Basal Ganglia and Movement Disorders

Overview of Movement Disorders

For the past 30 years, movement disorders have encompassed the study of a group of conditions characterized by poverty of movement, the akinetic-rigid syndromes, and those with excessive movements, the hyperkinetic movement disorders (tremor, dystonia, myoclonus, chorea/ballism, tics, and others). This traditional view, in which disorders of basal ganglia resulted in the aforementioned syndromes, has now expanded to include the ataxias and disorders of gait and posture. Advances in surgical techniques and imaging studies have broadened the clinical horizon and catchments of the movement disorders specialist. With the increasing indications for botulinum toxin therapy, spasticity and others disorders are now managed by many movement disorders neurologists.

Abnormal involuntary movements (AIMs) should be viewed as clinical signs with many causes. For example, parkinsonism may be the clinical manifestation of a variety of conditions with different or unclear etiologies. Defining the broad category of the movement disorder in a given patient precedes the classic approach to neurologic diagnosis: localizing the lesion and determining the etiology of the condition. A careful history with particular attention to family background, pregnancy, labor and delivery, early developmental milestones, trauma, infections, medical and psychiatric comorbidities, and use of illicit drugs and medications, especially neuroleptics, are particularly important when first evaluating a patient with abnormal involuntary movements and may suggest the underlying cause. A detailed general medical examination with emphasis on eye movements, presence of Kayser-Fleischer rings (suggesting Wilson disease), and funduscopic examination looking for retinopathy and optic nerve abnormalities (papillitis, papilledema, or optic nerve atrophy suggesting demyelinating diseases, metabolic disorders, or mitochondrial cytopathies); organomegaly (betraying metabolic or storage diseases); and skin discolorations or deposits (defining phakomatosis, xeroderma pigmentosum, vitaminosis, gastrointestinal disease, malabsorption, calcinosis, or cholesterol deposits, especially at the muscle tendons) may prove rewarding. Searching for additional clues, with a carefully performed neurologic examination, will help in the understanding of the patient's condition.

Once the abnormal movements have been classified, and the neurologic accompaniments documented and placed in context, the cause may become apparent and proper ancillary testing may be undertaken.

Anatomy of the Basal Ganglia and Related Structures

Anatomically, the basal ganglia constitute a complex circuitry that includes neurons of the caudate nucleus, putamen, subthalamic nucleus (STN) globus pallidus, and substantia nigra (SN). The output of the basal ganglia is directed at the motor thalamus (and from there to the frontal cortex) and the pedunculopontine nucleus (PPN).

Globus Pallidus. Divided by the internal medullary lamina into an external (GPe) and internal (GPi) segments, the globus pallidus borders laterally with the putamen, dorsomedially with the internal capsule and optic tract and ventrally with the substantia innominata, which, in turn, contains three major functional anatomic systems: the ventral striatopallidal system, the extended amygdala, and the nucleus basalis of Meynert. The latter nucleus, with its cholinergic and γ-aminobutyric acid (GABA-ergic) projections, plays an important role in disorders of memory and the treatment of dementias. The GPi is a major efferent structure of the basal ganglia, using three major projection systems: the ansa lenticularis, the lenticular fasciculus, and the pallidotegmental tract. The ansa lenticularis sweeps ventromedially around the internal capsule, joining the lenticular fasciculus to form the thalamic fasciculus, which, in turn, projects to different thalamic nuclei, especially the ventral anterior (VA), ventral lateral (VL), centromedian, and parafascicular intralaminar nuclei of the thalamus. The pallidotegmental tract terminates in the pedunculopontine nucleus.

Caudate Nucleus. The caudate nucleus resembles an elongated and curved exclamation mark. Its main part is an expanded head directly continuous with a smaller and attenuated body that merges into an elongated tail. The head bulges into the anterior horn of the lateral ventricle and forms its sloping floor. The caudate nucleus is separated from the lentiform nucleus by the anterior limb of the internal capsule, but the separation is incomplete because the head of the caudate nucleus and the putamen are connected, especially anteroinferiorly, by bands of gray matter traversing the white matter of the anterior limb. This admixture of gray and white matter produces the striated appearance that justifies the term “corpus striatum” applied to these nuclei. The head tapers into the narrower body that lies in the floor of the central part of the lateral ventricle, lateral to the superior surface of the thalamus and separated from it by a shallow sulcus lodging the stria terminalis and thalamostriate vein. The tail turns downward along the outer margin of the posterior surface of the thalamus, with the stria terminalis still lying in a slight groove between them. It then curves forward into the roof of the inferior horn of the lateral ventricle, where it separates from the thalamus and lentiform nucleus by the inferior part of the internal capsule and by fibers (including some from the anterior commissure) that spread into the temporal lobe.

Amygdaloid Body . The tail of the caudate nucleus ends in a small, almond-shaped expansion, the amygdaloid body, which is a complex of several small nuclei located in the forepart of the roof of the inferior horn of the lateral ventricle. The stria terminalis issues from the amygdaloid body and runs along the medial side of the caudate nucleus until it reaches the vicinity of the ipsilateral interventricular foramen. Here, some of its fibers join the anterior commissure, others pass to the “septal” region adjacent to the lamina terminalis, and the remainder descends to the hypothalamus and anterior perforated substance.

A nuclear midbrain complex, the substantia nigra (SN), is divided into a pigmented and dopamine-containing pars compacta (SNc) and a cell-poor, pigment-free pars reticularis (SNr). Most dopaminergic projections go to the striatum, while a smaller proportion of SNc axons terminate in the prefrontal cortex. The SNr is a major primary efferent structure of the basal ganglia, along with GPi. SNr goes primarily to thalamus, PPN, and the superior colliculus.

A biconvex structure, the subthalamic nuclei (STN) receives glutamatergic inputs from the cerebral cortex, GABA inhibition from the GPe, and provides glutamatergic innervations to the GPe, GPi, SN, and PPN. The STN has become a structure of interest because of its pivotal role in our understanding of basal ganglia function.

The postsynaptic dopamine receptors are divided into two major broad categories, D1/D5 and D2, D3, D4 family of receptors, segregated into two main pathways. The direct pathway, subserved by D1 dopamine receptors, sends its projections to the subthalamic nuclei via the GPi, and the indirect pathway, via the D2 family of receptors, influences the STN via the GPe.

Recently, the excitatory-inhibitory interplay between the direct and indirect pathways has been conceptualized as focused selection and tonic inhibition (surround inhibition hypothesis). By suppressing excitability in an area that is surrounding an activated neural network, neuronal activity focuses to select desired responses. Simultaneously, other pallidal neurons projecting to the thalamus, act to permit desired movements . By decreasing their discharge, through focused striatal output chiefly via the direct pathway, tonic inhibition to the thalamus is removed, releasing the cortical generators for normal or desired movement to occur. Therefore the presence of abnormal involuntary movements results from either failure of inhibition or excessive excitation of the surrounding structures.

Based on the models discussed above, it is important to recognize the pallidum as the major outflow structure of the basal ganglia. Most fugal pathways pass throught the fields of Forel. Presently, the STN is the preferred target for the surgical treatment of idiopathic Parkinson disease (iPD), the ventral intermediate (VIM) thalamus for the treatment of essential and certain other types of tremor, and the GPi for dystonia, with deep brain stimulation (DBS) being the favored surgical procedure.

Idiopathic Parkinson Disease

Idiopathic Parkinson disease is characterized by the presence of tremor, rigidity, or bradykinesia early in the course of the illness, with postural and/or gait disturbances usually developing late in the course of the disease. The presence of atypical symptoms and the rate of progression of the disease are important in distinguishing Parkinson disease from other parkinsonian syndromes. For example, early-onset postural instability, falls, and gait disturbances characterize progressive supranuclear palsy (PSP); marked autonomic disturbances, such as erectile dysfunction in men or urinary bladder incontinence in women may herald the onset of multiple system atrophy (MSA). Stooping, a masked facies, decreased blinking, micrographia, and hypophonia, are common features of parkinsonism but are not unique to Parkinson disease and may be present in other parkinsonian syndromes. Severe anterocollis and camptocormia (bent spine) are more likely to be due to MSA or paraspinalis muscle fatty atrophy/myopathy rather than Parkinson disease (see Plate 7-5 ). Excessive neck rigidity, primarily when accompanied by marked oculomotor disturbances, such as hypometric slowed saccades in downward gaze or a clear defect of voluntary ocular excursion to command or pursuit but a normal excursion on the doll's eye maneuver, particularly in the vertical plane, suggest PSP. Other oculomotor disturbances, such as saccadic intrusions (principally square wave jerks or ocular flutter), nystagmus, or ocular impersistence, may be present in PSP, MSA, corticobasal degeneration (CBD), Huntington disease (HD), and the cerebellar ataxias in variable combinations and degrees of severity.

It is estimated that approximately 80% of the dopaminergic neurons in the substantia nigra have been lost by the time that Parkinson disease is first diagnosed; hence the initial degenerative process leading to parkinsonism begins several years before the clinical diagnosis. Although it is usually difficult to diagnose Parkinson disease in the preclinical (premotor) stage, anosmia, constipation, and mood and personality changes may precede the onset of motor symptoms by a few years. For most patients, the onset of motor symptoms is subtle and may be obvious first to family members or coworkers.

Dopamine deficiency is responsible for the pathophysiology of motor symptoms in Parkinson disease. Although symptoms improve with dopaminergic replacement therapy, tremor and postural and gait disturbances tend to have only a partial response to treatment, particularly in the later stages of the disease, suggesting the substrate of such symptoms may lie somewhere else along the central nervous system. Indeed, it has been shown that the pedunculopontine nuclei (PPN), a cholinergic structure closely linked to the striatonigral system, may play a major role in gait control. In addition, preliminary studies using PPN-targeted neuromodulation have shown mild improvements in gait difficulties and freezing in some patients, although the final outcomes in such studies are unclear at this time.

Tremor is a classic feature of parkinsonism. Typically, it is a rest tremor, disappearing with movement but resuming when a static posture is achieved, and has a 3-Hz frequency. Although it is most commonly seen in Parkinson disease, it may occur in other parkinsonian conditions, such as MSA and in those states induced by dopamine-blocking or dopamine-depleting medications. Its origin is not clear, but some evidence suggests that the inferior olives or the cerebellum act as the central oscillators, driving tremor by using the cerebellothalamocortical loop as a reverberating system.

Untreated Parkinson disease may be divided into five stages. Stage 1 is characterized by mild unilateral disease. Tremor may be the only visible sign but other subtle findings, including slowness or rigidity, may be noted on examination. Gait is usually normal, but there may be mild decrease in arm swing on the most symptomatic side, and the upper limb may be carried slightly abducted at the shoulder and flexed at the elbow. Diminished facial expression, hypophonic speech, reduced manual dexterity, impaired rapid alternating movements, and micrographia with poorly formed letters may be present. As the disease advances to stage 2, there is bilateral involvement with postural changes. In this stage, the more classic phenotype is observed, with reduced facial mobility, stooped posture when standing, reduced arm swing on walking, and en bloc turning, Rapid alternating movements are impaired. Movements become slow and deliberate, and patients may complain of fatigue and weakness. Fatigue may be disabling in up to 75% of patients. The hand assumes the so-called striatal posture with dorsiflexed wrist, adducted fingers, flexed metacarpophalangeal and distal interphalangeal joints, and extended proximal interphalangeal joints. In some patients, a “striatal foot” may be present consisting of a varus position with clawing of toes. In stage 3 disease, retropulsion and propulsion reflect increasing impairment of postural reflexes and righting responses. Gait is festinating and shuffling. In this stage, the symptoms become increasingly pronounced, and the patient may require assistance in the activities of daily living. With further progression, a more advanced stage is reached ( stage 4 ), with severe disability, rigidity, bradykinesia, and gait disturbances. Standing is unsteady; a slight push precipitates severe retropulsion, culminating in a fall if the patient is not caught or is left unattended. Eventually, the patient becomes markedly bradykinetic, rigid, and confined to a wheelchair or bed ( stage 5 ). Drs. Melvin Yahr and Margaret Hoehn studied the natural progression of patients suffering with Parkinson disease and developed a staging scale that bears their names. This classification, known as the Hoehn and Yahr staging scale, emphasizes the disease by progression of symptoms; it is arbitrarily divided into five stages of disease progression, and although widely used, it provides only a crude estimate of disease severity.

Pathology

The pathologic hallmark of Parkinson disease is the loss of pigmentation of the substantia nigra, decreased neuromelanin-containing neurons, and deposition of a Lewy body in the motor nucleus of the vagus, locus ceruleus, and substantia nigra (see Plate 7-6 ). The Lewy body is an intracytoplasmic, eosinophilic inclusion composed primarily of ubiquitin, neurofilaments, and alpha-synuclein, an important component protein normally found throughout the brain, particularly at the synapse. The role that alpha-synuclein plays in the pathogenesis of Parkinson disease is not well understood. Point mutations, duplications, or amplifications in the region of chromosome 4q21 containing the gene encoding for alpha-synuclein have been found in some familial, early-onset cases. Excessive alpha-synuclein leads to protein aggregation and clumping. Other mutations affecting the genes encoding for parkin, an important protein of the ubiquitin/proteasome system ( DJ-1 and PINK1 ), may affect mitochondrial function leading to impaired free radical handling and energy production. The high concentration of iron in the substantia nigra and striatum increases cell vulnerability to oxidative stress. Recently, the progression of Parkinson disease and Lewy body deposition with degeneration have been conceptualized as beginning in the olfactory bulb and lower brainstem, progressing over time to the diencephalon, amygdala, and entorhinal and neocortex.

An example of a fully developed clinical syndrome due to generalized diffuse Lewy deposits is diffuse Lewy body disease/dementia complex.

Multiple System Atrophy

In multiple system atrophy (MSA), the unifying pathologic feature is the oligodendroglial cytoplasmic inclusion bodies (GCIs), which are present in striatonigral degeneration (SND), sporadic olivopontocerebellar atrophy (OPCA), and Shy-Drager syndrome, nosologic entities once considered unrelated disorders but now grouped under the rubric of MSA. The autonomic abnormalities that characterize Shy-Drager syndrome are found eventually in both disorders. Thus MSA is divided in two major groups, MSA-C (cerebellar) and MSA-P (parkinsonism). Other pathologic features include variable neuronal cell loss with gliosis in the putamen and, to a lesser degree, the pallidum, brainstem (particularly the basis pontis and inferior olive), cerebellum, intermediolateral columns of the spinal cord, and peripheral nerves. When OPCA/MSA-C is present, atrophy is predominant in the pons, cerebellum, and medullary olives. Tau and alpha-synuclein are the predominant components of GCIs. The MRI appearance is sometimes characteristic (see Plate 7-8 ).