system has also been associated with neurological toxicity, particularly in children less than three years of age, or in children receiving high dosages. Complications include an overall decrease in IQ, neuropsychological deficits, blindness or visual impairments, progressive necrotizing leukoencephalopathy, radionecrosis, intracerebral calcification, dilatation of the ventricular and subarachnoid spaces, and white-matter hypodensity [91].

A recent comprehensive review of symptoms experienced by all children dying in hospital during a nine-month period, identified six symptoms which occurred in over half of the children: lack of energy, drowsiness, skin changes, irritability, pain, and swelling of arms/legs [92]. The prevalence of neurological symptoms was less. Headaches occurred in slightly over a quarter of the children, insomnia in 20%, and numbness/tingling of the extremities in 10%.

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Assessment tools

Though assessment is discussed in depth elsewhere in this book, palliative care practitioners should be cognizant of the different types of tools available to assess children with neurological and neuromuscular symptoms. One type of assessment focuses on physical symptoms, sometimes with a psycho-social component. Neurological symptoms were under-represented in two of the most recent studies using tools in this category. One retrospective survey of pediatric cancer deaths in the United States assessed fatigue, pain, dyspnea, poor appetite, constipation, nausea and vomiting, and diarrhea [93]. Validation of the Memorial Symptom Assessment Scale in children looked at lethargy, pain, insomnia, itch, lack of appetite, worry, nausea, and sadness [94]. Several other physical assessment tools have been developed to assess specific symptoms in children, including fatigue and delirium [95, 96].

Another approach to assessment has been to look at the global functioning level of children studied. This has been attempted in children with cancer, via development of the play-performance scale [97]. A number of tools are available to assess the functional status of children with developmental disabilities, compared with normal controls. These adaptive-functional instruments include the Pediatric Evaluation of Disability Inventory, the Vineland Adaptive Behavior Scales, and the Battelle Developmental Inventory [98]. These assessment tools are maximum data sets, and involve detailed and extensive queries of self-care, mobility, communication, and social items. The Functional Independence Measure (WeeFIM) gives clinicians a shorter version of the same type of tool. Considerable validation has been done across cultural and geographic settings [99, 100]. The US National Center for Medical Rehabilitation Research has developed a model of disablement assessing five dimensions of human functioning: patho-physiology, impairment, functional limitations, disability, and societal limitations, which can be used to describe the functional strengths and challenges in children with a variety of genetic and metabolic syndromes [101].

A comprehensive review of health-related quality of life assessment tools in pediatric palliative care supports the assumption that unrelieved disease-specific symptoms are predictive of generic Health Related Quality of Life (HRQ), and reinforces the necessity for practitioners to assess and address symptoms [102]. Functional limitations not only impact children's lives, but those of their family caregivers. It has been established that care needs of children with severe disabilities have significant time costs to the family, do not decrease as children grow, and may prevent the caregiver from working outside the home, thus reducing total family economic resources [103]. In addition, depression and anxiety in caregivers closely correlate with demands on care-time, particularly in the case of children who are disabled on the basis of a terminal neurodegenerative disease, as opposed to a static handicap [104]. This burden on the family will be discussed further in the next section, but it should give added impetus to the clinician to aggressively approach symptom management of neurological conditions.

Movement and paroxysmal disorders

A movement disorder typically is defined as dysfunction in the implementation of appropriate targeting and velocity of intended movements, dysfunction of posture, the presence of abnormal involuntary movements, or the performance of normal-appearing movements at inappropriate or unintended times. The movement abnormalities are not due to weakness or abnormal muscle tone, but may be accompanied by weakness or abnormal tone [105]. ' The first major category of movement disorders is the hyper-kinetic disorders, often referred to as dyskinesias. This category of abnormal, repetitive, involuntary movements encompasses tics, chorea, dystonia, myoclonus, stereotypies, and tremors. Hypokinetic movements constitute the second major category, sometimes referred to as akinetic, or rigid, disorders. The primary movement disorder in this category is Parkinsonism. This second category is much less common in children. Only a few of the movement disorders are seen with any frequency in palliative care.

Chorea

Chorea is characterized by frequent, brief, purposeless movements that tend to flow from body part to body part chaotically and unpredictably [105]. They last longer than myoclonic jerks, but not so long as the sustained contraction of dystonia. The movements can be sudden and abrupt, but are more often continuing and flowing. The term choreathetosis is used for the latter case. The disorder is commonly exacerbated by emotion and fatigue. Primary chorea is almost always attributable to acute rheumatic fever, and does not present in palliative care. However, secondary chorea is associated with a number of neuro-degenerative diseases, including ataxia telangiectiasia, Niemann-Pick, gangliosidoses, Lesch Nyhan, perinatal asphyxia, and certain gene mutation syndromes. It can occur in hepatic and renal encephalopathy, hypo- and hypernatremia, and protein-calorie malnutrition. Numerous drugs, notably, haloperidol, isoniazid, reserpine, phenytoin, or phenothiazines, can also induce choreiform movements [105, 106]. If the chorea is symptomatic and warrants treatment, bed rest in a darkened, quiet room can greatly help in the short term. A number of drugs are also

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available as treatment, including sodium valproate (15 to 25 mg/kg p.o. per day), which generally controls the movements in 5 to 10 days. The drug can gradually be withdrawn after two to six months, to see if it is still needed [106].

Dystonia

Dystonia is a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal postures [105]. In palliative care, secondary causes dominate. Heredo-degenerative disorders associated with dystonia include ataxia telangiectasia, gangliosidoses, glutaric aciduria, Lesch-Nyhan, metachromatic leukodystrophy, mitochondrial disorders, Neimann-Pick, and methylmalonic academia. Certain classes of drugs are commonly associated with acute dystonic reactions in children [107]. These include the older dopamine, antagonist anti-psychotics like haloperidol, and the anti-emetics, notably metoclopramide, and to a lesser degree, ondansetron and chlorpromazine. Other palliative care drugs that may cause acute dystonias include the tricylic and SSRI antidepressants, and the anti-epileptics phenytoin, carbamazepine, and sodium valproate. Drug induced dystonias manifest with abnormal positioning of head and neck (torticollis), spasms of jaw muscles (trismus, grimacing), tongue dysfunction (dysarthria, protrusion), dysphagia, laryngo-pharyngeal spasm, dysphonia, and upward/downward/sidewise deviation of eyes (oculogyric crisis), as well as abnormal positioning of limbs or trunk. These movements, also referred to as extrapyramidal reactions, are frequently accompanied by high levels of anxiety in the affected children. They respond quickly and completely to treatment with anticholinergic medications such as diphenhydramine (1 mg/kg per dose p.o. q.6 h.) and benztropine (benzatropine) (0.5 2 mg per day p.o. divided b.i.d.) [105, 107]. These medications can be co-administered with the offending drug if it needs to be continued for symptom relief, but sedation can be expected. It may be necessary to continue the anticholinergic medication for a day or two after the offending drug is discontinued, in order to prevent the extra-pyramidal reaction from reoccurring.

Akathisia

Acute akathisia is a form of motor restlessness, in which children feel compelled to pace up and down, or to change body position frequently [107]. It almost always occurs secondarily to a drug, with haloperidol and prochlorperazine carrying the highest risk. Concurrent administration of morphine or sodium valproate may add to the incidence of akathisia. It commonly develops within days of starting the drug, and may continue to Parkinsonism, if the offending drug is not recognized and discontinued. If drug therapy is needed to obtain relief, a lipophilic beta-adrenoceptor antagonist may be used with good effect, such as propranolol (0.5 4 mg/kg/day p.o. divided q. 6 8 h.) [107].

Myoclonus

Myoclonic movements are very brief, abrupt, involuntary, non-suppressible, and jerky contractions involving a single muscle or muscle group [105]. These shock-like movements can be focal, multi-focal, segmental, or generalized. They are present in normal situations (associated with sleep onset, exercise, and anxiety), and also occur in a variety of pathological situations. The most significant one in palliative care is the myoclonus associated with opioid therapy. It is usually seen in the setting of high-dose and long-term therapy, or spinal opioid, or in cases of rapid dose escalation [108]. If the myoclonus is frequent and distressing to the child, lessening the dose of opioid, or rotating to a different one, may be tried. If neither of these options appears optimal, the myoclonic jerks can be ameliorated by adding a benzodiazepine, such as clonazepam (0.01 mg/kg/dose p.o. q. 12 h.), lorazepam (0.02 0.05 mg/kg/dose p.o, s.l., pr., or i.v. q. 4 8 h.), or diazepam (0.5 mg/kg/dose p.o., p.r., or i.v. q. 4 8 h.) [108, 109].

Seizures

Epilepsy may be defined as recurrent convulsive or nonconvulsive seizures caused by partial or generalized epileptogenic discharges in the cerebrum [110]. Seizures are the principal neurological manifestations of many of the metabolic and neuro-degenerative conditions seen in palliative care. Generalized tonic-clonic seizures are the most common epileptic manifestation of childhood. They are sometimes preceded by non-specific premonitory feelings, such as a sensation of dizziness, or an unusual feeling of ascending abdominal discomfort. Specific neurological symptoms (such as focal somato-sensory feelings, olfactory sensations, focal motor activity, vertigo and odd psychic feelings) may reflect focal onset of seizure activity in one part of the brain, which then spreads to cause a secondarily generalized tonic-clonic seizure. The occurrence of these focal neurological symptoms should alert the clinician to the potential presence of a focal lesion in the brain. These feelings are typically followed by rolling up of the eyes and loss of consciousness. A generalized tonic contraction of the entire body musculature occurs, and children can utter piercing, peculiar cries, followed by apnea and cyanosis. With the onset of the clonic phases of the convulsion, the trunk and extremities undergo rhythmic contraction and relaxation. The end of the seizure is signaled

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by a decrease in the rate of clonic contraction. After they cease altogether, children remain semi-conscious and confused for several hours. They may vomit and complain of a severe headache, and appear uncoordinated and confused. Attacks can occur at any time, although their frequency is somewhat greater shortly before, or after, children fall asleep, or wake up [111].

In palliative care, seizures may occur in a variety of clinical settings. Seizures occur in over half of children with neuro-degenerative and metabolic disorders, as part of the terminal symptomatology [86]. They can be due to progression of the underlying condition, non-therapeutic levels of anticonvulsant medications, increased sensitivity due to systemic illness such as fever or electrolyte imbalance, or a medication side-effect [112]. In children with cancer, seizures occur most frequently in primary CNS tumors and leukemia, with toxic-metabolic disturbances being the most common identifiable etiology. In children with solid tumors, seizures are statistically most often caused by metastases. Children undergoing bone marrow transplant are particularly susceptible to seizures [113]. Slightly over a third of children with cerebral palsy may have epilepsy, with over 40% of children with quadriplegia being affected. It is often severe and difficult to control, especially in children with associated intellectual delay or cognitive impairment [114].

There is ongoing discussion of whether seizures, in and of themselves, can damage to children's brains. The emerging perspective is that seizure-induced damage does lead to neuronal loss, and thus, has adverse long-term behavioral and cognitive consequences [115]. In addition, seizures themselves can cause death in some children. Sudden and Unexplained Death in Epilepsy (SUDEP) may be a risk for as high as 10% of children with epilepsy [116]. The exact cause and mechanism of death in these cases remain undetermined, though there is clinical evidence showing that the death is a seizure-mediated event [117, 118].

If children who are receiving palliative care have a generalized seizure, it may be appropriate to perform a diagnostic workup, to identify a specific etiology. The diagnostic approach will vary considerably, based on the underlying condition, but may include neuro-imaging studies, examination of cerebral spinal fluid, electroencephalography (EEG), blood chemistries (especially glucose and calcium), and metabolic and cytogenetic exams, if they have not previously been performed. If the underlying condition can be identified and treated, seizure control will be easier. If no etiology is found, or if the pathology cannot be corrected, most clinicians would institute anti-convulsant medication, particularly in children who have had more than one grand mal seizure in a year [119].

For many children, particularly those with known neurological abnormality, investigations will not be appropriate, and empirical treatment with an anticonvulsant should be considered.

Even if children have been diagnosed, and are on drugs, it helps if the palliative care practitioner understands the therapeutic principles of drug therapy [119, 120, 121]. These are summarized below:

  • The selection of the preferred drug is based on the type of seizure, and on the potential toxicity of the drug, in other words, on the balance of likely benefit and possible cost to the patient.

  • Treatment should begin with one drug, and the dosage should be increased until the seizures stop, or clinical toxicity ensues. If toxicity occurs before seizures are controlled, the first drug should be tapered, and a second single drug started.

  • The selection of anticonvulsant drugs varies among practitioners; however, the most frequently used drugs for generalized tonic-clonic seizures are carbamazepine, phenytoin, and valproate. Although phenobarbital is highly effective and useful in the terminal phase, there is the risk of adverse effects on behavior and cognition of children who are likely to need it for some time.

  • Adverse effects may reduce the benefits of anticonvulsants on quality of life, and it is helpful to be familiar with them. Diplopia is the most common side reaction to carbamazepine, followed by transient drowsiness, incoordination, and vertigo [122]. Toxicity with phenytoin may present as nystagmus, with lateral or upward gaze, lethargy, or aggravation of seizures. A syndrome of fever, rash, and lymphadenopathy may develop. Valproic acid causes gastrointestinal upset as the most frequent side effect. Increased appetite, with accompanying weight gain, is also seen. Thinning of hair is encountered less commonly.

  • It is particularly important to recognize the possible neurological complications of anticonvulsant therapy, lest their onset be confused with disease progression in children receiving palliative care. These are summarized in Table 26.3.

  • Alterations in dose should be made gradually, usually not more frequently than once every 5 to 7 days. If anticonvulsant medication is withdrawn, it should also be done gradually, as sudden discontinuation is one of the most common causes of status epilepticus [119].

  • Drug blood levels are often unhelpful. A great deal of information can be learned by talking with the parents, and examining children on the drug. Monitoring of hematologic and hepatic status has been recommended for some

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    anticonvulsants, but this should be considered discriminatingly in the context of palliative care. Children often exhibit clinical symptoms at the same time they develop blood chemistry abnormalities.

Table 26.3 Neurological complications of commonly used antiepileptic drugs

Drug

Most common neurological complications

Phenobarbital

Hyperkinetic behavior, drowsiness

Methylphenobarbital

Hyperkinetic behavior, drowsiness

Primidone

Drowsiness, ataxia, dizziness, dysarthria, diplopia, nystagmus, personality changes

Phenytoin

Nystagmus on vertical and horizontal gaze, truncal ataxia, intention tremor, dysarthria, aggravation of seizures, permanent cerebellar degeneration, personality disturbances

Ethosuximide

Headache, dizziness, hiccups, personality disturbances

Diazepam

Drowsiness, ataxia, hallucinations, blurred vision, diplopia, headaches, slurred speech, tremors, extra-pyramidal movements

Clonazepam

Ataxia, drowsiness, dysarthra, irritability, belligerence, other behavior disturbances

Carbamazepine

Diplopia, disturbed coordination, drowsiness, headaches, visual hallucinations, peripheral neuritis or paresthesias, extra-pyramidal movements

Valproic acid

Ataxia, tremor, asterixis, drowsiness, or stupor (when give with phenobarbital)

Vigabatrin

Dyskinesias, visual field defects

Topiramate

Dizziness, ataxia, somnolence, psychomotor slowing, impaired memory

Lamotrigine

Dizziness, ataxia, somnolence, diplopia, blurred vision

Gabapentin

Somnolence, diplopia, blurred vision

Felbamate

Insomnia, somnolence, mononeuritis, choreoathetosis

(Used with permission from Menkes J.H. and Sankar R. Paroxysmal disorders. In J.H. Menkes and H.B. Sarnat, eds. Child Neurology, sixth edition Lippincott Williams and Wilkins 2000, p.952.)

  • Renal and hepatic disease may affect blood levels of anti-epileptic drugs. Carbamazepine levels are altered in hepatic disease, but not in renal failure [123]. In cirrhosis and renal failure, the free fraction of valproic acid increases, but the drug's metabolism is reduced, so that the net effect is nearly normal clearance rates. The metabolism of the benzodiazepines, and newer anti-epileptic drugs such as gabapentin, topiramate and lamotrigine, is relatively unaffected by hepatic or renal failure.

Even after carefully following the approach outlines above, as many as 25% of children may continue to have seizures [119]. Addition of a second drug may improve seizure control. A newer anti-convulsant drug may also be considered. A number of new anti-convulsant drugs are available, including felbamate, gabapentin, tiagabine, lamotrigine, topiramate, oxcarbazepine, levetiracepam, and zonisaminde. Clobazam, nitrazepam, and vigabatrin are also available in many countries. Each of these drugs has specific patterns of efficacy and toxicity, so clinicians unfamiliar with them should consult with a neurologist, or an epilepsy specialist, before prescribing one of these drugs for children receiving palliative care [120, 124].

The ketogenic diet is a dramatic, but sometimes effective, way to reduce seizures in some children refractory to traditional drug therapy, or in those with multiple allergies [120]. This diet, which attempts to reproduce the ketosis and acidosis of starvation by restricting protein and carbohydrate intake, and supplying 80% of caloric intake through fats, was introduced in 1921. Though the biochemical mechanism of effectiveness is unknown, 30 50% of children who successfully maintain a ketotic state will have improvement in their seizure control, though at the cost of significant increases in atherogenic lipoproteins [120, 125, 126].

Surgical management of intractable pediatric epilepsy continues to become more attractive, as microsurgical techniques lessen the morbidity of the procedures. In children with brain tumors, the surgical approach has been a mainstay of treatment for cancer and for associated seizures [127, 128]. In children with other etiologies of their epilepsy, attempts are made to localize and remove the seizure focus, if possible. More non-specific surgery may also be successful, including corpus callosotomy, subpial transection, unilateral hemispheric removal, and temporal lobectomy [120, 128, 129].

Status epilepticus

Children are said to be in status epilepticus when seizures occur so frequently that over the course of thirty or more minutes, they have not recovered from the coma produced by one attack, before the next attack supervenes [130]. ' Unrelieved, continuous generalized tonic-clonic seizures lead to hypoxia, brain damage, and death. Management of children in status begins with maintenance of vital functions, chiefly, maintaining an airway, preventing aspiration, and protecting them from injury induced by violent movements.

Next, drug therapy is instituted to control the seizures. Although many drugs have been shown to be efficacious, the

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most commonly used class in palliative care medicine has been the benzodiazepines [131]. Lorazepam may be administered i.v., p.r., p.o., or s.l., in doses of 0.06 0.1 mg/kg/dose, and has been shown to be highly effective in relieving status [132, 133]. If given i.v., infusion should be over several minutes, to lessen the risk of apnea. Doses may be repeated after 10 min if seizures persist. Diazepam may be administered i.v., p.o., or p.r., at 0.3 0.5 mg/kg/dose [109, 130]. A rectal gel is available, or the i.v. solution may be used by attaching a tube to the syringe, so that the drug can be inserted 4 to 5 cm. beyond the anus [132, 134]. Midazolam is being used with increasing frequency, administered most often as a continuous infusion [135]. An initial bolus of 0.15 mg/kg over a minute is given, followed by infusion of 1 7 g/kg/min [136]. Midazolam may also be administered rectally, at a dose of 1 mg/kg (max. 20 mg), or p.o., via the buccal mucosa, at a dose of 0.5 0.7 mg/kg/dose [137]. A recent study examining treatment of prolonged seizures in a group comprised chiefly of adolescents, showed 10 mg (2 ml) of buccal midazolam to be equally effective as 10 mg rectal diazepam [138]. Both acted within 6 8 min, but the buccal route was preferred by patient and staff.

Respiratory depression is a rare, but feared, complication of benzodiazepine therapy. It can be reversed with flumazenil, administered initially at a dose of 0.1 mg/kg i.v. [139]. If no response occurs after a couple of minutes, may be repeated doses at one-minute intervals, upto a maximum dose of 1 mg.

If seizures are uncontrolled with benzodiazepine therapy, other anti-epileptic drugs may be used, such as fosphenytoin, i.v. phenobarbital, or intravenous anesthetic agents. However, close monitoring and aggressive maintenance of the airway and blood pressure usually necessitate transfer to an in-patient intensive care setting [140, 141].

Terminal seizures

In a terminal phase, seizures may occur with increasing frequency, even when they do not merge into a continuous seizure. Underlying causes can include progression of the underlying condition, intercurrent illness, or children's inability to swallow or absorb their usual anti-epileptic medications. When this occurs, intervention and treatment should be consistent with the goals set by children and their families, to maximize their quality of life. Small, self-limiting seizures that do not distress the patient may not need treatment. If treatment is desired, the mainstays of seizure management in the terminal phase are phenobarbital (enterally or by subcutaneous infusion), and midazolam, by infusion. Phenobarbital, given at an initial dose of 10 20 mg/kg, followed by 3 5 mg/kg/day i.v. or p.o. in two divided doses, offers good seizure control, as well as anxiolysis [112]. In some children, it is quite sedating. While for many this is a desirable effect, for others it is not. Phenobarbital cannot be combined with any other drug in a syringe driver. Midazolam is also anti-convulsant and anxiolytic. Although it too carries a risk of sedation, it is more easily titrated than phenobarbital, because of its very short half-life. Pentobarbitol, a shorter acting barbituate, has also been used, at a dose of 4 mg/kg/p.r. q. 12 h, to control frequent or intractable seizures [142].

Like all symptoms in the terminal phase, it is important to have medication in the home, if terminal seizures are anticipated. They are particularly likely when children have a pre-existing seizure disorder, brain cancer, or are at high risk of cerebral hemorrhage.

Nerve pain and its treatment

Neuropathic pain arises from injury, disease, or altered excitability of portions of the peripheral, central, or autonomic nervous system. It is one of the few types of pain that is not protective, since the painful sensation persists independent of ongoing tissue injury or inflammation [143]. Common features of neuropathic pain conditions include sensory disturbances, such as allodynia, cold hypersensitivity, paresthesias and sensory deficits. Sometimes, there are motor findings, such as spasm, tremor, weakness and atrophy. Possible autonomic abnormalities include cyanosis, erythema, mottling, edema, and increased sweating. Neuropathic pain is frequently described by verbal children as having shock-like characteristics of burning, stabbing, and shooting [143, 144].

Incidence and etiology

Current estimates suggest that 1 1.5% of the general adult population suffers from some sort of neuropathic pain, including the most common conditions of diabetic neuropathy, trigeminal neuralgia, post-herpetic neuralgia and spinal cord injury [144]. The incidence is unknown in the pediatric population, and the most common adult etiologies are rarely found in children. Practitioners can expect that children with neuropathic pain will be over-represented in the palliative care population. A review of the children seen at one large pediatric pain service showed that 40% of out-patient referrals included disorders with a neuropathic component [143]. The most common conditions in this group were post-traumatic and post-surgical peripheral pain, complex regional pain syndromes, and pain due to tumor involvement of peripheral or central nervous system. Metabolic and toxic neuropathies, neurodegenerative disorders, and pain after CNS injury were represented less frequently. Approximately 6% of children dying of cancer require extraordinary doses and means to control their pain, and in this group, most children had solid

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tumors metastatic to spine and major nerves [145]. In yet another review of terminal children with cancer, those with neuropathic pain in addition had higher baseline requirement of opioids and benzodiazepines, and also required rapid increases of both drugs in the last few days of life [146].

Assessment

Though pain assessment is considered in detail in other chapters of this book, it is worth noting that assessment of neuropathic pain is particularly challenging, because of the sophistication needed by children to recognize and characterize this type of pain. As a result, parents often feel as if their children have learned to live with significant levels of discomfort, without it being recognized by medical caregivers [147]. In non-communicative children, or in those with delayed development, the problem is exacerbated [1]. Development and standardization of assessment tools for children with cognitive impairments and the inability to verbally communicate has begun, and relies heavily on the parents' interpretation of children's perceptions [148, 149]. The Paediatric Pain Profile , a behavior rating scale to assess pain in children with severe neurological disability, has been validated in children undergoing gastro-intestinal or orthopedic surgery [148]. Another tool, the Non-Communicating Children's Pain Checklist has recently been used to help characterize subtle variations in patterns of self-injurious behavior of children, with and without chronic pain [150].

Treatment of neuropathic pain

An interdisciplinary approach works best with neuropathic pain, as it is rarely possible to achieve resolution of the pain with any one therapy [143]. Depending on the etiology of the pain, different types of approaches may be emphasized. Physical therapy and rehabilitation play a main role, and many children find cognitive-behavioral treatments helpful in decreasing pain, improving strength, and promoting functional improvement. Neurosurgical interventions or nerve blocks may be indicated for some problems. Acupuncture and hypnosis have been successfully used to treat chronic pediatric pain [143, 151].

Several mechanisms exist to explain effective drug therapy of neuropathic pain. Some classes of drugs act as modulators of peripheral sensitization. These include a number of the anti-epileptic drugs that are sodium channel modulators (carbamazepine, oxcarbazepine, phenytoin, topiramate, and lamotrigine), as well as membrane stabilizing agents (lidocaine and mexiletine). Other classes of drugs act as modulators of the descending inhibitory pathways. These include the antidepressants (tricyclics, selective serotonin re-uptake inhibitors, and serotonin and norepinephrine re-uptake inhibitors), and tramadol. The opioids also have this mechanism of action, though they exert their analgesic effect predominately as modulators of central sensitization, which is the third important mechanism. Some drugs inhibit central sensitization by blocking calcium channels (gabapentin, levetiracetam, oxcarbazepine, and lamotrigine), while others exert their effect via N-methyl-D-aspartate (NMDA) antagonism (ketamine, dextrometorphan, memantine, and methadone) [152]. Table 26.4 contains sample dose-titration schedules for therapy for pediatric neuropathic pain involving notriptyline and gabapentin, the non-opioids most often used in pediatrics.

Traditional teaching that neuropathic pain does not respond as well to opioid therapy as does nocioceptive pain is controversial, because opioids are clearly effective in the treatment of some adults and children with neuropathic pain syndromes [153, 154]. Prolonged, high-dose opioid therapy has been associated with the development of tolerance, hormonal effects, and immuno-suppression, but low-dose chronic therapy can relieve pain, and improve mood and functioning, without significant side-effects [155].

Increased intracranial pressure

While not normally considered a neuropathic pain syndrome, increased intracranial pressure (ICP) in palliative care often occurs because of the underlying involvement of brain or nerve tissue. Raised ICP is seen in several different scenarios. In infants, it can be a result of post-hemorrhagic hydro-cephalus, asphyxia with subsequent brain swelling, cerebral edema from metabolic derangements, or hydrocephalus due to CNS malformations [156]. Treatment normally takes place in neonatal intensive care units, and includes careful attention to positioning, suppression of any neck, skull and abdominal compression, stimuli limitation, and fluid restriction. Babies may benefit from mechanical ventilation, hypothermia, surgical ventricular shunting, and enteral nutrition. A variety of drugs are used to decrease pressure, such as diuretics, sedatives and analgesics, barbiturates, anti-epileptic drugs, and steroids [156, 157].

The same types of interventions and supports are used in older children, whose increased ICP most commonly is the result of trauma [158]. Though the treatment normally also takes place in the intensive care unit, the palliative care team may be involved because of the life-threatening nature of the condition. It is important to acknowledge that some of the treatments for raised ICP limit the contact between children and their families, and both will need support around this issue while therapies continue. It is also common for families to misinterpret news about success in controlling the ICP,

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thinking that the underlying pathology is also being treated [158, 159].

Table 26.4 Nortriptyline and gabapentin dose titration regimen for neuropathic pain

 

Nortriptyline dosage escalation schedule

A. For ambulatory patients

 

<50 kg

>50 kg

Day 1 4

0.2 mg/kg q.h.s.

10 mg q.h.s.

Day 5 8

0.4 mg/kg q.h.s.

20 mg q.h.s.

Increase as tolerated every 4 6 days until:

  1. good analgesia is achieved;

  2. limiting side effects occur, or;

  3. dosage reaches 1 mg/kg/day (<50 kg) or 50 mg (>50 kg).

B. For in-patients or others with severe and uncontrolled pain, begin with the above doses but titrate upwards every 1 2 days.

Gabapentin dosage escalation schedule

A. For ambulatory patients

 

<50 kg

>50 kg

Day 1

2 mg/kg q.h.s.

100 mg q.h.s.

Day 2

2 mg/kg b.i.d.

100 mg b.i.d.

Day 3

2 mg/kg t.i.d.

100 mg.t.i.d.

Day 4

2 mg/kg a.m. and midday, 4 mg/kg q.h.s.

100 mg a.m. and midday, 200 mg q.h.s.

Continue to increase by 2 mg/kg (<50 kg) or 100 mg (>50 kg) each day, alternating the timing of the increased dose, so that at least half the daily dose is at night-time. Dose escalation should continue until:

  1. good analgesia is achieved;

  2. side effects occur, or;

  3. dosage reaches 60 mg/kg.

B. For in-patients or others with severe and uncontrolled pain, a similar scheme is used, but triple the dose given at each increment.

(Adapted with permission from Berde C.B., Lebel A.A., Olsson G. Neuropathic pain in children. In N.L. Schechter and C.B. Berde, eds. Pain in Infants, Children, and Adolescents, second edition, Philadelphia Lippincott Williams & Wilkins, 2003, p. 626.)

In children with primary or metastatic brain cancer, increased ICP may occur directly, from tumor infiltration, or compression of normal brain tissue, or indirectly, from obstruction of CSF pathways. Initial clues to increasing pressure are often subtle, with intermittent headaches, personality changes, and poor school performance. Over time, morning headaches, vomiting, and lethargy ensue [160]. There may come a point in palliative care of these children that surgical intervention, radiation therapy, and chemotherapeutic treatment of the underlying tumor will not be beneficial, or are no longer desired by children and their families. At this point, drug treatment with a corticosteroid is often offered, because of its effectiveness in relieving headache, pain, and other symptoms of the expanding lesion. A loading dose of 1 2 mg/kg of dexamethasone p.o. or i.v., followed by a maintenance dose of 0.1 mg/kg p.o., can often be dramatically effective [161]. However, the projected time course and expected dosage of continued therapy should be evaluated carefully, because of the many undesireable side-effects of prolonged, or high dose, steroid therapy [162]. Personality changes can be prominent, and can include voracious appetite with associated weight gain, mood swings, aggressiveness, confusion and inability to concentrate, and interference with sleep. Besides weight gain, other significant physical complications may be edema, fat deposits on shoulder and hips, gastrointestinal ulceration, the development of diabetes, increased susceptibility to infection, hypertension, and muscle weakness. After prolonged usage, adrenal suppression occurs, requiring additional steroid support during times of physical stress, and a gradual tapering of the drug when discontinued. Older children, in particular, may choose to forego escalation of steroid therapy, because of the side effect profile [163].

Spinal cord compression

Acute compression of the spinal cord occurs in 3 5% of children with cancer [164]. Sarcomas, especially Ewing's sarcoma, account for most spinal metastases, followed by neuroblastoma, germ cell tumors, lymphoma, and metastases from primary CNS tumors. Clinical presentation depends on

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the location of disease, but often includes weakness/paralysis, sensory deficits, loss of bowel and bladder control, and central back pain. Therapeutic options include surgical decompression and tumor removal, radiation therapy, or drug treatment using chemotherapy or steroids. Dexamethasone is the corticosteroid used most often, at an initial dose of 1 2 mg/kg p.o or i.v. [161]. In some centers, palliative care practitioners have used maintenance doses of 6 10 mg three or four times a day, in older ambulatory patients [165]. Others limit doses of dexamethasone to 16 mg daily, because of the increased incidence of side-effects with very high-dose steroids [166]. Each treatment has its advantages and disadvantages, as discussed above, and each clinical situation will have to be evaluated with affected children and their families. Left untreated, compression leads to permanent neurological deficits [164].

Phantom limb pain

Phantom limb pain is the unpleasant sensation children feel after a body part is removed surgically or traumatically. The indication for amputation may be a congenital deformity, infection or trauma, or cancer. The sensation is as if the body part continues to be there; the pain may be described as stabbing, squeezing, tightness, burning, shooting, cramping, itching, or an unnatural position of the limb [167]. The incidence varies greatly from series to series, but occurs at least half the time. In all series, it tends to diminish over time [168, 169]. A variety of treatments have been tried to impact this type of neuropathic pain, including afferent block of the nerves to be severed prior to amputation, and physical therapy with early and vigorous use of a prosthesis. Different classes of drug therapy have been employed, including NMDA antagonists, opioids, anti-depressants, and anti-epileptic drugs, particularly gabapentin [167, 170].

Peripheral neuropathy

The two sub-types of extremity sensory neuropathy have different clinical presentations [171]. Involvement of small nerve fibers results in sharp pain, burning or shooting sensations, and aching in fingers and toes. It occurs most often in the elderly. When large nerve fibers are involved, pain is usually not a central feature. Instead, decreased proprioception, vibratory sensation, muscle-stretch reflexes and muscle strength are affected. Thus, although many chemotherapeutic agents cause peripheral neuropathy, it is uncommon for them to cause pain in the extremities [172, 173]. Similarly, a review of children with human immunodeficiency virus infection indicates that approximately one-third have symptoms or signs of peripheral nerve involvement [174]. In general, however, the features are less severe than the distal sensory polyneuropathy described in adults. When neuropathy does occur, the etiologies are diverse, and may include distal sensory or sensorimotor axonal neuropathy, median nerve compression at the carpal tunnel, demyelinating neuropathies, and occasionally, lumbosacral polyradiculopathy [175]. Less than one-fourth of the affected children have pain [174]. Although this type of pain responds variably to therapy, drug administration of an anti-depressant or anti-convulsant is warranted [171].

Peripheral neuropathies are also seen in the context of heredodegenerative diseases [176]. The most common of these are the different forms of Charcot-Marie-Tooth Disease, inherited generally in an autosomal dominant fashion. They are characterized pathologically by extensive segmental demyelination and remeylination of peripheral nerves, leading to muscle weakness and atrophy. The congenital neuropathies are generally not fatal in childhood.

Neuroirritability

The incidence of pain in children with metabolic diseases and other types of neuro-degenerative disorders remains unknown [177]. Clinicians recognize that many of these children may present with, or develop, a syndrome of long-standing severe irritability, or persistent crying and screaming [86, 177]. These symptoms may be particularly prominent in children with leukodystrophies and mitochondrial disorders. Identifiable etiologies for the irritability include pain from muscle spasm, joint involvement, and spasticity. Sources of neuropathic pain in this population include visceral nerve involvement, with associated gastrointestinal dsymotility, and peripheral demyelination. However, often a treatable etiology remains unrecognized. A trial of anti-convulsant therapy is probably indicated in these situations, since there have been anecdotal reports of improvement [177, 178]. Phenobarbital, with its combined anti-convulsant, sedative and anxiolytic effect, is a useful first line, but should not be continued indefinitely, due to the incidence of long-term side effects. An increase in understanding of the nerve damage in these disorders, coupled with a more complete understanding of the drug mechanism of action, may improve the possibilities for effective therapy [152].

Anesthetic and neurosurgical approaches to pain treatment

Regional anesthesia is most commonly used in pediatrics for pain relief during surgery and procedures. In palliative care, there is a limited role for epidural or subarachnoid (intrathecal) infusions in the treatment of severe neuropathic pain in those children whose pain cannot be relieved with oral or

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parenteral opioids plus adjuvants, or in those who suffer intolerable side-effects [177]. Most often these children have solid cancers, metastatic to the spine, or to nerve plexi. A large retrospective review of severe pain in childhood malignancy found that 4% of such children needed regional anesthesia to relieve their pain [145]. Effective long-term pain control can be achieved in these children by the infusion of either narcotics such as fentanyl and morphine, or local anesthetic agents such as bupivacaine, or 2 agonists such as clonidine [179]. In palliative care, these agents are typically administered via an implantable catheter, alleviating the necessity of repeated punctures. Intraspinal agents produce selective analgesia, without affecting non-nociceptive sensory modalities, and motor or autonomic reflexes [179].

Potential complications of regional anesthesia include dural puncture headache, mild respiratory depression, and infection [180]. These modalities can be safely used in the home setting, with proper training of staff, children, and their families. Both regional anesthesia and the neurosurgical treatments outlined below generally require evaluation and institution of care at a hospital or inpatient facility, which may limit their usefulness for some children.

Neurosurgical ablative procedures permanently interrupt the connection of afferent pain fibers with the spinal cord and brain. Different procedures have been developed to destroy principal pain pathways [181]. These include: neurectomy (division of a peripheral nerve), rhizotomy (division of a dorsal root), dorsal root entry zone (division at the point of entry into the substantia gelatinosa), myelotomy (midline interruption of crossing fibers in the anterior commissure), and cordotomy (ablation of the lateral spinothalamic tract). The major benefit of these procedures is permanent relief of pain, without further need of narcotics or adjuvant medication. However, sometimes it is difficult to cut all of the fibers communicating pain signals, and only those fibers. Therefore, pain relief is sometimes incomplete, or a new symptom, such as motor weakness, develops. Steady progress has been made in the 50 years that these procedures have been used, to maximize their effectiveness and minimize their unintended side-effects [181].

Other neurologically based symptoms

A number of other symptoms attributable to nerve or brain involvement may be problematic for children receiving palliative care. Some of these, such as swallowing disorders and bowel motility issues, are covered elsewhere in this book. Two other common concerns are discussed below.

Spasticity

Spasticity is characterized by an initial resistance to passive movement, followed by a sudden release call the clasp-knife phenomenon [182]. Spasticity is most apparent in the upper extremity flexors and lower extremity extensor muscles. It is often associated with increased tone, spasms, increased deep tendon reflexes, and clonus. These signs are coupled with the negative signs of weakness and loss of dexterity. It can be a significant source of discomfort and pain for children [86, 183]. If left untreated, spasticity not only interferes with motor function, but also contributes to the development of deformities (arched body with pointed toes). This adversely impacts care, positioning, and comfort [184]. This symptom may occur in any condition affecting the motoneuron, including brain hemorrhage, tumors, anoxia, and the vegetative state. Spasticity is the most important disorder of motor control in children with cerebral palsy [185].

The management of spasticity can be challenging, and is often best accomplished through an interdisciplinary team using a combination of medical and surgical approaches [184]. The goals of the affected children and their families must be considered. For non-ambulatory children, the principal challenges are improving comfort, reducing pain, easing the burden of caregivers, slowing the progression of deformities, and perhaps, improving function. For those children who can ambulate, the functional and performance goals tend to dominate.

Physiotherapy and bracing are the most traditional and principal non-surgical forms of treatment; however, despite early, appropriate and intensive intervention, approximately half of children with cerebral palsy will require surgery or other therapy [185]. Children with spastic quadriplegia, in particular, have a high incidence of spinal deformities, as well as progressive hip displacement or dislocation. Many of these children have traditionally required surgery between 4 and 8 years of age, to lengthen or release muscles and tendons [185].

Various neurosurgical techniques have been developed to reduce the excessive hypertonia, without suppressing the muscle tone and limb functions [186]. These include the neuroablative techniques of peripheral neurotomies, dorsal rhizotomies, and dorsal root entry zone-otomies (DREZotomy) [186, 187]. In addition, implanted pumps may be used for the administration of intrathecal baclofen [188, 189]. Spasticity in both upper and lower extremities decreases significantly with this therapy, which continues to be effective even when administered for years. Baclofen doses often have to be titrated upward initially, but after two years, a stable mean dose of 300 mg/day is usually achieved [189]. Complications are

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frequent initially. Adverse symptoms from the baclofen include lethargy and hypotonia; surgical complications include catheter-related problems, seromas, and cerebrospinal fluid leaks [189]. If the palliative care team is involved with these children and families during this time of intensive treatment, it can facilitate communication and pain management. It can also help with some of the technical issues that arise when children with terminal illnesses, and possibly do-not-resuscitate orders, come to the operating room for surgery or procedures [190].

A technique of reversible chemodenervation is the injection of botulinum A toxin into the spastic muscle, in order to neutralize neuro-muscular junction activity [191]. The toxin significantly reduces spasticity in about three-quarters of those treated. The effect lasts for months in almost all children, and in 1 2 years, is approximately halved [191, 192]. Although the dose used varies considerably from center to center, nearly all children are able to receive treatment without general anesthesia [193].

Drug therapy for spasticity has been disappointing. Baclofen, diazepam, and tizanidine act principally on spinal and supraspinal sites within the central nervous system, while dantrolene and quinine act on muscle [194]. In children, the most frequently used drugs have been benzodiazepines, baclofen, dantrolene, 2-adrenergic agonists, and gabapentin [195]. Oral baclofen is often tried first, at a flat dose of 5 mg two to three times a day. It can be increased in 5 mg increments every 3 days until efficacy, or intolerable side-effects (sedation and hypotension are most common) occur. Effective doses for spasticity are generally in the range of 20 mg or less, three times a day (100 mg/day maximum dose). If no improvement occurs within 6 weeks with the maximally tolerated dose, the drug should be tapered slowly, since abrupt discontinuation may cause seizures [194].

Sleep disturbances

More than 20% of a general pediatric practice concerns issues relating to sleep, so it is no surprise that sleep disorders come up frequently in palliative care [196]. Sleep-related disorders have a profound impact on daily living, for both children and their families. Lack of restful sleep can lead to daytime drowsiness and inattention, headaches, depression, and school or work problems, for children and parents alike [197]. Since the underlying etiologies and associated therapies vary so greatly, it is important for the practitioner to obtain a clear and complete history, including a sleep diary, for complex cases.

An understanding of normal developmental changes in children's sleep patterns is helpful for practitioners and families. Newborns start out sleeping 16 20 h/day, with 1 2 h awake periods alternating with 1 4 h sleep periods around the clock. Between 6 weeks to 3 months, night differentiation develops, and by 9 months, about three-quarters of infants sleep through the night. Total sleep needs decline to 11 12 h/day by school entry, and most children give up naps by age five. Most children sleep about 10 h/day during the middle childhood years, and most adolescents should sleep 9 h/day [198]. Common sleep disturbances in well and sick children alike include: increased latency (the time it takes to fall asleep), parsomnias (sleepwalking, night terrors, nightmares, and rhythmic movement disorders), and night awakenings, in which children need parental intervention to re-establish sleep [199].

Anatomic pre-requisites exist for the development of a normal circadian cycle. States of wakefulness are thought to be regulated by diencephalic and brainstem nuclei, whereas the establishment of circadian rhythms require the development of the suprachiasmatic nucleus of the hypothalamus and its connections [196]. Therefore, children with midline brain maldevelopment are at high risk of sleep disorders. Some portions of the cerebral hemispheres also contribute to sleep-wake cycles, because children with hydranencephaly, lacking cerebral hemispheres, but having an intact brainstem and cerebellum, also have profound sleep disturbances.

Sleep-related breathing disorders may also be associated with anatomic abnormalities [200]. Cranio-facial deformities, common in children with trisomy defects and myelomeningocele, can lead to night-time obstructive apnea. The hypercapnic ventilatory and arousal response is also frequently blunted. Centrally mediated apnea may be identified with polysomno-graphic studies [197]. Central and obstructive apneas are also common complications for children with myopathies and neuro-muscular disease [197]. In addition, they face the real risk of ventilatory muscle fatigue, particularly in the latter hours of the night. This hypoventilation leads to arousal, daytime sleepiness, and headaches [200]. Yet another anatomical source of sleep disorders are seizures. Sleep-related epilepsy accounts for 30% of seizure disorders in children [197]. Frequent nocturnal seizures can fragment sleep, and negatively affect daytime performance.

Establishment of circadian rhythm also benefits from children's perceptions of environmental cues, known as zeitgebers [196]. Disturbed sleep can arise from blindness or poor vision, therefore, because of children's inability to distinguish light-darkness cycles. In general, children who are moderately or profoundly mentally challenged have difficulty in interpreting the social cues families use to promote healthy sleep cycles. Infants who are exposed to constant light, as in some neonatal intensive care units, can also suffer from lack of circadian rhythmicity [201].

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A variety of other medical conditions frequently associated with neurological disorders may also hamper restful sleep. These include reflux, colic, hypoxia, and pulmonary edema associated with cardiac disease, pain, muscle spasm, headaches, and movement disorders [196, 199]. In addition, many of the therapeutic drugs used in pediatric palliative care can disrupt normal sleep patterns. These include opioids, anti-epileptic drugs, stimulating agents, and anti-asthmatic medication [196]. Hospitalization and episodic illness can also interfere with consistent sleep, because of disruption of normal routines [196, 199].

Psychologic stressors that hinder sleep onset are common in palliative care. Children may have worries about their situation, fears of the dark, compounded by fears of death, extreme separation anxiety, or a variety of other legitimate concerns that manifest by poor sleep patterns. They may also have negative associations with their bed, if it is linked with stressors, such as pain or procedures [197].

It should be clear that a complete history is always necessary, and a diagnostic workup sometimes necessary, to hope to successfully address sleep disorders in this group of children. The obstructive apnea of a child with trisomy may best be addressed via adenoidectomy; seizures, with anti-epileptic medication; headaches due to brain tumor growth, with steroids; muscle fatigue, with nighttime ventilatory assistance, and so forth. A number of studies have documented the effectiveness of melatonin in reducing sleep latency in many children with developmental disorders [202, 203, 204]. When melatonin is administered in doses ranging from 2 to 10 mg 2 h before bedtime, approximately three-quarters of children are able to fall asleep faster, and may stay asleep longer [202, 203].

The use of hypnotics in children is less satisfactory [205]. Two benzodiazepines (flurazepam and delorazepam), one anti-histamine (niaprazine) and one phenothiazine (trimeprazine) (alimemazine), have been shown to be effective in the short-term treatment of insomnia in children, but none are officially approved. Tachyphylaxis precludes the long-term use of these medications [205]. If short-term therapy is indicated, hospices have tended to use drugs that might already be in the home for other reasons. Therefore, diphenhydramine, 1 mg/kg/dose p.o. at bedtime, with a repeat in an hour if necessary, or lorazepam, 0.05 mg/kg/dose p.o. q. 4 8 h, are commonly used, as is chloral hydrate 5 15 mg/kg/dose p.o. q. 6 8 h [206]. Several complementary and alternative treatments show promise for insomnia, including herbal therapy with valerian, and aromatherapy with bitter orange essential oil [207]. Anecdotal evidence from a palliative in-patient use promotes the use of lavender oils in a warm bath, and music therapy in selected cases [208].

The palliative care team would do well to teach and reinforce basic principles of sleep hygiene for children, since even ill children are likely to benefit [198]. These include keeping a child busy and active during the day, and limiting naps after mid-afternoon. Children sleep better after exercise, and after spending time outside each day. Even very sick children might benefit from having separate places in which to spend days and nights. Children hungry at bedtime are soothed more with a light snack, than with a full meal. A set bedtime should be established, along with a set bedtime routine. The hour before bedtime should be a quiet time for shared pleasures, with television, computer games, and other stimulating activities restricted. A cool, quiet, comfortable bedroom will promote sleep. Children are often comforted by a dim nightlight and a familiar transitional object, such as a stuffed animal. Finally, restful sleep is promoted by arising at about the same time each day, both on school days and weekends [198]. Simple measures such as these may go a long way in increasing restful sleep for the whole family, particularly if the palliative care team keeps nighttime medications and other interventions to a bare minimum.

Impact of neurological and neuromuscular conditions and symptoms on children and their families

A full consideration of the psychological consequences of life-threatening illness on children and their families may be found elsewhere in this book. No discussion of neurological and neuromuscular symptoms would be complete, however, without mentioning the particular stressors associated with these conditions. Parent voices heard by the authors over decades of care, as well as several studies, have helped identify these unique issues [209, 210]. Several of these points have been highlighted by clinical vignettes to show the impact this group of disorders has on families.

  • The diagnosis of neurological and neuromuscular diseases is often delayed, because of the vagueness and ubiquity of the symptoms, and the sophisticated, specialized laboratory testing necessary to confirm diagnoses. The diseases are often rare, and sometimes cannot be firmly established. Prognostic uncertainty often accompanies the scant diagnostic information, again because the condition is so rare, or expression of the defect is so variable from child to child.

  • Families sometimes face the challenge of multiple children having the same fatal condition. Often the first child is not diagnosed (or even symptomatic) before other babies are

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    born. Prenatal testing is available for some of the conditions, but even then, families have the burden of deciding whether they want to know, and how they will act on the knowledge.

  • The guilt associated with having children die of inherited conditions cannot be underestimated. Mothers may feel guilty because of deferring childbirth until they were older, or having done something wrong during pregnancy that caused the defect. The relationship between parents may be strained if one or the other carries the lethal gene.

  • Having children with severe neurological or neuro-muscular symptoms often leads a family to social isolation. Children who are bedbound or require life-sustaining equipment may be difficult or impossible to transport out of the house. Others less severely affected may still look, smell, or act abnormal. Even a simple outing, such as going to a restaurant for dinner, can be difficult for children with poorly controlled seizures, unpredictable urinary or fecal incontinence, or extensive drooling.

  • Families become extremely sensitized to medical jargon, and may find some expressions offensive. Terms commonly used to describe their children, such as neurodegenerative or vegetative , may cause parental anger or suffering.

  • For non-communicative children, the burden of translation may be heavy on parents and siblings. They often find themselves continually interpreting the needs of an affected child to professionals, and all too often, their experience is one of constantly struggling to be believed. Generally speaking, the people best qualified to understand the needs and problems of affected children are the family. When considering prescribing an analgesic, for example, the palliative care practitioner usually should not ask do I believe the child is in pain?' but, why should I disbelieve it?

  • This can have the incidental effect of making the family carry the responsibility for medical decisions. It is important that reluctant doctors and nurses do not need to be persuaded to prescribe appropriate medications, but are proactive in offering them as the most appropriate medical intervention.

  • Finally, there are special coordination and financial challenges in caring for children who may never be able to provide for themselves, or live independently. Parents sometimes spend the first couple of decades praying that their children will live, but then have to start worrying about who will continue the care when they themselves become frail, or die.

For all these reasons and more, easing the symptom burden of children with neurological or neuro-muscular disorders will make a difficult situation bearable. Identifying and anticipating symptoms, leading the family through a discussion of options, and listening to their goals and therapeutic decisions will help maximize children's potential. Hopefully, the palliative care team will employ both the art and the science of medicine, in mitigating neurological and neuromuscular symptoms.

Responding to family needs: Hope and reality

Our health coverage wouldn't pay for speech and occupational therapy services, because they were rehabilitative services. Your daughter has a terminal illness, and is appropriate for palliative care only. Yes, we certainly wanted to keep her comfortable, but we also wanted to keep her in school as long as possible, and to be a part of our family as fully as possible.

Our nurse and physician became our advocates. They helped others understand the place of therapy services in her care. They helped the rehabilitation staff to incorporate anticipated declines into their goal setting. They helped us to explain these changes to her teachers, our relatives, and our other children. They helped us focus on obtainable goals, such as continuing school, and making a trip to see her grandparents.

Many people talked to us about hope vs. reality. Our team helped us understand that these do not need to compete with each other. We now understand our daughter's life as living out hope and reality.

Responding to family needs: Communication and language

The first physician we met with gave us the diagnosis. She explained how the brain worked, and what was wrong with our daughter's brain. I didn't understand half of what she said. She told us that our daughter had a neurologically degenerative disease. All I heard was the word degenerative. At the end, she asked us if we had considered an institution for her. We left the visit feeling hopeless and lost.

Next, we met with the developmental pediatrician. The first thing she asked us was, What is your worst fear and how can I help you with it? Rather than medical jargon, she addressed our fears that our daughter would never speak, be toilet-trained, or know us as her parents. She also helped us find the words to explain the illness to our other children. The visit didn't take any longer than with our first physician, but we left feeling listened to, and confident that we could care of her.

Many years later, we met with the same physician to talk about our daughter's progress in school. Now in the later stages of her disease, she was losing his ability to speak. I was

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going to school with her every day to help her write, using my hand over hers. The school staff began to question if the writing represented my thoughts, not hers. This wonderful physician responded, You are doing what parents always do when their child is not able to speak. You are her voice in the world.

Now that she has died, I find reassurance knowing that I gave voice to her life, that she made gains many thought were impossible, and that we found strength as a family that we never knew we had.

Responding to family needs: When there is no diagnosis

There were many parents in the Intensive Care Unit whose children had neurological conditions. Our son had some of the same symptoms, but no one could give us a diagnosis. Other parents talked about the wonderful support they found in the disease-specific support groups. We didn't have a support group where we fit in. We didn't know what to expect. We had no prognosis other than, He probably won't live to adulthood. How were we supposed to prepare for the unknown?

The nurse carefully showed us how to care for his symptoms as they arose. She assured us that despite not yet understanding his underlying disease, we could keep him comfortable and happy.

The social worker connected us to two other families whose children also did not have definitive diagnoses. Even though their symptoms were different, we found comfort in having supportive relationships where we felt we belonged.

The physician ordered all available medical and genetic testing. Even though we never did receive a definitive answer, we did rule out many possibilities. We didn't need to carry around the weight of considering all the possibilities.

The chaplain talked to us about our child's life, his place in the world, and his value to us and others. He helped us see our son as more than a collection of symptoms.

The team understood our fear of not knowing what to expect because we didn't have a definitive diagnosis. One member of the team was assigned to call us weekly, to talk about our needs as they came up. By the time we were ready to go home, our planning was based not on the expected course of a known disease, but rather on a responsive team who understood our unique needs.

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Oxford Textbook of Palliative Care for Children
Oxford Textbook of Palliative Care for Children (Liben, Oxford Textbook of Palliative Care for Children)
ISBN: 0198526539
EAN: 2147483647
Year: 2004
Pages: 47

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