Idiopathic Parkinson’s disease (PD) is associated with the degeneration of the dopaminergic neurons of the SNc which, as stated previously, have an excitatory effect on the direct pathway and an inhibitory effect on the indirect pathway. A loss of dopaminergic stimulation in the neostriatum would result in a net inhibition of movement through both direct and indirect pathways (Fig. 11.8). The onset of PD is gradual in nature, but slowly and progressively continues until eventual severe disability. The cardinal signs and symptoms include tremor at rest, bradykinesia (slowness of movement), muscular rigidity, akinesia (impairment in initiation and poverty of movement), and loss of postural reflexes (Wichmann & DeLong 2002). The clinical diagnosis of PD can only be tentative because the major symptoms described above are not specific for PD. Some degree of certainty of the diagnosis can be achieved if the patient responds favourably to levodopa, a precursor in the formation of dopamine synthesis.

Figure 11.8 Pathological function of the dopaminergic neurons in the development of idiopathic Parkinson’s disease (PD).

PD must be distinguished from other disorders with extrapyramidal, cerebellar, or oculomotor features resembling PD, which are referred to as atypical Parkinson’s or Parkinson-plus syndromes. These disorders include progressive supranuclear palsy, olivopontocerebellar atrophy, corticobasalar ganglionic degeneration, and Shy-Drager syndrome, all of which can frequently be identified by specific clinical features. In addition to the motor abnormalities, patients with PD frequently have cognitive and affective disturbances. Depression is common in PD and in many patients predates the extrapyramidal features. Dementia also commonly occurs in PD patients; prevalence data suggest that about 50% of PD cases have significant cognitive impairment. This too seems to be an integral part of the spectrum of clinical manifestations of PD.

The pathological hallmark of PD is intracellular inclusions called Lewy bodies. These occur inside the dopamine-producing neurons in the substantia nigra pars compacta. These inclusions probably accumulate in neurons as breakdown products of dopamine and probably increase in concentration in neurons undergoing degeneration. During the past decade it has become clear that Lewy bodies are not limited to the substantia nigra in PD, but may occur in a widespread distribution in the cortex. Diffuse Lewy body disease is a pathological entity whose clinical correlates have not yet been defined. Patients commonly have cognitive decline and Parkinsonian features, and either one may dominate the picture (Korczyn 2000).

The number of dopamine (DA)-producing neurons progressively diminishes in PD over time. It is important to note that only DA neurons in the substantia nigra whose axons are destined to go to the putamen (less so to the caudate) in the nigrostriatal tract are affected. Chemical analysis shows progressive loss of DA in the striatum, with the clinical symptoms first becoming apparent when DA content in the striatum is reduced by about 70%. This process may take as long as 20 years before symptoms become apparent (Hornykiewicz 1988; Scherman et al. 1989).

Other neurotransmitter systems are also affected in PD. These include norepinephrine (NE) loss in the cell bodies of the locus ceruleus, serotonin (5-hydroxytryptamine (5-HT)) loss in the raphe nuclei, and cholinergic cell loss in the nucleus basalis of Meynert. These deficiencies probably contribute to the affective and cognitive changes in PD but may also be involved in motor dysfunction.

The aetiology of PD is uncertain but is most probably multifactorial in nature with both genetic and environmental factors contributing to the development of the disease. One theory that has gained some popularity recently is that excessive concentrations of excitatory amino acids, particularly glutamate, may be involved in causing irreversible neuronal damage (Sonsalla et al. 1989). This is particularly relevant for PD because of the massive cortical, glutaminergic innervation received by the corpus striatum. The neurotoxicity is thought to be produced by over- or sustained activation of N-methyl- D-aspartate (NMDA) receptors on the neuron membranes. One environmental hypothesis suggests that a selective increase in lipid peroxidation in the substantia nigra neurons may occur in PD. This process may lead to excessive production of free radicals, which may in turn result in cellular damage and death (Ben Shachar et al. 1991). A particularly relevant fact concerning this theory is that DA degradation may involve the sequestration of iron in free radical formation in the process of lipid peroxidation. Both the substantia nigra and globus pallidum are rich in iron, and the iron concentration increases with age, particularly in PD.

The gold standard treatment of PD is replacement of DA using levodopa. Levodopa is absorbed from the gastrointestinal tract and converted to DA in both the brain and the periphery by the enzyme 1-amino acid decarboxylase (1-AAD) (Clough 1991). The peripheral conversion of levodopa to DA can be inhibited by the actions of benserazide and carbidopa. Most patients today are treated by a combination of levodopa and benserazide or carbidopa. The aim of using this combination is to prevent the peripheral conversion of levodopa to DA, because DA may act in the periphery to produce undesirable side effects such as orthostatic hypotension and nausea (Cederbaum et al. 1991).

Surgical interventions of PD include ablative and transplanting approaches. Targets for functional stereotactic neurosurgical lesions, which reduce tremor, are the ventrolateral thalamus and the posteroventral pallidum. There has been extensive interest in transplanting DA tissue removed from aborted fetal midbrains into the caudate or putamen in PD; however, the results remained confusing because of small cohort sizes and disease severity issues of the participants (Widner & Rehncrona 1993).

The prevalence of dementia in PD is far greater than that in the general population. PD dementia may be preceded by mild memory loss, transient confusional episodes, or hallucinosis. The progression of the cognitive decline is unrelated to that of the motor disability, and the only robust predictor for the development of dementia is the patient’s age. Clinically, the dementia of PD differs from that of Alzheimer’s disease (AD). PD patients rarely develop dysfunctions of the isocortical association areas, such as dysphasia or agnosia, and their dementia resembles a ‘frontal’ type of dementia.

Depression is also rather common in PD. Because depression is potentially treatable, every patient with PD must be assessed for possible depressive symptomatology (Cummings 1992). Several tests are available for diagnosing depression. These include neuropsychological evaluations, self-reports, and projection tests. However, while all these tests have important roles in research, none is superior to the clinical assessment by a competent clinician. The clinical evaluation of the affective state of PD patients may be difficult because the motionless face, the slowness of movement, and the bradyphrenia may create an erroneous impression of depression. The distinction from depressive motor retardation is obviously very important.

In Huntington’s disease (HD) the neurons in the neostriatum degenerate. The degeneration appears to be more pronounced in the output neostriatal neurons of the indirect pathway (Albin et al. 1992). This results in the disinhibition of the GPe, which in turn results in an overinhibition of the subthalamic nucleus. The functional overinhibition of the subthalamic nucleus results in a situation that resembles an ablative lesion to the subthalamic nucleus and results in a hyperkinetic movement disorder (Fig. 11.9). In the latter stages of HD neostriatal degeneration spreads to include the output neurons of both the direct and indirect pathways, resulting in hypokinetic Parkinson-like activities (Young et al. 1986).

Figure 11.9 The pathology observed in Huntington’s disease (HD) in which the neurons in the neostriatum degenerate.

Although a juvenile form of HD does occur and the onset of HD can range from as young as 2 years to as old as 80 years, disease onset typically occurs in adults in their mid-thirties to mid-forties. The disease affects men and women in equal frequencies, ranging from 5 to 10 per 100 000 (Kandel et al. 2000). The disorder is characterised by insidious onset of both neurological and psychiatric symptoms. Initial symptoms include personality change and the gradual appearance of small involuntary movements; as the disease progresses, chorea becomes more obvious and incapacitating (Harper 1996). Over time, motor symptoms worsen such that walking, speaking, and eating becomes more difficult, and weight loss is common because of the extra energy required for movement and an increase in their basal metabolic rate. A large percentage of HD patients eventually succumb to aspiration pneumonia, resulting from the inability to coordinate pharyngeal muscles and vocal cords, which results in swallowing difficulties. It has a large genetic component.

The juvenile form of HD, which is also referred to as the Westphal variant form of HD, occurs in about 10% of reported cases. The initial presentation is more Parkinsonian in nature with bradykinesia, rigidity, and tremor rather than chorea as the prominent symptoms. Juvenile-onset HD is usually the result from paternal transmission and in individuals who develop symptoms before age 10; more than 90% have an affected father (Folstein 1989). There is a unique tendency for juvenile HD to have a younger age of onset in successive generations, which is referred to as anticipation. Anticipation in juvenile HD is especially pronounced in cases of paternal transmission.

Within the striatum, HD differentially affects subpopulations of neurons, with projection neurons rather than interneurons preferentially being lost (DiFiglia 1990). Consistent with the finding of loss of projection neurons is the fact that GABA levels are markedly reduced in the caudate–putamen of HD patients. Of the two populations of striatal projection neurons, the neurons of the indirect pathway are affected first; thus, the indirect pathway is predominantly disrupted. With interruption of the indirect pathway, the current models of basal ganglionic circuitry predict an overall increase in movement, manifested as chorea and ballism. The functional result of degeneration of both the direct and indirect pathways is a rigid bradykinetic state, which occurs in the later stages of adult HD. In the case of juvenile HD where the symptoms resemble Parkinson’s disease early in the presentation, degeneration of both direct and indirect pathway striatal neurons occurs from the onset (Albin et al. 1989).

The mode by which neurons die in HD is still unclear although the process of apoptosis or preprogrammed cell death may be the final common pathway through which neurons are terminated. Prior to the discovery of the HD gene, the leading hypotheses concerning the pathogenesis of HD implicated either excitotoxicity or metabolic dysfunction. The protein huntingtin, which is coded for by the huntingtin gene, has no clear relationship to excitatory amino acid neurotransmission, or to mitochondrial energetics. The normal function of huntingtin is not completely known, although it has been implicated in membrane recycling (DiFiglia et al. 1995). Thus, the influence of the huntingtin protein remains unclear as it relates to these hypotheses.

Excitotoxicity is the process in which neuronal cells die as a result of excessive excitatory amino acid neurotransmission. This process has been well documented with respect to overstimulation or excessive stimulation of glutaminergic NMDA receptors. This overstimulation can result in excessive amounts of Ca⁺⁺ ions entering neurons and triggering preprogrammed genetic termination pathways in the neuron. Glutamate has been postulated to trigger neuron death in a number of neurological disorders, including hypoxia-ischaemia, head trauma, epilepsy, schizophrenia, and neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (Fagg et al. 1986; Choi & Rothman 1990; Kornbuber & Wiltfang 1998).

Mitochondrial dysfunction has also been implicated as a pathologic mechanism in HD, potentially rendering cells vulnerable to normal ambient levels of extracellular glutamate (Albin & Greenamyre 1992). Positron emission tomography and MRI spectroscopy studies have demonstrated abnormalities in glucose metabolism in HD patients (Mazziotta et al. 1987). The impact or contribution of mitochondrial dysfunction in the development of HD remains under investigation; however, at least one study has demonstrated that administration of coenzyme Q₁₀, an essential cofactor of the mitochondrial electron transport chain, lowers elevated cortical lactate levels in HD patients back to levels seen in normal controls (Koroshetz et al. 1997). This suggests that mitochondrial energetic processes are in some way contributing to the development of HD.

The discovery of the huntingtin gene was unusual in that the usual genetic mutations observed in human diseases include point mutations, deletions, duplications, or missense mutations. The mutation in the huntingtin gene (IT-15 gene), however, resides in an unstable region of the gene, where mutation can result in an expansion of a normally appearing trinucleotide repeat motif present in the alleles of HD patients. CAG is the codon for glutamine, and the trinucleotide repeat of this motif gives rise to a polyglutamine moiety within the huntingtin protein. Normal huntingtin alleles contain from 6 to 35 CAG repeats, giving rise to 6 to 35 glutamines in the mature protein. Patients with Huntington’s disease invariably have alleles with greater than 35 repeats. While repeats greater than 40 invariably give rise to Huntington’s disease, there is a ‘grey area’, between 35 and 39 repeats, where there is some uncertainty whether the disease will develop (Cha & Young 2000).

There are currently no effective therapies for preventing the onset or slowing the progression of HD. Current therapies are symptomatic, and include the use of neuroleptics to decrease chorea, and the use of psychotropic medications to address depression, obsessive-compulsive symptoms, or psychosis. In addition, speech therapy and physiotherapy are useful in addressing the swallowing and walking difficulties that many HD patients experience (Ranen et al. 1993).

Ballismus or ballism includes a group of conditions characterised by flinging, large-amplitude, rotary movements, usually involving the proximal limb muscles. The most common form of this condition occurs unilaterally and is referred to as hemiballism. The cause is classically a basal ganglionic lesion in the contralateral subthalamic nucleus, but contralateral lesions in the neostriatum can also result in ballismic dyskinesia (Provenzale & Schwarzschild 1994) (Fig. 11.10).

Figure 11.10 The pathology seen in ballismus or ballism.

This syndrome develops after an infection with group A streptococcal bacteria that has not been treated with the appropriate antibiotics. The most frequently involved population is adolescent females. The onset is usually 4–5 months following the infection and begins with an increased feeling of restlessness and increased periods of fidgeting. Occasionally, periods of emotional lability and obsessive-compulsive behaviours will also accompany the motor symptoms. The symptoms become gradually worse over weeks to months and then subside. The symptoms will recur in about 20% of those affected in later life. The cause is thought to involve a cross-reaction of anti-streptococcal antibodies with receptors on striatal neurons.

The diagnosis of TS is based solely on the patient history presented. The DSM-IV diagnostic criteria for TS is the frequent occurrence of multiple motor tics and one or more types of vocal tic present and occurring over a continuous interval for most of 1 year. Usually, the onset of symptoms must have occurred early in life, before the age of 21, to be considered as TS (American Psychiatric Association 1994).

Tics are sudden, rapid, recurrent, nonrhythmic, stereotyped movements or vocalisations. Simple tics are brief circumscribed movements or sounds that resemble ‘chunks’ of movement or sounds rather than meaningful or recognisable actions. These may include facial grimaces, mouth movements, head jerking, and shoulder, arm, and leg jerks. Complex tics are more sustained and elaborate movements or more recognisable words or sounds that can give the perception of being intentionally produced (Swerdlow & Leckman 2002). In a small percentage (10%) of those with TS vocal tics can involve vulgar or obscene expletives. This form of expression is referred to as coprolalia. Tics can be voluntarily suppressed but, like obsessive-compulsive tendencies, the suppression builds up anxiety and results in a more forceful expression when the tic is eventually expressed. Many children express tics as a normal activity as they pass through various phases of development. These normal or developmental tics have usually completely disappeared by 18 years of age (Shapiro et al. 1978).

The usual presentation of TS typically begins between the ages of 3 and 8 years old, with periods of worsening and remission of the tics throughout childhood. The period of 8–12 years of age seems to be the period of greatest severity in most children, with a steady decline to the age of 18 years where as many as 50% of the children will present as tic free (Leckman et al. 1998). For those who maintain their tics into adulthood a more predictable pattern usually emerges with the frequency and intensity of the tics increasing during periods of increased stress or emotional excitement and generally over time.

The cause of TS has a high degree of concordance with a genetically generated dysfunction that has been postulated to involve the cortico-neostriatal-thalamo-cortical circuits in a variety of locations and in a variety of ways that seem to affect the function of the whole system rather than any one part of the system. Four areas of dysfunction have been suggested:

Treatment of TS is aimed at developing flexible, integrated biosocial and biopsychological strategies to allow the build-up of anxiety to be dissipated in a controlled fashion, and control the excitement in emotional situations.

The characteristic features of dystonia are the distorted postures and movements caused by spasmodic muscular activity in people with this condition. If the spasmodic muscular activity is maintained for long periods it is referred to as dystonic posturing. If the spasmodic muscular activity results in slowly changing repetitive activity then it is referred to as dystonic movements (Rothwell et al. 1983).

The hallmarks of dystonia include:

The excessive involvement of antagonistic muscles and overflow of contraction suggest that the normal spinal inhi­bitory feedback mechanisms are dysfunctional in this condition. However, this does not appear to be the case. The classic spinal disynaptic pathway involving 1a reciprocal inhibition of antagonist muscles remains intact in dystonic patients (Nakashima et al. 1989). However, the presynaptic or supraspinal inhibition of these reflexes is dysfunctional. The cause of the dysfunctional descending inhibition is thought to be due to altered function of the basal ganglionic circuits that relay back to the cortex via the thalamus.

Dystonias can be described in terms of the extent of spasmodic involvement. Focal dystonias include torticollis, which is spasm of the neck muscles; blepharospasm, which is spasm of the orbicularis oris muscle surrounding the eye; spasmodic dysphonia, which involves the muscles of the larynx and vocal cords; and writer’s cramp, which involves the muscles of the hand. Generalised dystonias involve large areas of the body and can be unilateral or bilateral in nature.

The syndrome of primary idiopathic torsional dystonia (ITD) is a rare hereditary generalised dystonia that can affect most muscles of the body, although usually the muscles controlling eye movement and the sphincter muscles are spared. The cause of ITD is thought to involve the DYT1 gene on the chromosome 9q34. This gene codes for the enzyme dopamine beta-hydroxylase (DBH). The activity of the gene is thought to be related to the stimulus activity of neurons in the basal ganglia in such a way that when activation levels fall below a certain frequency the gene is activated. Such a situation might occur following an injury. It has been postulated that peripheral trauma may be a precipitating event to the development of ITD in gene carriers.

Clinical case answers

Case 11.1

11.1.1

Dyskinesias are disorders of movement, usually involving the basal ganglionic–cortical loops. Several types of dyskinesias have been identified including tics, athetosis, choreiform, ballismus.

11.1.2

This woman’s symptoms are most likely the result of a dysfunction in the subthalamic nucleus. Understanding the inhibition and excitation circuits involved in direct and indirect pathways of the basal ganglia will help one to understand the spectrum of functional disorders ranging from hyperkinetic to hypokinetic, involving movement and thought processes caused by basal ganglia disorders.

In the direct pathway, the output neurons of the neostriatum project axons that synapse on the neurons of the globus pallidus pars internus (GPi) and/or on the neurons in the substantia nigra pars reticulata (SNr). These projections, arising from the neostriatum, release GABA, substance P, and dynorphin, which act in an inhibitory fashion on the target neurons in the GPi and the SNr.

In the indirect pathway, axons from the neurons of the neostriatum project to neurons in the globus pallidus pars externa (GPe) where they release the neurotransmitter GABA, enkephalin, and neurotensin, which act in an inhibitory nature on the neurons of the GPe. The neurons of the GPe in turn project to the neurons located in the subthalamic nucleus of Luys (STN), where they release the neurotransmitter GABA and act to inhibit the output neurons of the subthalamic nuclei. The neurons of the subthalamic nuclei project to the neurons of the GPi via the subthalamic fasciculus where they release glutamate and are excitatory in nature. The subthalamic output neurons are the only excitatory neurons in the basal ganglionic circuits. These STN neurons project to neurons in the GPi.

Dysfunction in this nucleus allow the thalamus to escape from the inhibition of the GPi and result in ballistic movements (Fig 11.1.2).

Case 11.2

11.2.1

Idiopathic Parkinson’s disease (PD) is associated with the degeneration of the dopaminergic neurons of the substantia nigra pars compacta (SNc) which, as stated previously, have an excitatory effect on the direct pathway and an inhibitory effect on the indirect pathway. A loss of dopaminergic stimulation in the neostriatum would result in a net inhibition of movement through both direct and indirect pathways. The onset of PD is gradual in nature, but slowly and progressively continues until eventual severe disability. The cardinal signs and symptoms include tremor at rest, bradykinesia (slowness of movement), muscular rigidity, akinesia (impairment in initiation and poverty of movement), and loss of postural reflexes. This gentleman is exhibiting tremor at rest, and muscular rigidity.

11.2.2

Dysfunction in the direct pathway is thought to be responsible for hypokinesia. In the direct pathway, the output neurons of the neostriatum project axons that synapse on the neurons of the GPi and/or on the neurons in the SNr. These projections, arising from the neostriatum, release GABA, substance P, and dynorphin, which act in an inhibitory fashion on the target neurons in the GPi and the SNr (Fig. 11.2.2).

11.2.3

The gold standard treatment of PD is replacement of DA using levodopa. Levodopa is absorbed from the gastrointestinal tract and converted to DA in both the brain and the periphery by the enzyme 1-amino acid decarboxylase (1-AAD). The peripheral conversion of levodopa to DA can be inhibited by the actions of benserazide and carbidopa. Most patients today are treated by a combination of levodopa and benserazide or carbidopa. The aim of using this combination is to prevent the peripheral conversion of levodopa to DA, because DA may act in the periphery to produce undesirable side effects such as orthostatic hypotension and nausea. Surgical interventions of PD include ablative and transplanting approaches. Targets for functional stereotactic neurosurgical lesions, which reduce tremor, are the ventrolateral thalamus and the posteroventral pallidum. There has been extensive interest in transplanting DA tissue removed from aborted fetal midbrains into the caudate or putamen in PD; however, the results remained confusing because of small cohort sizes and disease severity issues of the participants. Treatment aimed at increasing the cortical stimulus to the neostriatum may also be of benefit.

Case 11.3

11.3.1

Ballismus or ballism includes a group of conditions characterised by flinging, large-amplitude, rotary movements, usually involving the proximal limb muscles. The most common form of this condition occurs unilaterally and is referred to as hemiballism. The cause is classically a basal ganglionic lesion in the contralateral subthalamic nucleus, but contralateral lesions in the neostriatum can also result in ballismic dyskinesia.

Chorea consists of repetitive, brief jerky large-scale dance-like, uncontrolled movements that start in one part of the body and move abruptly and unpredictably to other parts of the body.

Athetosis is a continuous stream of slow, sinuous, writhing movements, generally of the hands and feet.

11.3.2

Disorders of the indirect loop are thought to produce hyperkinetic movement disorders (see Fig. 11.1.2).

11.3.3

Huntington’s disease is characterised by insidious onset of both neurological and psychiatric symptoms. Initial symptoms include personality change and the gradual appearance of small involuntary movements; as the disease progresses, chorea becomes more obvious and incapacitating (Harper 1996). Over time, motor symptoms worsen such that walking, speaking, and eating becomes more difficult, and weight loss is common because of the extra energy required for movement and an increase in their basal metabolic rate. A large percentage of HD patients eventually succumb to aspiration pneumonia, resulting from the inability to coordinate pharyngeal muscles and vocal cords which results in swallowing difficulties. It has a large genetic component.

Sydenham’s chorea develops after an infection with group A streptococcal bacteria that has not been treated with the appropriate antibiotics. The most frequently involved population is adolescent females. The onset is usually 4–5 months following the infection and begins with an increased feeling of restlessness and increased periods of fidgeting. Occasionally, periods of emotional lability and obsessive-compulsive behaviours will also accompany the motor symptoms. The symptoms become gradually worse over weeks to months and then subside. The symptoms will recur in about 20% of those affected in later life. The cause is thought to involve a cross-reaction of anti-streptococcal antibodies with receptors on striatal neurons.