UNIT V_The Neurologic System FIGURE 17-25 Huntington Disease. On th right is 2 normal train witha rormalcaudat (nthe lt is atrain rom a individual th Huntington disease showing severe atropty ofthe caudate (Aan a enlagod lateral verti. From Stevens A, Lowe J, Sct: Cre patoloy 43, London, 008, Mosby) dopaminergic function, The huntingtin protein also may alter mitochondrial function, which in turn activates apoptotic path- ‘ways and causes neuronal death, Neurotrophic factors aso may ‘be depleted, leading to loss of neurons.” Early in the disease, selective loss of the striatal GABA/ dopamine-enkephalin pathway to the lateral aspect of the pallidum occurs. The striatum of the basal ganglia normally contains 2 preponderance of GABAergic (GABA-secreting) neurons, including the pathway between the basal ganglia and substantia nigra (pallidonigral pathway-express dopamine Dereceptors, dynorphin, and substance P). Basal ganglia and nigral depletion of GABA, an inhibitory neurotransmitter, is the principal biochemical alteration in HD, Degeneration of the GABAergic pallidonigral pathway causes GABA depletion in the substantia nigra with decreased inhibitory GABA activity ‘on dopaminergic neurons in the substantia nigra and a relative excess of dopaminergic activity in the basal ganglia feedback circuit within the cerebral coriex. A relative excess of dopami- netgic activity in this circuit, asin HD, is manifested by hypo- tonia and hyperkinesia (involuntary, fragmentary movements such a8 chorea). Loss of excitatory glutamate may liberate the pathway from the thalamus to the premotor cortex, impaiting ‘modulation of movement later in the course ofthe disease. Pro- ducing energy for brain activity is dificult and there is resultant ‘buildup of lactic acid CLINICAL MANIFESTATIONS. The classic manifestations of HD) are abnormal movements that occur without conscious effort, motional lability, and progressive dysfunction of cognitive processes (dementia). Any one of these features may mark the ‘onset of the disease. Cognitive impairment may precede motor symptoms by up to 15 years.” Charea is the most common type of abnormal movement and begins in the face end arms, eventually affecting the entire body. It can be combined with athetosis (twisting and writhing). Symptoms of frontal lobe dysfunction include executive attention deficits and short-term memory loss (working memory); reduced capacity to plan, ‘organize, and sequence, as well as bradyphrenia (slow think- ng); and apathy. Restlessness, disinhibition, and irritability are common. Affectively, euphoria or depression or both may be present, Progression of the disease is fatal. EVALUATION AND TREATMENT. The diagnosis of FD is based on family history, clinical presentation ofthe disorder, and genetic testing, No known treatment is effective in halting the degen- ‘ration or progression of symptoms, Chorea is treated with dopamine receptor-blocking or dopamine receptor—depleting agents. Medication and nonmedical care for depression and aggressive behavior may be required, Efforts are in progress to identify biomarkers for early diagnosis and to monitor disease progression.”"”* Hypokinesia Hypokinesia (decreased movement) is loss of voluntary move- ‘ment despite preserved consciousness and normal peripheral nerve and muscle function, Types of hypokinesia include aki- resi, bradykinesia, and loss of associated! movement, ‘Akinesia. Akinesia is an absence, poverty, or lack of control of associated and voluntary muscle movements, There is a disturbancein the timeit takesto perform amovement. Akinesia is related to dysfunction of the extrapyramidal system, as in parkinsonism. Pathogenesis is related to either a deficiency of dopamine ar a detect of the postsynaptic dopamine receptors which occurs in parkinsonism (see Parkinson disease below). Bradykinesia. Bradykinesia is slowness of voluntary move- ‘ments, There isa disturbance in the time it takes to perform a ‘movement. In bradykinesia all voluntary movements become slow, labored, and deliberate. Bradykinesia consists of: (1) diff culty in initiating movernents, (2) dificalty in continuing move- ‘ments smoothly, and (3) dficulty in performing synchronous (at the same time) and consecutive tasks. Difficulty in initiating ‘movements ranges from sight hesitancy to severe freezing (tran- sient, helpless immobility). Each intended movement requires ‘effort. Difficulty in continuing motions smoothly causes jerky, irregular, rapid: movements, which then decrease in rate and amplitude until they stop. The individual is scarcely aware ofthe cessation, Difficulty in performing synchronous and consecs- tive tasks means that each motor act is performed separately. The individual is unable to integrate two acts orto change from one ‘motor pattern to the next with a single smooth motion. Loss of Associated Movement. In hypokinesia the normal, habitually associated movements that provide skill, grace, and balance to voluntary movements are lost, Decreased associated movements accompanying emotional expression cause an ‘expressionless face, a statue-like posture, absence of speech inflection, and absence of spontancous gestures. Decreased associated movements accompanying locomotion cause reduction in arm and shoulder movements, in hip swinging, and in rotary motion ofthe cervical spine. Parkinson Disease Parkinson disease (PD) is a complex motor disorder accom- panied by systemic nonmotor and neurologic symptoms. The rain disease feature is degeneration ofthe basal ganglia (corpus striatum, globus pallidus, subthalamic nucleus, and substan- tia nigra) involving the dopaminergic (dopamine-secreting) nigrostriatal pathway. Nigrostriatal disorders produce aCHAPTER 17 Alterations in Cognitive Systems, Cerebral Hemodynamics BOX 17-5 PRIMARY AND SECONDARY CAUSES OF PARKINSONISM Primary Parkinsonism Spore idiopathic mst corer form Genet: autosemal dominant; autosomal recessive Phenotype maybe infuarced by gene-iranmnent interactions ‘Secondary Parkinsonism Newodagonaratve disorders sporadic or gonati) Disorders assoatd wth alpnasyoclein patlogy “utile sstom atopios al andnowrnal inclusions) Nigrsiatal degerration ‘OT voprtacrabllaratoahy Shy-Drager syndrome Motor neuron isase with PO features Deramia wit Lewy bis erica and trainstom neural nlisions) Disorders associated rth primary tu pathology Tavopathies") Progressive suprenacleerpasy Corticobasal degeneration Frontoterporal derontia Disorders associated ith oda anyloid pathology (amylidopathies"), ‘Almoimar disease wth parensonism Genetically mesiated sores wit occasional pattrsonian features ‘Wika dvease Hallovordor Spat dsoaso hidalcigash syndrome ‘SCA spincerbelar ataxia XAinkad dstonia-garknsonism (DY) FragleX prrta on assaciad wit atai-renor-gartinsanism syndrome Huringon disease Westphal variant) Pron disease Miscllaneausarquiod conditions \Vascub parkinsoniamathorosclrsis, art angiopathy Nora grossa byatecophals Carat Cerebral pay Repeated head rauna{‘demortiapuilistiea" with parkinsonian eats) Invotius and posinvotou disasos Postencepralitic Cretrfeld Jakob disease Nowosyphils Marable cantons Hypoparatryoitsm or pseutohypopertnyridsm with basal ganglia caliications Nontaltoran hopataletculardogenoraton Matplesclrsis Neoplasic cisease Drags Nowooptis typical antipsychotics) Selected apical aninsenais Antieretis e..,congarine, metclogramide) Dopamine doplting agonts fos, ttaberarin) ceMathyldopa Ltvionearbonate Vabeoic acid Fuowetine Terns |-Mothy1.2.etahydopyritino (MPTP) Manganese Gyande Mathanal Carton menaide Carton aise Hexane Dara fom Delong MR, June0s I: Parkinson's dlsese and other extrapyramidal movement disorders, In Fauci AS eal, editors: Haeson’s pin ples of internal medicine, ed 17, p 258, New York, 2008, McGraw, Lang A. Parknsan'sm. In Goldman, Ausiello 0, editors 19423, p2728, Priladelpris, 2008, Seunders. syndrome of abnormal movement called parkinsonism (Par- kkinson syndrome, parkinsonian syndrome). Fiologic classification of parkinsonism includes primary par- kkinsonism and secondary parkinsonism (Box 17-5), The onset of PD occurs after 40 years of age, with mean onset of 60 years of age.” PD is one of the most prevalent ofthe primary CNS dis- orders and a leading cause of neurologic disability in individuals older than 60 years. Approximately 60,000 people in the United States are diagnosed cach year and an estimated 10 million peo- pile worldwide are living with PD. Men are 150% more likely to have PD than women.!" The familial form represents about 10% of PD; however, the majority of eases are sporadic or idiopathic. PATHOPHYSIOLOGY. The pathogenesis of primary PD is unknown, Several PD genes have been identified, the most sig- nificant of which ae listed in Table 17-13 (p. $47). The hallmark pathologic features of PD are loss of dopaminergic pigmented ‘neurons in the substantia nigra (SN) pars compacta with dope- rinergic deficiency in the putamen portion of the striatum (the siriatum includes the putamen and caudate nucleus) (Figure 17-26). Dopamine loss in other brain areas including the brain- stem, thalamus, and cortex also occurs: Degeneration of the Cecil medicine, FIGURE 17-26 Aaphic Substanti Nigra (A} Compared with Normal Contra (Bam Parkin GO a. Also lial nourlagy. od 3, Pid, oN, Saunders dopaminergic nigrostriatal pathway to the basal ganglia results in underactvity of the direct motor pathway (normally facili- {ates movement) (Figure 17-27) and overactivity of the indirect ‘motorloop (normally inhibits movement). Ths results in inhibi- tion of the motor cortex manifested with bradykinesia and rigid- ity. The subthalamic nucleus (STN) overactivity also influences the limbic system,” accounting for emotional signs and symp- toms, Neuronal loss within the cerebral cortex is found in half of individuals with PD. Mechanisms of cell dysfunction and deathUNIT V_The Neurologic System FIGURE 17-27 Reduced Fuorodopain Parkinson Disease. Postn-emision tomography sen shawn ragga uptake he basal gang consistent wth nurade Porn GD otal ties of inelude mitochondrial dysfunction, oxidative stress, altered pro- tein handling, and inflammatory changes with autophagy and apoptosis? Lewy bodies, fibrillar intracellular eosinophilic inclusions, and high concentrations of alpha-synucicin, ubiquitin, tau protein, tuberculin, and other proteins are found in the sub- stantia nigra (SN), locus ceruleus (LC), and other areas of the brain. They are a marker for neuronal degeneration."® Degen- eration of the LC, which contains noradrenergic neurons, also ‘occurs in PD. Norepinephrine is thought to be neuroprotec~ tive and loss of LC neurons may be associated with a wors- ening of disease progression and the behavioral symptoms of PD. Molecular events thought to be associated with the neurodegeneration of PD include mitochondrial dysfunction, ‘oxidative stress, abnormal folding and accumulation of alpha- synuclein, abnormal phosphorylation, and dysfunction of the ubiquitin proteasome system (regulates intracellular protein processing)*®" (Figure 17-28). CLINICAL MANIFESTATIONS, Onset of symptoms is insidious and symptoms appear after a 70% to 80% loss of pigmented nigral neurons and a 60% to 90% loss of striatal dopamine."” ‘The classic motor manifestations of PD are resting tremor, bradykinesia/akinesia (poverty of movement), rigidity (muscle stiffness), and postural abnormalities. These mani- festations may develop alone or in combination; however, as the disease progresses, all four are usually present to at Teast some degree. There is no true paralysis. A modified Hochn and Yahr scale"? can be used to assess progression of symptoms: © Novisible disease 1. Unilateral involvement, may have tremor of one limb 2. Bilateral involvement, balance intact 3. Bilateral involvement, slowing of body movement, mild to moderate postural instability, and gait difficulty 4 Bilateral involvement with severe postural instability, rigidity, and bradykinesia present 5. Bilateral involvement with inability to walk, confinement to wheelchair, cachexia present nical neurology 3,Piadlgha, 2011, Saunders ced yJearpared wth & rama cota ft om ‘Oxidative stress Genetic Mitochonctal dysfunction predisposition Loss of nerve growth factors (15%) Apoptosis I | a \Nigrostriatal dopaminergic in residual neurons. ‘neurodegeneration in [=| (proteins misfolding basal ganglia ‘and accumulation of alpha-synuctein) | ‘Unopposed cholinergic activity (promotes, muscle tone) FIGURE 17-28 Pathophysiology of Parkinson Disease. In early stages of the disease, reflex, sensory, and mental sta- tus are usually normal, Nonmotor symptoms associated with PI inelude byposmia fatigue, pain, autonomie dysfunction sleep frag- ‘mentation, depression, and dementia with or without psychosis.” Parkinsonian tremor, the most conspicuous and most vari- able symptom, is usually the first motor symptom to appear. It is a tremor at rest, disappearing briefly during the course of a voluntary movement and reappearing when the limb is held ina stationary position. Intensity and amplitude of the tremor vary. The arm is more affected than the leg. Most individuals with PD have this tremor and tremors are increased by stress and anxiety,CHAPTER 17 Alterations in Cognitive Systems, Cerebral Hemodynamics Eu Parkinsonian tremor appears to result from instability of feedback from the basal ganglia to the cerebral cortex caused by loss of the inhibitory influence of dopamine in the basal ‘ganglia Increased oscillation in the normal feedback cycles of the motor outflow feedback circuit when the museles are at rest produces the tremor. When the individual performs vol- unlary movements, the tremor becomes temporarily blocked, presumably because other motor control signals arriving in the thalamus override the abnormal basal ganglia signals. As the disorder worsens, tremor may lessen as rigidity supervenes ‘The postural tremor is associated with damage to the cerebel- lofugal pathway to the red nucleus, 2 pathway that subserves communication from muscle spindles to the thalamus and motor cortex. Parkinsonian rigidity is an increased resistance to the pas- sive movement ofa joint that impedes active and passive move- ‘ment, The first symptoms of rigidity may be painful musele cramps in the toes or hands. More commonly the limb feels stiff, heavy, tired, or aching, Plastic rigidity is constant throughout the entire range of motion and is felt as lead-pipe resistance during passive movement. Cogwheel rigidity, brief palpable jerks, is accompanied by tremor. The mechanism underlying rigidity is unclear, but there is increased resting muscle activity of antagonistic muscle groups with enhancement of the long- latency component of the stretch reflex.” Parkinsonian bradykinesia is poverty of associated and voluntary movements. It is the most prevalent and crippling symptom and often is overlooked in the early tages. The patho- physiology underlying the bradykinesia is an overactive sub- thalamic nucleus (STN) that inhibits the motor thalamus and ‘motor cortex.” It is associated with dopamine deficiency and failure of the mechanism programming movement patterns manifested as a defect in the voluntary production of smooth motions at different speeds.”” All striated muscles—extremity, trunk, ocular, facial—are affected eventually, including muscles of mastication (chew- ing), deglutition (swallowing), and articulation. Micrographia (small handwriting) is present, Extreme underactivity in the individual with PD makes the person appear stiff, even when resistance to passive movement cannot be felt. Bradykinesia is a separate phenomenon from rigidity and may be severe ‘even in the presence of rigidity. Individuals state that they feel “wooden” (as though moving against resistance) and complain of rapid, severe fatigue Hypokinesia, or decreased frequency or absence of associ ated movements, is one of the earliest symptoms. Individuals ‘with BD sit and lie motionless for long periods without the little shifts an unaffected person makes to prevent discomfort and stiffness. Bradykinesia, or slowness of voluntary movements, is characterized by difficulty initiating, continuing, or synchro- nizing movements, Both associated and voluntary movements are interspersed by freezing (an inability to continue move- ‘ment). Freezing may be precipitated by (1) increasing the effort to move, (2) turning, and (3) initiating certain types of tactile and visual contac! Postural Abnormalities. Three types ofposturalabnormalities ‘occur in individuals with PD: (1) disorders of postural fixation, a FIGURE 17-29 Stooped Posture of Parkinson Disease. (From Pekin GD ‘tak Alas of lca ourleay 643, Pilacalghia, 2011, Sauncors (2) disorders of equilibrium, and (3) disorders of righting, The disorder of postural fixation associated with PD is involuntary flexion of the head and neck. The individual is unable to maintain an upright position of the trunk while standing or walking, Postural abnormalities of the hands and feet also ‘occur. Postural abnormalities are caused by a loss of normal postural reflexes, muscular rigidity, axial dystonia, weakness caused by myopathy, and impaired proprioception.*! Disorders of equilibrium result from loss of postural stabil- ity. The person with PD is unable to make the appropriate pos- tural adjustment to tilting or falling and falls like a post when starting to tlt, The festinating gait (short, accelerating steps) of the person with PD is an attempt to maintain an upright posi- tion while walking (Figure 17-29). Individuals also are unable to right themselves when changing from a reclining or erouch- {ng position to a standing position and when rolling over from. 1 supine to a lateral or prone position, Autonomic and Neuroendocrine Symptoms. Autonomic and neuroendocrine dysfunctions in PD produce nonmotor symptoms that are distressing but not incapacitating. The basal ganglia influence hypothalamic function (autonomic and neuroendocrine) through pathways connecting thehypothalamus with the basal ganglia and cerebral cortex. Common autonomic symptoms in PD include inappropriate diaphoresis, gastric retention, constipation, and urinary retention, Cardiac sympathetic denervation is common and causes neurogenic orthostatichypotension. Asymptomattributedtoneuroendocrine dysfunction is seborthea. Hypothalamic hypersecretion of hormone-releasing factors acting on the anterior pituitary causesUNIT V_The Neurologic System hypersecretion of androgenotropic hormones, producing sebum, hypersecretion by sebaceous glands. The resulting seborrhea is characterized by oily skin with sebortheic dermatitis along the hairline and in chin-nasal creases.” Cognitive-Affective Symptoms and Dementia. Approximately 30% to 40% of people with PD have a depression that is now believed to be an inherent part of the pathologic state of the disease (an endogenous depression), not a response to the situation. Mild cognitive impairment not associated with cither dementia or depression is associated with dopaminergic dysmodulation. Bradyphrenia (slowness of thinking) also is present. These disorders may appear early in the course of the disease and may progress to dementia, Bradyphrenia is caused by disruption of the caudal basal ganglion connections and ‘outflows. The elinical manifestations are slowness of thinking, poverty of thought (diminished imagination and insight), and difficulty formulating thoughts (decreased ability to conceptualize, plan, decide, or improvise).”° Of individuals treated on an outpatient basis for PD, 30% have a dementia, and 80% of those with PD requiring insti- tutional care have dementia as well Dementia is more com- ‘mon in individuals older than 70 years, Pathologically, in those with dementia, findings include loss of cholinergic cells in the basal nucleus of Meynert (nucleus basalis); neuronal loss, senile plaques, and neurofibrillary tangles in the neocortex; and amyloid changes in small blood vessels. Lewy bodies (alpha- synuclein inclusions) are distributed diffusely in many neurons, making this a Lewy body dementia.” The individual evidences, disorientation; confusion; memory loss; distractibility; and difficulty with concept formation, abstraction, calculations, thinking, and judgment. Although the symptoms fluctuate, they progressively worsen. Anxiety disorders, impulse-control disorders, and punding (a disorder of stereotypical motor bbchavior in which there is intense fascination with repetitive handling and examining of mechanical objects) are recognized features of PD. Other nonmotor symptoms are common in PD including sensory dysfunction with anosmia, ageusia, pain, paresthesia, fatigue and weight loss, sweating, urinary and gastrointesti- nal dysfunction, and eye tremor." Sleep disorders are com- mon including disturbances in the sleep-wake cycle, excessive daytime sleepiness, obstructive sleep apnea, and restless leg syndrome.” Influence of Symptoms. Early in the disease, people often experience asleep benefit; that is, symptoms decrease with sleep. Symptoms also fluctuate in an on-off pattern, Stress influences symptoms adversely, but the underlying mechanism is unclear. ‘The person’s mental status may be further compromised by the side effects of the medication taken to control symptoms. ‘The combination of ll the parkinsonian symptoms gives the individual a characteristic appearance: a wide-eyed, unblink- ing, staring expression with the facial muscles smoothed out, and almost immobile, Saliva frequently drools from the corners of the slightly open mouth. The skin of the face is frequently agxcasy. The gait is pathognomonic: the individual walks with slow, short, shuffling steps; the arms are flexed, abducted, and held stiffly atthe side; and the trunk is bent slightly forward. The person may break into a run spontaneously or when pushed forward or backward. Because of the disorder of postural fixa- tion, the tendency isto fall to the side, Postural instability, sleep disorders, and difficulty concentrating are some of the most depressing symptoms for people with PD.) EVALUATION AND TREATMENT. The diagnosis of primary PD is ‘made on the basis of the four cardinal symptoms: (1) resting tremor, (2) cogwheel rigidity, (3) akinesia, and (4) postural instability. This group of symptoms has the acronym TRAP. ‘The exclusion of other causes of parkinsonism and a combi ‘nation of imaging techniques, clinical evaluations, biochemical markers, and genetic tests support the diagnosis of PD.°10 Early nonmotor symptoms of PD can precede motor symptoms and their identification may assist early diagnosis and guide isease-modifying strategies.!°> Median time between diag- nosis and death is between 7 and 15 years. Disease progression varies with age of discase onset, comorbidities, quality of care, and among different populations.!°:°? ‘The aim of drug therapy is to restore striatal dopamine lev- cls using oral drugs such as levodopa (t-dopa), a precursor of dopamine (dopamine does not cross the blood-brain barrier), dopamine agonists that directly stimulate dopamine recep- tors, anticholinergic drugs, antihistamines, and amantadine; t-dopa is effective in reducing symptoms in early PD but can cause motor fluctuations, “oll” periods, and dyskinesia in the long term. Monoamine oxidase B inhibitors, which inhibit the breakdown of endogenous dopamine, may improve symptoms, reduce motor fluctuations, and delay the need for t-dopa but can cause adverse effects. Adding catechol-O-methyltransferase (COMT) inhibitor prolongs the half-life of dopamine (COMT. ‘metabolizes dopamine in the synapse). Dopamine agonists to t-dopa or a dopamine agonist alone may reduce “off” time or improve symptoms but can also increase disability Surgery may be considered in later stages of PD. Thalamotomy and Pallidotomy are surgical options. Deep brain stimulation is an approach to controlling medically resistant motor symptoms and r-dopa-related peak dose dyskinesia." Gene- and cell- based therapies hold promise for fature treatment.” Dysphagia and general immobility are special problems of the individual ‘with PD requiring preventive, symptomatic, supportive, and rehabilitative management, such as physiotherapy and speech therapy.” Nursing interventions, occupational therapy (OT), physical therapy (PT), and speech, language, and swallowing therapy are effective and safe for improving functional status. Upper and Lower Motor Neuron Syndromes Paresis and paralysis are symptoms of upper and lower motor ‘neuron syndromes (Table 17-23), Paresis (weakness) is impairment of motor function, that is, partial paralysis with incomplete loss of muscle power. Paralysisis loss of motor function, thats, inability of muscle group to over- come gravity. The characteristics of paresis or paralysis are related to involvement of either the upper or the lower motor neurons, Upper Motor Neuron Syndromes. Upper motor neuron pparesis/paralysis is known also as spastic paresis/paralysis and different terms are used to describe the specific disorders, ‘Hemiparesis or hemiplegia is paresis or paralysis, respectively,