Cerebellum Case File

Cerebellum Case File

EUGENE C.TOY, MD, RAHUL JANDIAL, MD, PhD, EVAN YALE SNYDER, MD, PhD, MARTIN T. PAUKERT, MD

CASE 26

A 56-year-old man presents to the emergency room with complaints of difficulty walking and frequent falls over the past 48 hours. He has a 30-year history of chronic alcoholism. His nutritional status is poor and he admits to spending all of his money on alcohol instead of buying food to eat. Prior to his presentation, he describes an alcoholic binge and several days of anorexia. On physical examination he is noted to walk with a wide-based, irregular gait. He has poor coordination on tests requiring rapid leg movements.

Based on the patient’s history of severe alcoholism and malnutrition, alcoholic cerebellar degeneration was thought to be the most likely diagnosis. After treatment with vitamin B1 (thiamine), aggressive hydration with intravenous fluids, and good nutrition, the patient’s symptoms gradually improved and he was discharged to alcohol treatment program.

• Which part of the cerebellum is most likely affected?
• If left untreated, what disease is he at risk for?

ANSWERS TO CASE 26: CEREBELLUM

Summary: A 56-year-old man with 2 days of difficulty walking, frequent falls, and a wide-based, irregular gait with poor coordination of his lower extremities. He has a history of chronic alcoholism and poor nutrition. He was treated with vitamin B1 (thiamine), aggressive hydration with intravenous fluids, and good nutrition. His symptoms gradually improved and he was discharged to alcohol treatment program with a normal gait.

• Area of the cerebellum affected: Degenerative changes appear in the anterior and superior parts of the cerebellar vermis and are associated with ataxia of gait but preservation of speech and coordination of upper extremities.
• Disease at risk for if symptoms untreated: Wernicke-Korsakoff disease is a far more serious disease that also results from malnutrition and frequently chronic alcoholism. It results from severe thiamine deficiency, which leads to a degeneration of the eye movement nuclei and the cerebellar vermis and cortex, particularly the Purkinje cell layer. The symptoms include ataxia, ophthalmoplegia, and confusion. If untreated, the symptoms can progress to coma and death.

CLINICAL CORRELATION

Alcoholic cerebellar degeneration is caused by toxic degeneration of Purkinje cells, and is clinically characterized by impaired gait, tremor, and truncal ataxia. The midline cerebellar structures are predominantly involved with resulting effect of the lower extremities. The disease is thought to be caused by a combination of alcohol neurotoxicity and nutritional deficiency. The treatment of alcoholic cerebellar degeneration is alcohol abstinence, adequate calorie intake, and thiamine supplementation. While the effects on the cerebellum are frequently permanent, early treatment can lead to an improvement in symptoms and prevent the development of more serious pathology, such as Wernicke-Korsakoff disease.

APPROACH TO CEREBELLUM

Objectives

1. Know the key components of cerebellar anatomy.
2. Understand the functions of the cerebellum.
3. Know the afferent and efferent connections of the cerebellum.

Definitions

Ataxia: Problems with movement resulting from the combined effects of dysmetria and decomposition of movement.

Dysdiadochokinesia: Reduced ability to perform rapidly alternating movements.

Dysmetria: Disturbance of the trajectory or placement of a body part during active movements.

Mossy fibers: Originating neurons from spinal and brainstem nuclei (except the inferior olive) that form synapses with granule cells in the cerebellar cortex and have excitatory input to many Purkinje cells.

Nystagmus: Rapid and involuntary oscillatory movement of the eye.

Spinocerebellum: Comprises the vermis and the intermediate zones of the cerebellar cortex, the fastigial and interpose nuclei. Receives major input from the spinocerebellar tract. Major output to rubrospinal, vestibulospinal, and reticulospinal tracts.

Vestibulocerebellum: Flocculonodular lobe and its connection with the lateral vestibular nuclei. Involved in vestibular reflexes and maintenance of posture.

DISCUSSION

The cerebellum participates in the execution of a wide variety of movements. It maintains the fine control and coordination of both simple and complex movements. It is essential for coordinating posture and balance in walking and running, executing sequential movements, producing rapidly alternating repetitive movements and smooth-pursuit movements, and controlling the trajectory, velocity, and acceleration of movements.

The cerebellar cortex is comprised of gray matter arranged in slim, folded layers called folia. Three layers of cells constitute the cortex: the molecular layer, the Purkinje cell layer, and the granular layer. The Purkinje cells mediate all of the outgoing signaling of the cerebellum. Below the cortical layers, the white matter of the cerebellum houses the afferent and efferent fibers. Within the white matter are the cerebellar nuclei. These nuclei play an important mediating role in the cerebellar efferent connections.

The cerebellum includes a midline structure called the vermis and two large lateral structures known as the cerebellar hemispheres. Together, the vermis and hemispheres can be transversely divided into the flocculonodular lobe, the anterior lobe, and the posterior lobe. The flocculonodular lobe is the phylogenetically oldest portion of the cerebellum. It is comprised of the flocculus which is connected by a thin stalk to the nodulus, itself a portion of the vermis within the midline. The remaining portion of the vermis and the cerebellar hemispheres are termed the corpus cerebelli. The medial most portions of the cerebellar hemispheres are defined as the intermediate zones. The primary fissure divides the remaining functional areas of the cerebellum into the posterior and anterior lobes.

Information pertaining to the movement and relative position of the head is relayed primarily to the vestibular nuclei. Connections also occur, however, between the flocculonodular lobe and posterior portion of the vermis, allowing for cerebellar mediation of eye movements and movements related to balance.

The cerebellar cortex receives constant information from the skin, joints, and muscles of the limbs and trunk through the dorsal, ventral, and rostral spinocerebellar tracts and through the cuneocerebellar tract. All of this information is integrated with input from the auditory, vestibular, and visual sensory systems in order to determine the progress of motor movements within the cerebellum. The spinocerebellar tracts are somatotopically organized and provide the physiological basis for the cerebellar somatotopic organization.

The pontine nuclei provide the cerebellum with its greatest number of afferent connections via the pontocerebellar tract. These nuclei function as mediators of information between the cerebellum and cerebrum. The cerebrum sends information to the pontine nuclei via the corticopontine tract. The majority of the fibers of the corticopontine tract begin in the motor cortex and somatosensory cortex with significant connections also coming from the premotor area, supplemental motor area, posterior parietal cortex, and prefrontal and visual cortex. These connections allow the cerebellum to evaluate and coordinate motor movements. In addition, the pontine nuclei receive cortical projections from the cingulate gyrus and hypothalamus providing the physiological basis for the influence of emotion on motor movements. The pathways involving the cerebellar cortex, pontine nuclei, and cerebellum are referred to as the corticopontocerebellar pathway.

The medial portion of the cerebellum, the vermis, is characterized by afferents from the spinal cord. The lateral portions of the cerebellar lobes receive their afferents mainly from the cerebrum. The area between the vermis and the lateral portions of the cerebellar lobes, termed the intermediate zone, receives afferents from both the spinal cord and the cerebral cortex.

The cerebellar cortex is made up of three layers: the molecular layer, Purkinje cell layer, and granular layer. The molecular cell layer possesses few cell bodies and is primarily composed of axons and dendrites whose cell bodies lie in deeper layers. The Purkinje cell layer, as its name suggests, consists of mostly Purkinje cells which are arranged in a single layer. The dendrites of the Purkinje cells are very dense and receive numerous synaptic connections with the parallel fibers (~200,000 per cell). The Purkinje cells are GABAergic and thus inhibitory. The Purkinje cells are also the only cells to project out of the cerebellar cortex. The granular layer is the deepest layer of the cerebellar cortex. The granule cells project their axons to the molecular layer, where they split in two directions and run parallel with the cortical surface. These cells are termed parallel fibers and synapse with many Purkinje cells. The granule cells release glutamate and create an excitatory effect on the Purkinje cells.

The cerebellar cortex receives two forms of afferent connections: mossy fibers and climbing fibers. Because each mossy fiber forms synapses with many granule cells which then synapse with many Purkinje cells, the mossy fibers have the ability to excite many Purkinje cells. The effect on a Purkinje cell from a mossy fiber is, however, relatively weak. Mossy fibers originate from almost all nuclei except the inferior olive and generally fire at a high frequency of about 50–100 synapses per second. The fibers from the inferior olive consist of climbing fibers, which project to the molecular layer. As the climbing fibers travel, each one forms many synapses with the dendrites of the Purkinje cells it “climbs” alongside. Whereas each Purkinje cell receives synapses from only one climbing fiber, one climbing fiber may synapse with many Purkinje cells, allowing a single action potential from a climbing fiber to create an excitatory effect in numerous Purkinje cells. The frequency of climbing fiber firing is very low, normally firing less than once per second. These different forms of afferent connections allow the cerebellar cortex to receive very precise signals. The mossy fibers mainly convey information of the force, velocity, direction, and individual muscles involved in motor movements. Climbing fibers provide “error signals” regarding motor movement and may also be involved in certain aspects of motor learning.

The majority of cerebellar efferents arise from the cerebellar nuclei. Four different bodies constitute the cerebellar nuclei: the fastigial nucleus, dentate nucleus, globose nucleus, and emboliform nucleus. They are located within the deep white matter in each hemisphere. The cerebellar hemispheres exert their effect on the ipsilateral portion of the body. A cerebellar lesion will therefore clinically manifest symptoms on the same side of the body as the lesion. The cerebellar hemispheres send their cortical efferents mainly to the motor cortex, with some minor connections also reaching the supplemental premotor area and lateral premotor area. These minor connections are the basis of the cerebellar effect on cognition. The efferents from the dentate nucleus cross the midline after exiting the cerebellar peduncles ending, primarily, in the ventrolateral nucleus of the thalamus. The inferior and middle cerebellar peduncles convey mainly inputs to the cerebellum, and the superior cerebellar peduncle conveys the outputs of the cerebellum. The efferent output from the intermediate zone projects to the interposed nuclei, where it influences motor neurons through either the rubrospinal or pyramidal tracts. The fastigial nucleus sends fibers to the reticular formation and vestibular nuclei, allowing cerebellar control of motor neurons via reticulospinal and vestibulospinal tracts. These tracts facilitate cerebellar influence on posture and autonomic movements.

Damage to different areas of the cerebellum (see Figure 26-1) creates characteristic symptoms. A lesion of the flocculonodular lobe or midline will usually result in problems with stance and gait, titubation, head posture, and ocular-motor disorders resulting in nystagmus. Anterior lobe lesions typically result in gait ataxia. Disease infiltrating the neocerebellum often presents with ataxia involving voluntary movements. Lesions of the lateral hemispheres can also result in asynergia, gait ataxia, hypotonia, dysarthria and speech ataxia, dysmetria, dysdiadochokinesia, asynergia or the decomposition of complex movements, and intentional tremors as well as static tremors.

Figure 26-1. Diagram of the cerebellum, illustrating the major fissures, lobes, and lobules and the major phylogenetic divisions. (With permission from Adam and Victor’s Principles of Neurology. 7th ed. Figure 5-1, page 87.)

COMPREHENSION QUESTIONS

Refer to the following case scenario to answer questions 26.1-26.2:

A 4-year-old girl is brought into your clinic by her parents because of headaches, vomiting, and lethargy for 3 weeks. She is also having difficulty using silverware with her right hand. She has no problem performing fingerto- nose pointing with her left side, but consistently past points on the right and her movements on that side are very coarse. On funduscopic examination you note bilateral papilledema and order an MRI. It shows a tumor in the posterior fossa.

[26.1] Based on her symptoms, which is the most likely location of this tumor?

A. Left cerebellar hemisphere

B. Right cerebellar hemisphere

C. Cerebellar midline

D. Within the fourth ventricle

[26.2] Through which cerebellar nucleus is the outflow from the lateral cerebellar hemispheres mediated?

A. Dentate

B. Globose

C. Fastigal

D. Emboliform

[26.3] A 35-year-old concert pianist is involved in an auto accident in which he sustains a head injury, resulting in damage to the left side of his cerebellum among other injuries. Following a lengthy hospital stay and recovery period, he discovers that he is no longer able to play the piano with the same ease and grace that he did prior to the accident. Even after extensive practice and retraining, he is still unable to play at the same level as before. Which of the following inputs to the cerebellum is thought to play a key role in motor learning?

A. Excitatory input from mossy fibers

B. Inhibitory input from mossy fibers

C. Excitatory input from climbing fibers

D. Inhibitory input from climbing fibers

Answers

[26.1] B. This girl has right-sided cerebellar symptoms: difficulty with fine movements and past pointing on finger-to-nose. Since the cerebellar hemispheres affect movement in the limbs, and the cerebellum acts ipsilaterally, the defect must be in the right cerebellar hemisphere. A left side lesion would cause left-sided symptoms, and a lesion in the midline would cause truncal and gait ataxia. The rest of this girl’s symptoms are explained by mass effect from the tumor causing increased intracranial pressure (ICP), which causes headaches, vomiting, lethargy, and papilledema.

[26.2] A. The primary outflow from the cerebellum is through the deep nuclei (dentate, emboliform, globose, and fastigial nuclei) depending on where the input is coming from, with (1) the lateral cerebellar hemispheres projecting to the dentate nucleus; (2) the intermediate zone of the cerebellar cortex projecting to the globose and emboliform nuclei, which are also known as the interposed nuclei; and (3) the cerebellar vermis projecting to the fastigial nucleus. From the dentate nucleus, cerebellar outflow projects through the superior cerebellar peduncle to the red nucleus and the ventral anterior and ventrolateral nuclei of the thalamus.

[26.3] C. It is thought that the firing of excitatory climbing fibers represents some sort of error signal to the cerebellum, and is integral in the process of motor learning. The two types of input to the cerebellum are mossy fibers and climbing fibers, both of which are excitatory. Climbing fibers originate in the inferior olivary nucleus, enter the cerebellum via the inferior cerebellar peduncle, and synapse directly onto Purkinje cells with a rather strong excitatory effect. Mossy fibers affect Purkinje cells less directly, and therefore, in a relatively weak manner. Mossy fibers synapse onto granule cells, which send out parallel fibers that interact with Purkinje cells.

NEUROSCIENCE PEARLS ❖ The symptoms of cerebellar lesions manifest on the same side of the body as the lesion. ❖ The Purkinje cells mediate all of the efferent projections from the cerebellum. ❖ Afferent input to the cerebellum is provided by the mossy fibers from spinal cord and brain stem nuclei, and from climbing fibers from the inferior olive.

REFERENCES

Brodal P. The cerebellum. The Central Nervous System: Structure and Function. 3rd ed. New York, NY: Oxford University Press; 2004. 

Ghez C, Thach WT. The cerebellum. In: Kandel ER, Schwartz. JH, Jessell TM. Principles of Neural Science. 4th ed. New York, NY: McGraw-Hill; 2000. 

Ropper AH, Brown RH. Incoordination and other disorders of cerebellar function. Adam’s and Victor’s Principles of Neurology. 8th ed. New York, NY: McGraw- Hill; 2005.

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