The cerebellum is one of three major divisions of the vertebrate brain and covers the dorsal aspect of the brainstem. It is located below and behind the cerebral hemispheres in the posterior cranial fossa. A fibrous membrane, the tentorium cerebelli, delimits the posterior cranial fossa superiorly and separates the cerebellum from the cerebral hemispheres. The caudal limit of the posterior cranial fossa is the basal portion of the occipital bone. The occipital bone, at the level of the foramen magnum, protects the cerebellum interiorly.
Embryology and Neurophysiology
Cerebellar development commences between the 60th and 80th gestational days.1 Neuroblasts proliferate in the periventricular germinal zone of the pontine flexure roof and form the embryonal rudiment of the human cerebellum and its related structures.2 Primitive cerebellar tissue next develops outer marginal, interposed mantle and inner ventricular germinal zones.1 The deep layer of the mantle zone men differentiates into the large neurons of the cerebellar roof plate nuclei; more superficially placed mantle cells differentiate into Purkinje cells. Human Purkinje cell growth sans cell division occurs between the eighth fetal and the 11th postnatal months.1 Rhombic lip germinal zone neuroblasts, at the margin of the cerebellar anläge with the posterior medullary velum, next migrate over the developing cerebellum to form the transient developmental cortical external granular cell layer.
Microscopic evidence of myelination is visible in a cerebellar afferent pathway, the thoracic spinal cord portion of the dorsal spinocerebellar tract, at 20 weeks gestational age.3 Other cerebellar pathways initiate myelination between 24 and 38 weeks. Myelination progresses rapidly, in a period of less than six weeks in some pathways such as the dorsal spinocerebellar tract. Other pathways, such as the superior cerebellar penduncle, myelinate at an intermediate rate of between six and eight weeks; yet others, such as the cerebellar hemispheres, myelinate at a slow rate of longer than eight weeks.
Migration, cytodifferentiation (into mature granule, basket, and stellate cells) and selective cell death of human external granular layer cells is completed between 18 months and 2 years of age.4 Sixty percent of the adult cerebellar weight and a mature histologic organization of external molecular, intermediate Purkinje cell and internal granular layers are achieved by the preschool years.5·6
All of the sensory input of the cerebellar cortex is transmitted by climbing and mossy fibers that enter the cerebellum via its peduncles (Figure 1). The climbing fibers are axons of neurons that originate in the contralateral inferior olivary nucleus of the brainstem and mainly synapse on the dendrites of Purkinje cells in the molecular layer of die mature cerebellar cortex. A single climbing fiber makes multiple synaptic contacts with a single Purkinje cell.7 A few climbing fibers also may terminate on molecular layer intemeurons, ie, stellate and basket cells.
Mossy fibers have more diverse origins and destinations than the climbing fibers. They include second order segmental neuronal axons from somatic motor stretch receptors (proprioceptive), exteroceptors (cutaneous and joint), as well as direct vestibular receptor and second order vestibular nucleus neuronal axons7 (Figure 2). Medulla oblongata precerebellar reticular nuclei, pons nuclei that receive projections from the cerebral cortex, and trigeminal nuclei also send mossy fiber axons to the cerebellar cortex. Some axon collaterals of segmental second order neurons synapse in the deep cerebellar nuclei (fastigial. interposed, and dendate) that in turn contribute to the cerebellar cortex mossy fiber system (Figure 3).
Figure 2. L&M RTS = lateral and medial retículo spinal tracts; RS = rubrospinal tracts; VS = vestibulospinal tracts.
Mossy fibers synapse on granular layer granule and Golgi cell dendrites (Figure 3). Granule cell axons subsequently synapse on some granular layer Golgi cell dendrites, or bifurcate in the molecular layer as parallel fibers that synapse with Purkinje cell dendrites and molecular layer stellate and basket cells.
The synaptic organization of the cerebellum ensures that all cortical interneuron axons (Golgi, stellate, and basket cell) are synaptically related to Purkinje cells (Figure 3). Golgi cells are intimately related to the molecular layer parallel fiber-Purkinje cell dendrite complex. Stellate cell axons also synapse with Purkinje cell molecular layer dendrites. Deep molecular layer basket cell axons synapse with Purkinje cell bodies and their axon hillock area. Purkinje cell axon collaterals additionally synapse with interneuronal dendrites (superficial molecular layer stellate cells, deep molecular layer basket cells, and granular layer Golgi cells).
Climbing fiber and granule cell impulses activate Purkinje cell dendrites; granule cell parallel fiber impulses activate the three varieties of cerebellar cortical inlerneurons (Figure 3). Activated basket and stellate cells inhibit Purkinje cells. Golgi cell interneurons are activated by parallel fiber and mossy fiber stimulation. Activated Golgi cells inhibit granule cells. Activated Purkinje cells inhibit deep cerebellar nuclei and vestibular nucleus neurons (Figure 3) as well as synaptically related Purkinje cells.
AU of the efferent output of the cerebellum occurs via cortical Purkinje cells. Purkinje cells project to the deep cerebellar and vestibular nuclei. The deep cerebellar nuclei project on descending bulbar reticular pathways and the red nucleus; ascending pathways also project to the thalamus and somatosensory cortex of the cerebral hemispheres. Even though these neuronal organization and synaptic relationships provide some insight into cerebellar function, it should nevertheless be emphasized that a complete understanding of the cerebellar neural processing mechanism(s) that impart the quality of synergy - smoothness and spatial efficiency of force - to voluntary motor and locomotor performance has not been achieved.
Cerebellar input includes neural information concerning the initiation and goal of volitional movement as well as target location. The dynamic state of somatic motor contraction as well as the dynamic gravitational and angular accelerational forces that the body experiences during the execution of motor acts is also required for normal movements. Cerebellar integration provides smooth and efficient movement. Voluntary motor acts as well as gait and posture are, in part, a reflection of cerebellar neural processing.
CLINICAL MANIFESTATIONS OF CEREBELLAR DISEASE
Symptoms and signs of cerebellar dysfunction are the direct result of cerebellar parenchymal pathology. Associated clinical findings may occur and are the consequences of secondary changes in related structures such as the cerebrospinal fluid circulation pathway, contiguous blood vessels, and brainstem.
The clinical manifestations of cerebellar dysfunction include disorders of movement, gait and posture, abnormal muscle tone and tendon reflexes, disturbances of speech articulation, and altered ocular motility.
Disorders of Movement, Gait, and Posture
Cerebellar ataxia results from chaotic sequencing of the component muscle contractions that are required to perform a voluntary act skillfully. These dysnergic movements lack a smooth flow and overshoot or undershoot the intended target; ie, are dysmetric. Head wobbling, or an inability to stabilize the upright head, in infants who are older than 3 to 5 months may be due to ataxia; truncal titubation in infants older than 5 to 7 months is a similar ataxic manifestation. Gait ataxia in older infants and children who have learned to walk, is shown by walking with a wide base in a lurching, staggering, and unsteady fashion. Deficient heel to toe walking on a straight line discloses the inability to walk with a narrow base in older children who also often lurch or fall when requested to walk in a clockwise and counterclockwise direction on a circle of several feet diameter. Dysmetric upper extremity movements can be disclosed by block play and raisin eating during midinfancy, as well as by the finger-to-finger and finger-tonose tests in older children
Kinetic (intention) tremor of cerebellar disease is produced by involuntary, dysrhythmic contractions of synergic and antagonistic muscle groups. Cerebellar tremor usually abates at rest and intensifies with action as a target is neared. However, postural muscle contractions, even during presumed rest, may occasionally cause resting tremor in some cerebellar diseases.
Dysdiadochokinesia is the diminished ability to execute rapidly alternating movements. In older children, this sign of cerebellar dysfunction is indicated by slowness, clumsiness, and irregularity in reciprocally executing supination and pronation forearm movements. Dysmetric decomposition of movement imparts a jerky, unsyncopated quality to the performance of this motor act.
Abnormal Muscle Tone and Tendon Reflexes
Hypotonia and diminished tendon reflexes are found in patients with cerebellar disease. These somatic motor signs of cerebellar dysfunction often have an ipsilateral localization, ie, are on the same side as lateralized cerebellar pathology.7 The extremities are excessively flappable and there is diminished resistance to passive movement. Joints controlled by affected muscles are hyperextensible. The diminished tendon jerks may be pendular; the initial response is spontaneously followed by oscillations of diminishing vigor.
A complete explanation for the altered muscle tone and tendon reflexes associated with cerebellar dysfunction is not known. However, it is probable that they are the result of deficient cerebellar regulation of alpha and gamma motor neurons. Alpha motor neurons innervate extrafusai fibers that are the muscle stretch reflex effectors. Gamma motor neurons innervate intrafusal fibers which regulate the sensitivity of stretch reflex receptors. The tonic activity of these spinal cord neurons is responsive to cerebellar cortex and nuclei regulation via vestibulospinal as well as other descending projections (Figure 4).
The ability to enunciate and join speech sounds together is frequently impaired in patients with cerebellar dysfunction. Comprehension, syntax, choice of appropriate words, and meaning are unimpaired. However, words that are appropriately chosen lack a facile and harmonious delivery. Thus, cerebellar dysarthria is characterized by dysprosody. Intonations, melodic qualities, and accentuation imparted to syllable and word sequences are deficient. Scanning, slow, hesitant, explosive, slurred, staccato, and garbled are commonly used to describe some of the qualities of cerebellar dysarthria.
Disturbances of Ocular Motility
Normal eye movement is determined by the presence of adequate refractive mediae, as well as by neural processes that include the visual pathways, the vestibular system, gaze control mechanisms, and the extraocular muscles. Gaze control mechanisms temporally compute neural information concerning the spatial location of visual targets in order to adjust saccadic eye movements for ocular fixation and following.7 The brainstem and cerebellum are components of the neural gaze control system.
Nystagmus is defined as excessive, rhythmical ocular jerks. Some varieties of nystagmus can be elicited physiologically; other varieties are caused by the presence of pathology. Gaze evoked (gaze paretic or gaze direction) nystagmus, rebound nystagmus, ocular dysmetria and some abnormalities of opticokinetic nystagmus (OKN) are frequent concomitants of cerebellar lesions.
Gaze evoked nystagmus may be horizontal, vertical, or vector combinations of both (rotary). Children with gaze evoked nystagmus are unable to maintain one or both eyes away from midposition. A slow return of gaze to the midposition (slow phase) phasically recurs when fixation is directed away from the midposition (fast phase).
Rebound nystagmus is usually seen in chronic cerebellar lesions. It is elicited by directing gaze away from the midposition. Ocular oscillations momentarily occur after a few degrees of eccentric fixation and exhibit a fast component in the direction of gaze change. Refixation to the midposition evokes similar momentary oscillations with their fast component in the opposite direction.
Ocular dysmetria is the inability to smoothly fix a visual target. It is most easily demonstrated by having children fix a midposition visual target from an initial eccentric position. The induced saccades momentarily successively undershoot and overshoot the target.
Abnormalities of opticokinetic nystagmus (OKN). OKN is a physiologic response that is induced by moving a series of visual targets across the visual fields. Its slow component is in the direction of target movement. Chronic cerebellar lesions may increase the amplitude of the slow and fast components of OKN. More acute lesions may be associated with loss of the fast component and asymmetric or inconsistent responses.7 Lesions that are localized in other areas of the nervous system also are associated with OKN abnormalities.
Specific clinical findings of cerebellar dysfunction have been attributed, in the past, to relatively discretely localized areas of cerebellar pathology.8·9 Midline cerebellar pathologies were classically associated with abnormalities of gait, stance and gaze paretic nystagmus; lateralized hypotonia with diminished pendular reflexes, lateralized dysdiadochokinesia and dysmetria, and dysarthria were attributed to homolateral cerebellar hemisphere pathologies. However, this distinction is not absolute and findings that were classically attributed to midline cerebellar disease occur with lateralized pathologies as well as vice versa.7
N ? ? -cerebellar Localization Clinical Findings That May Be Associated with Cerebellar Diseases
The consequences of primary cerebellar pathology may result in secondary changes in contiguous structures. Symptoms and signs related to such secondary changes include headache, vomiting, papilledema, cranial nerve palsies, altered mentation, and vital sign changes.
Headache occurs in most pediatric patients with increased intracranial pressure. Some cerebellar pathologies obstruct cerebrospinal fluid circulation and/or are associated with increased intracranial pressure.
The posterior cranial fossa vasculature and dura mater are innervated by cranial nerves IX and X; similar structures in the other cranial fossae are innervated by cranial nerve V. The headache of increased intracranial pressure is attributed to neural tissue distortion of, and pressure on, pain sensitive dural and vascular structures.
Ine headache of increased intracranial pressure may be generalized or focal. It is prominent on arising from sleep. Lying flat diminishes the headache; coughing, sneezing, defecating, or crying worsens it. Macrocrania may be an associated finding in infants and preschool children who have not achieved fibrous union of the cranial sutures.
Vomiting, especially without associated nausea, is frequently present in pediatric patients with increased intracranial pressure. Posterior fossa tumors may be the primary cause and should be excluded in all children with chronic vomiting who do not have objective evidence of gastrointestinal pathology.
Papilledema, swelling of the optic disc, is the most important ophthalmologic sign of increased intracranial pressure in children who are older than 2 years. White matter sodium and water contents are increased during cerebrospinal fluid pathway obstruction.10 This experimental finding may explain the choked appearance of the optic nerve head and retinal venous engorgement in some cases with papilledema. The developmental absence of myelin in infants with open sutures correlates with the rarity of papilledema in this age group and also is consistent with these experimental findings. Blind spot enlargement occurs when papilledema is present. Preretinal, subhyaloid, hemorrhages are often seen in children who experience acute increases of intracranial pressure.
Ophthalmoscopic changes may also occur in cerebellar diseases of inflammatory and vascular origin. Secondary optic atrophy and visual acuity loss are the sequelae of papilledema.
Altered mentation occurs in pediatric patients who have cerebellar lesions associated with increased intracranial pressure. This may vary from irritability and moodiness to frank lethargy and coma. Memory loss and a decreased academic performance are associated with slowly progressive increased intracranial pressure. Loss of previously learned attainments (dementia) may occur in cerebellar degenerative diseases.
Cranial nerve palsies often accompany cerebellar diseases associated with increased intracranial pressure and/or cerebellopontine angle pathology; such lesions may cause traction on cranial nerves VI and VII. Upward (transtentorial) or downward (tonsillar) cerebellar herniation, associated with increased intracranial pressure, can cause fatal brainstem Duret hemorrhages. Upward herniation is associated with cranial nerve III palsy - paralysis of upward gaze and pupillary paralysis. The manifestations of tonsillar herniation include lower cranial nerve palsies, head tilt, and neck stiffness.
Vital sign changes of increased intracranial pressure include a decreased pulse rate, increased blood pressure systolic usually > diastolic), as well as slow and irregular respiration.11 These findings often accompany the cranial nerve palsies of cerebellar herniations and have grave prognostic significance.
ETIOLOGICAL FACTORS IN PEDIATRIC AGE ONSET CEREBELLAR DISEASES
The cerebellum, in common with other portions of the nervous system, is subject to injury by multiple noxious influences. Genetic factors, unknown congenital influences, trauma, intoxications, infections, neoplasms, endocrine disease, vascular disorders, and metabolic derangements may cause cerebellar disease. The resulting signs of cerebellar dysfunction do not usually indicate a specific inciting cause. However, clinical information such as the family and environmental histories, gender, age at onset of cerebellar dysfunction and its rapidity of progress, as well as the presence or absence of symptoms and signs that reflect dysfunction in non-cerebellar tissues is exceedingly useful in establishing the etiologic diagnosis of cerebellar disease.
Infection with viral, bacterial, fungal, and parasitic agents may be associated with cerebellar dysfunction.
Viral Causes of Cerebellar Disease
Recognition of a self-limiting acute cerebellar syndrome, acute cerebellar ataxia, in children is attributable to Batten in 1905. 12 The disorder may occur without apparent cause or during the course of a known viral disease. Most cases occur in older infants and preschool children.13 A previously normal child develops profound truncal ataxia of sufficient severity to subvert sitting; the child frequently seems to be most comfortable lying in a crib corner. Many patients with acute cerebellar ataxia have nystagmus. Hypotonia, dysarthria and other cerebellar signs also may be present. Complaints of headache, dizziness and photophobia may occur. Macrocran ia, papilledema and other signs of increased intracranial pressure are absent.
Cerebrospinal fluid (CSF) abnormalities are restricted to a mild pleocytosis (<90 WBC/mm3) and occasional slight elevations of protein content. The CSF glucose concentration and manometric pressure are normal. Acute and convalescent serologic findings may indicate the presence of concomitant ECHO, Coxsackie, poliomyelitis or Herpes simplex viral infection; acute neurotropic effects may be causative in these cases. Significant cerebellar cortex neuronal damage occurs in Japanese B, arthropod borne, encephalitis. However, this disease acutely afflicts the nervous system more widely, and in contradistinction to the acute cerebellar syndrome, is associated with marked sequelae in survivors.
Post- or parainfectious, monoepisodic, perivenular demyelination of the nervous system also may cause the acute cerebellar syndrome. A child who has varicella- herpes zoster, rubeola, rubella, mumps, or infectious mononucleosis develops typical symptoms. The benign course of such cases militates against histopathologic studies to prove a white matter autoimmune causation. However, CTT findings are compatible with this hypothesis.14
Fisher syndrome is a rare condition that occasionally occurs in children.15 This disorder is characterized by an acute onset of ophthalmoplegia, ataxia and hyporeflexia; there are no clinical or CTT scan findings of increased intracranial pressure. An antecedent upper respiratory infection may occur prodromally. In spite of the presence of awesome neurologic signs that are usually associated with central nervous system diseases of a grave nature, most cases spontaneously recover without sequelae. Both a GuillainBarré, autoimmune, and a brainstem encephalitis16·17 pathogenesis have been suggested.
Chronic, slow, virus infection can produce cerebellar disease in children.18 Kuru, a slow virus degenerative disease, occurred in the Fore people of New Guinea and has been controlled by their abandoning cannibalistic practices. Late preschool-age children and women who cooked human cadavers for ingestion were afflicted. The usual one year course was marked by progressive ataxia, dysarthria, dysphagia, tremors, involuntary movements, dementia, and death. Childhood onset Gerstman-Sträussler syndrome ataxia, associated with Creutzfeldt- Jacob disease slow virus infection, has not been described to date.19
Bacterial Causes of Cerebellar Disease
The acute cerebellar ataxia syndrome occasionally occurs in association with non-neural, systemic, bacterial infections. Scarlet fever, diphtheria, leptospirosis, typhoid fever,20 and other presumed bacterial enteritides or pneumonias have been implicated.12 Non-neural mycoplasma pneumoniae isolates and serologic changes have been obtained in rare cases of the acute cerebellar ataxia syndrome.21 The pathogenetic mechanism of these effects is unknown.
Postmeningitic cerebellar ataxia. Two to three percent of children who recover from acute pyogenic meningitides have cerebellar residua.22·23 The occurrence of prolonged fever, prolonged hyponatremia, and septic arthritis (during the acute phase of the meningeal infection) increases the likelihood that this unusual complication will occur. Sensorineural deafness is a frequent concomitant. Though postmeningitic ataxia slowly improves, some deficit may persist for at least one to two years.
Cerebellar abscess usually occurs in children with chronic middle ear infections.24 Bacterial contamination via the contiguous petrosal venous sinuses is the usual route of dissemination. Bacteremia in children with cyanotic congenital heart disease is causative in a minority of cases. The clinical findings of cerebellar abscess are due to the presence of increased intracranial pressure (vomiting, alterations of consciousness, and papilledema), meningeal irritation associated with increased intracranial pressure and/or focal inflammation, as well as cerebellar dysfunction (nystagmus and ataxia). CTT efficiently confirms this clinical diagnosis. Histopathologic evidence indicates that gram-negative organisms are more frequently present in cerebellar than in cerebral abscesses. Combined surgical and appropriate antibiotic therapy may be curative.
Nervous system tuberculosis/tuberculomas are relatively rare in the US at the present time,25 but are not uncommon in developing countries.26 The cerebellum is a comparatively frequent site of occurrence of nervous system tuberculosis/tuberculomas in a pediatric population.27 Multiple site involvement is not unusual. Hematogenous dissemination of miliary tuberculosis as well as contiguous spread of tuberculous otitis media and mastoiditis are invoked as the causes of cerebellar tuberculomas.
The clinical features of cerebellar tuberculosis/tuberculoma include signs and symptoms of increased intracranial pressure in association with the findings of cerebellar dysfunction. Many tuberculomas are unexpectedly discovered during operation for a "brain tumor" or at autopsy.28 CTT scans of tuberculomas initially note ring lesions with diminished central attenuation and external edema; as fibrous encapsulation ensues they become isodense and have no surrounding edema.29 Very mature tuberculomas calcify and exhibit increased attenuation. The CTT scan differential diagnosis of cerebellar tuberculomas includes cystic astrocytoma, pyogenic abscess, and hydatid cysts. A diagnosis of cerebellar tuberculoma should be considered in any child with a history of tuberculous exposure, a positive dermal tuberculin test and evidence of non-nervous system tuberculosis.
The treatment of cerebellar tuberculomas is controversial. Cure is recorded with a combination of medical treatment (isoniazid, ethambutol, streptomycin, rifampicin, and steroids) and surgery,30 as well as medical treatment only.31
A congenitally acquired Treponema pallidum infection is rarely associated with juvenile paresis.25 The clinical picture includes late preschool -age or adolescent onset memory loss, personality change, and failure of academic progress. Previously learned attainments are lost. Personality disturbances include mild euphoria, apathy, and slight grandiosity. Stigmata of congenital syphilis, cerebellar dysarthria, ataxia, brisk tendon reflexes, and absent pupillary light reflexes are found on physical examination, and optic atrophy may be present. Cerebrospinal fluid findings include a slight mononuclear pleocytosis, increased globulin content, and positive Wasserman reaction.
The course is stated to be relentless. Dementia is followed by a vegetative state, cachexia, and death. Antiluetic treatment is stated to be ineffectual.
Cerebellar Parasitic Infestation with Echinococcus granulosa - Unilocular Hydatid Cyst
This infestation occasionally occurs in some South American countries.32 Echinococcus multilocularis is causative in other areas, such as Russia, the Balkans, and North Africa, and produces multiloculated cysts. Dogs and related species are the definitive hosts. Sheep and other grazing animals serve as intermediate hosts. Humans are accidentally infected; the cysts' scolex is a larval form.
Nervous system Echinococcosis occurs more frequently in children than adults. The clinical features include the signs and symptoms of increased intracranial pressure as well as findings of cerebellar dysfunction.33 However, most cysts occur supratentorially and cerebellar signs may falsely localize their position. Study via CTT is stated to localize hydatid cysts; findings include hypodense ring lesions with ventricular displacement.34 Some cysts may calcify. Immunologic tests of Echinococcus exposure are frequently negative because nervous system cysts often occur without involvement of other organs. Surgical removal without disruption of the cyst wall may be curative.32 Combined medical (mebendazole) and surgical treatment of nervous system Echinococcosis has been described.35
NEOPLASTIC CAUSES OF CEREBELLAR DISEASE
Cerebellar tumors are relatively common. Their approximate mean annual incidence rate is 1 .06/100,000 children in the US,36 and they account for 45% of pediatric brain tumors. Early detection and specific diagnosis of cerebellar tumors is imperative because some can be cured; early treatment of others significantly improves the length and quality of an afflicted child's survival.
Tumors of the cerebellum are caused either by the neoplastic transformation of cerebellar constituents, or by invasion from contiguous structures. Medulloblastomas that are hypothesized to arise from cerebellar fetal external granular layer cells, and astrocytomas, of neuroglial cell origin, are the most frequent intraparenchymal cerebellar tumors. Medulloblastomas and astrocytomas each constitute approximately 20% of pediatric brain tumors. Intraparenchymal hemangioblastomas, angiomas, benign cysts, and dermoids also infrequently occur in the cerebelli of pediatric patients.
Infratentorial ependymomas constitute about 7% of childhood brain tumors and may spread to the cerebellum. The somewhat more common brainstem (pons, medulla oblongata and midbrain) astrocytomas also may infiltrate the cerebellum via the cerebellar peduncles or by exophytic extension to the cerebellopontine angle. Bilateral eighth cranial nerve schwannomas, in the cerebellopontine angle, may compress the cerebellum and are a rare cause of cerebellar dysfunction in children with neurofibromatosis. Cerebellar metastases usually do not occur in pediatric patients.
One half of a pediatric population with cerebellar tumors experience their onset of increased intracranial pressure and cerebellar dysfunction during the first decade of life. However, onset during early infancy is distinctly unusual. Tumors that are located in the vermis are usually clinically apparent at an earlier age than those located in the cerebellar hemispheres. Thus, the duration of symptoms prior to diagnosis is longer for cerebellar astrocytomas that may arise in any area of the cerebellum, than for medulloblastomas, that usually arise in the vermis. The early symptoms of some preschool children who initially respond to increased intracranial pressure by separating their sutures, may transiently abate and can be fallaciously attributed to gastrointestinal illness.37-38
CTT brain scan is the current diagnostic test of choice for children who may harbor a cerebellar tumor. Location and size of the ventricular cavities, shape and location of the cerebellum, gross enlargement of the subarachnoid spaces, as well as tumor location and neuroradiology characteristics are exquisitely demonstrated by CTT scans.39 In the future, nuclear magnetic tomography may displace CTT because of its superior resolution and absence of ionizing radiation exposure.40 !Preoperative arteriography is an adjunct of CTT and may assist the neurosurgeon in formulating operative plans. Lumbar puncture is contraindicated in children who are cerebellar tumor suspects.
Medulloblastomas occur more frequently in boys than in girls. Symptoms of progressive increased intracranial pressure (morning headache, vomiting, inordinate cap size, diplopia and a decreasing level of consciousness) in addition to gait clumsiness and mild nystagmus have usually been present for only one to two months at the time of diagnosis. Lateralized appendicular cerebellar dysfunction may occur in some cases. Neurologic examination notes the presence of papilledema and other signs of increased intracranial pressure in association with findings of cerebellar dysfunction. CTT scanning usually demonstrates the presence of a uniformly contrast enhanced, midline, solid mass of increased density in the fourth ventricle. The mass is associated with obstructive hydrocephalus. Definitive diagnosis is based on the histologic characteristics of the soft, fleshy tissue that is removed at the time of bulk tumor excision.
Classical medulloblastomas are extremely cellular and are composed of small cells with scant cytoplasm and hyperchromatic nuclei. Rosettes, formed by circular arrays of carrot-shaped cells with tapered cytoplasm and peripheral nuclei, as well as pseudorosettes, formed by tumor cells arranged around supporting vasculature, are present in many microscopic fields. Histologic differentiation from cerebellar sarcomas may be difficult.
Medulloblastomas recur locally and seed to other portions of the neuraxis after surgical removal. This characteristic was associated with a 1.6% three-year survival rate in Cushing's 1930 series. Subsequent inclusion of postoperative radiotherapy to the entire neuraxis, and more recently, combination chemotherapy to the medulloblastoma treatment regimen have increased the five-year survival rate to approximately 50%. 4O The use of cerebrospinal fluid polyamine (putrescine, spermidine, and spermine) concentrations to detect medulloblastoma recurrences before clinical, CTT scan, and myelography changes occur may support the monitored presymptomatic use of chemotherapy.
Cerebellar astrocytomas occur with equal frequency in boys and in girls. The duration of symptoms (increased intracranial pressure and cerebellar dysfunction) before diagnosis may vary from one to two months up to one to two years. The average duration is longer than that for medulloblastomas. Papilledema, upper extremity ataxia, gait ataxia, and gaze paretic nystagmus are the most common physical signs.40 Plain skull x-rays may reveal thinning of the occipital bone as well as stigmata of increased pressure and intracranial calcification. CTT scanning demonstrates the presence of a cerebellar solid tumor, or a mural nodule of slightly decreased density in a cyst. Cystic tumors are exquisitely delineated by CTT scanning. The cysts may or may not enhance upon administration of contrast media. Mural nodules and solid cerebellar astrocytomas enhance uniformly. CTT scanning easily demonstrates associated tumor induced obstructive hydrocephalus.
The majority of cerebellar astrocytomas are cystic and contain a mural nodule. Excised tumors are well demarcated from the cerebellar parenchyma and do not invade surrounding tissue. The cyst cavity contains a coagulable, high protein content fluid. Solid tumors have small cystic foci. Cyst walls may be poorly cellular and contain non-neoplastic elements, or may be fringed by tumor cells. The most frequently observed microscopic changes include alternating areas with either a compact or a spongy appearance. Compact areas are composed of slender, pilocytic cells that contain neuroglial fibrils and Rosenthal fibers.40 Spongy areas contain cells of a somewhat stellate shape that are oriented around numerous blood vessels. The vasculature is distributed in a menstruum of microcystic degeneration and sparse protoplasmic cells. Diffuse piloidal tumors and tumors with "juvenile" pilocytic characteristics occur rarely. Microscopic calcification is seen in about 20% of cases. Some investigators state that tumor histology correlates with prognosis.40
Complete resection of cystic cerebellar astrocytoma cysts and their enclosed mural nodule is curative. Cyst removal without the mural nodule is associated with local recurrence. Radiotherapy is felt to prolong the relapse-free survival period in cases treated by partial resection.
Cerebellar hemangioblastoma, retinal and spinal cord angiomas, congenital cysts of the pancreas and kidney, retinal, epididymal, and adrenal neoplasms occur together in patients with von Hippel-Lindau disease.41 Von HippelLindau disease is inherited as an autosomal dominant condition and exhibits variable penetrance. A significant number of patients with cerebellar hemangioblastoma have polycythemia rubra vera secondary to an excessive erythropoietin secretion. Most cerebellar hemangioblastomas become symptomatic after the first decade of life; presymptomatic CTT diagnosis can be achieved in atrisk kindred. Patients with cerebellar hemangioblastoma may present either with progressive symptoms of increased intracranial pressure and cerebellar dysfunction, or with catastrophic symptoms of cerebellar hemorrhage. Complete surgical excision is curative.
Extra Cerebellar Tumors
lnfratentorial ependymomas constitute approximately 7% of childhood brain tumors. Symptoms of increasing raised intracranial pressure and unsteady gait are usually present for several weeks to one to two years. Grossly invasive tumors usually progress more rapidly than histologically benign lesions. Papilledema, neck stiffness, nystagmus, and unsteady gait are the most common neurologic findings.40 Plain skull x-rays show the stigmata of increased intracranial pressure, and a few cases also have posterior fossa intracranial calcification. CTT scans delineate a midline, fourth ventricle mass of increased density in association with obstructive hydrocephalus. Cyst formation, contrast enhancement, and diffuse calcification may be present.39
Histologic examination of excised, partially encapsulated, cystic tumor fragments from the fourth ventricle establishes the diagnosis of an infratentorial ependymoma. The microscopic findings of rosette formation (tumor cells dispersed around a small central lumen) by cuboidal or polygonal cells is diagnostic. The degree of anaplasia varies between patients.
Approximately one-fifth of posterior fossa ependymomas in pediatric patients seed to the spinal cord. This complication occurs most frequently with histologically malignant ependymomas that occur in very young patients; thus, surgery may not be curative. The five-year survival in children with infratentorial ependymomas is approximately 30%. Local or craniospinal radiotherapy is an adjunct to surgery in some cases. Combination chemotherapy has not yet been demonstrated to markedly alter the poor prognosis of some cases.
Brainstem gliomas are the third most frequent pediatric brain tumor.40 The pathology is variable. Some patients' tumors consist of infiltrating cells that may be bipolar or fibrillary in character; others contain more malignant glioblastoma forms.42
Brainstem gliomas occur with slightly greater frequency in boys than in girls. The classical clinical findings include a combination of pyramidal signs, vomiting without evidence of increased intracranial pressure, cranial nerve palsies, and ataxia. However, ventricular dilatation and papilledema may occur relatively early in cases that are histologically aggressive. A remitting and exacerbating course is seen in some cases.
CTT scan tumor findings vary. Isodense, low density, high density, and mixed changes may occur. Calcification and cystic changes may be present. Enhancement with contrast administration is present in more than one-half of cases. Definitive diagnosis, as with earlier air studies, depends on finding a specific pattern of distortion of the cerebrospinal fluid pathways (elevation of the posterior portion of the third ventricle, encroachment on the prepontine cystern, as well as dorsal displacement of the aqueduct of Sylvius and upper portion of the fourth ventricle). Coronal CTT reconstructions are helpful in documenting these findings. In some cases ventricular dilatation may be present at the time of diagnosis. Delays of brainstem auditory evoked responses (later wave forms) physiologically confirm the presence of intrinsic brain pathology.
Results of radiation, surgery, and combined chemotherapy treatments of brainstem gliomas are discouraging. The fiveyear survival rate is approximately 30%. Tumor location and histopathology probably determine the long-term prognosis. Future treatment research possibilities include immunotherapy, recombinant DNA induced tumor transformation, and cell-targeted chemotherapy carrier systems.
Neurofibromatosis is an autosomal dominant disease with variable penetrance. Bilateral schwannomas of the eighth cranial nerve are one of the multiple manifestations of neurofibromatosis43 and a rare cause of cerebellar dysfunction in children. Compression of structures within and contiguous to the cerebellopontine angle produces tinnitus, vertigo, retrocochlear deafness, facial weakness, and facial pain. Early clumsiness is the result of vestibular dysfunction. Late clinical findings include ataxia and the stigmata of increased intracranial pressure. Early surgery is curative and a possible diagnosis of this complication should be considered in appropriate children who have von Recklinghausen disease (neurofibromatosis).
Cerebellar malformations are the probable sequelae of unknown teratogenic exposures during me long period of human cerebellar development as well as a phenotypic expression of genetic influences.
Agenesis of the Cerebellum
Complete agenesis of the cerebellum without other central nervous malformations is rare.44 Cerebellar aplasia in association with other nervous system malformations is not uncommon, but there is no stereotyped clinical picture. Knowledge of the existence of an aplasia may be gained in the course of study for complaints that have a noncerebellar localization. If cognition is sufficient in symptomatic cases, compensatory mechanisms are utilized in the delayed acquisition of locomotor and fine-motor adaptive skills.
Partial or complete cerebellar vermis agenesis occasionally occurs in otherwise normal children. In some cases, these anomalies may be asymptomatic and are incidentally detected at autopsy. In other cases, motor development is delayed and there is a history of hypotonia during early infancy. If findings of cerebellar dysfunction are present in early life, they lessen as the involved child matures. Joubert et al describe a familial disorder characterized by cerebellar vermis aplasia associated with other midline central nervous system malformations.45 The clinical features of Joubert syndrome include pendular or rotary eye movements, ataxia, hypotonia, mental retardation, and episodic hyperpnea that alternates with brief periods of apnea. The physiologic cause of the respiratory abnormality is not known and improves with maturation. Partial aplasia of the cerebellar vermis occurs in trisomies 5 and 13. Dysplastic tissue is found in the vermis in trisomy 18.
Familial46 and sporadic cases of generalized cerebellar hypoplasia occur. Generalized cerebellar hypoplasia also may accompany progressive neurologic diseases such as GM2 gangliosidosis, infantile spinal muscular atrophy, and Menkes steely hair syndrome.47 Cerebellar size, in proportion to brain weight, is reduced in trisomy 21.
Cerebellar hemiagenesis occasionally occurs in association with nuclei pont is, inferior olive, and contralateral red nucleus hypoplasia.48 There are no associated clinical manifestations.
The Dandy-Walker Malformation
The Dandy-Walker malformation consists of cystic dilatation of the fourth ventricle, imperforate fourth ventricle foramina, hydrocephalus, enlargement of the posterior fossa, as well as rostral displacement of the posterior fossa venous sinuses and tentorium. Other nervous system and systemic anomalies frequently occur in association with the DandyWalker malformation.49 Macromania associated with hydrocephalus or developmental retardation are the usual presenting symptoms in infants. The cyst often transilluminates. Pyramidal signs, cranial nerve palsies, and abnormalities of respiration may be present. The symptoms of increased intracranial pressure and locomotor ataxia dominate the clinical picture in children who become symptomatic at later ages. CTT scanning is diagnostic.39 Ventriculo-peritoneal shunting is the probable therapy of choice.
Types 1, 2 and 3 Arnold-Chiari Malformations
Types 1, 2 and 3 Arnold-Chiari malformations consist of a congenitally determined, anomalous location of the cerebellum and medulla oblongata. They are frequently associated with defects of neural tube closure, an event that normally occurs during the third gestational week. The clinical picture of the type 2 malformation is characterized by the almost inevitable presence of a meningomyelocele in association with congenital hydrocephalus. CTT scanning, below the level of the foramen magnum, demonstrates caudal displacement of the cerebellum and brainstem. The displacement is less marked in type 1 malformations. Midline closure deficits are infrequent in type 1 malformations; symptoms of increased intracranial pressure, ataxia, and lower cranial nerve palsies may not occur until the onset of school attendance or adulthood. Type 3 malformations consist of cerebellar placement in a cervical dysraphic defect. The surgical treatment of Arnold-Chiari malformations is delineated in neurosurgical treatises.50
Platybasia, or congenital basilar impression, occurs en isole or in conjunction with Arnold-Chiari malformations. This mesenchymal anomaly is caused by a failure of occipital bone and upper cervical vertebrae segmentation during the second to third fetal months. Basilar impression without other anomalies is usually asymptomatic throughout the first decade of life. The clinical features include complaints of neck stiffness, head tilt, and difficulty in walking. Physical signs may include a low hairline, short neck, aberrant head posture and restricted neck motion, nystagmus, ataxia, lower cranial nerve palsies, upper extremity sensory impairment, and lower extremity pyramidal signs. True lateral skull x-rays confirm the diagnosis by demonstrating that the odontoid process is located above a line drawn from the hard palate to the posterior margin of the foramen magnum.51 Surgical decompression is the treatment of choice.
METABOLIC AND DEGENERATIVE DISEASES ASSOCIATED WITH CEREBELLAR DYSFUNCTION
Metabolic and degenerative diseases associated with cerebellar dysfunction may either be genetically deteimined or acquired. The metabolic and degenerative causes of cerebellar dysfunction can be classified either by the chemical characteristics of involved metabolites and/or by their clinical features (inheritance pattern, tendon reflex findings, age of onset, and site of pathology). Table 1 enumerates some of the inherited cerebellar diseases that afflict children; their clinical features and, when known, cursory biochemical characteristics are listed. Diseases involving the cerebellum as part of a diffuse nervous system pathology that do not have cerebellar dysfunction as a prominent clinical feature are not included.
Friedreich's ataxia (Table 1), though rare, probably has the highest incidence rate (1 to 2/100,000) of all the hereditary ataxias.85 The earliest symptom is gait disability of insidious onset and slow progression. Dysarthria develops early in the disease and speech soon becomes unintelligible. Physical signs include pes cavus and kyphoscoliosis. The lower extremity tendon reflexes are lost early in the disease and the loss soon advances to the upper extremities. All of the signs of cerebellar dysfunction can be elicited. Vibration, position and other senses mediated by the dorsal columns are lost. Superficial sensibility is preserved. The plantar response is extensor. Cognition is usually normal. Bowel and bladder control may be lost late in the disease.
The neuropathology findings in Friedreich's ataxia are most marked in the lumbosacral region and diminish in intensity rostrally. The principal degenerative changes are found in the dorsal roots, dorsal columns, dorsal and ventral spinocerebellar tracts, pyramidal tracts, and Clarke's columns of the spinal cord.
Non-neurologic difficulties associated with Friedreich's ataxia include a progressive cardiomyopathy. Diabetes mellitus and glucose tolerance test provoked abnormalities of blood pyruvic acid oxidation are present in some patients.79 These latter findings and the demonstration of mitochondrial cytochrome b deficiency in a father-son pair, who evidenced a myopathy as well as some Friedreich's disease features86 suggest that the Friedreich's disease phenotype may result from oxidative metabolism deficiencies.
Cerebellar dysfunction also is reported in one variety of 5N-methyl-tetrahydrofolate-homocysteine methyl transferase deficiency homocystinuria,56 and pyroglutamic aciduria.87 These exceedingly rare disorders are not listed in Table 1.
Wernicke encephalopathy is an acquired metabolic cause of cerebellar dysfunction in sick children who receive a thiamine deficient diet.88 A detailed dietary history in concert with organic mental symptoms, ophthalmoplegia and ataxia suffice to establish a clinical diagnosis. The presence of depressed erythrocyte transketolase activity is confirmatory. Spastic-ataxic paraparesis and peripheral neuropathy occasionally occur in children with pellagra.88 Exposed skin surface lesions, glossal mucosal atrophy, diarrhea, and a diet restricted to maize or sorghum should always alert the pediatrician to the possibility of niacin deficiency. Laboratory documentation of a reduced urinary excretion of N-methyl-2-pyridone-5-carboxylamide confirms the diagnosis of pellagra as an acquired metabolic cause of ataxia. Cerebellar dysfunction, in association with peripheral neuropathy and disorders of eye movement, occurs in children with chronic biliary tract disease89 and with cystic fibrosis. Low serum concentrations of serum retinoids (vitamin A) and tocopherols (vitamin E) correlate with the occurrence of these neurologic complications. Vitamin E deficiency is felt to be causative; the neurologic manifestations of abetalipoproteinemia may have a similar pathogenesis.
STRUCTURAL VASCULAR ETIOLOGIES OF CEREBELLAR DYSFUNCTION
Structural vascular etiologies of cerebellar dysfunction are infrequent in pediatric patients. However, prompt diagnosis and appropriate therapy of some of these disorders may be lifesaving.
Symptomatic posterior fossa aneurysms and vascular malformations are quite rare before the third decade of life. The intracranial aneurysms that are diagnosed in pediatric patients often occur in children with aortic coarctation. Both disorders may have a subarachnoid hemorrhage, posterior fossa tumor, or catastrophic cerebellar hemorrhage presentation. An associated bruit is not usually detected. Diagnosis is made by CTT scanning and posterior fossa angiography.
Cerebellar infarction is an infrequent complication of pediatric age group head and neck injuries. Traumatic delivery may cause vertebral artery injury.90 Traumatic intimai tears at later ages91,92 also cause cerebellar infarctions that may exhibit either an immediate or delayed onset of clinical findings. Recovery as well as fatal outcome occur.
Venous infarction induced cerebellar hemorrhage occurs relatively frequently in premature newborns who do not survive the neonatal period.93 Obstruction of posterior fossa venous return with face masks that distort a moldable cranium, etc. may cause this complication of prematurity. Antemortem diagnosis can be made via noninvasive realtime ultrasonography.94,95
Cerebellar hemorrhage was considered a fatal disorder prior to the advent of CTT scanning. The current availability of this diagnostic modality has made neurosurgical intervention feasible. The frequency of occurrence of cerebellar hemorrhage in children who survive without surgical intervention, ie, those without a rapid progression of brainstem decompensation, is not known at present.
Juvenile basilar artery migraine is the term used to describe a syndrome that is characterized by episodic attacks of ataxia, vertigo and alternating hemiplegia in children.96 A positive family history and the transient nature of cerebellar dysfunction signs assist in making this diagnosis. Vasodilatation symptoms of headache are infrequent in this age group. CTT scan studies are normal. Transient electroencephalographic alterations occur.97
EXPOSURE TO INTOXICANTS
Exposure to some intoxicants causes cerebellar dysfunction. Heavy metals, anticonvulsant drugs, alcohol, and tick neurotoxin are the most frequently observed in pediatric practice.
Cerebellar pathology is a prominent portion of the neuropathology of childhood lead encephalopathy. The acute generalized pericapillary edema and endothelial proliferative changes associated with lead encephalopathy are most intense in the cerebellum and cerebrum. Chronic cerebellar changes occur in survivors of childhood lead encephalopathy; they include Purkinje cell and internal granular layer neuronal loss. However, ataxia is not a prominent clinical feature, in the reviewers' experience, of either chronic childhood lead poisoning or acute encephalopathy.
INHERITED METABOLIC AND DEGENERATIVE ATAXIAS
INHERITED METABOLIC AND DEGENERATIVE ATAXIAS
INHERITED METABOLIC AND DEGENERATIVE ATAXIAS
INHERITED METABOLIC AND DEGENERATIVE ATAXIAS\
INHERITED METABOLIC AND DEGENERATIVE ATAXIAS
INHERITED METABOLIC AND DEGENERATIVE ATAXIAS
Ataxia is a prominent clinical feature of organic mercurial intoxication.98 Other findings include peripheral neuropathy, involuntary movements, visual field changes, alterations of the sensorium, and convulsions. Dimercaprol and penillamine are effective treatments.
Ethyl alcohol is probably the first toxic agent that many young persons ingest. Knowledge of its ability to induce dysequilibration no doubt antedates written human history. The degree of nervous system impairment correlates with blood ethanol concentration.
The introduction of relatively accurate anticonvulsant drug blood concentration tests to clinical practice has probably markedly reduced the frequency of anticonvulsant druginduced ataxia in epileptic children. However, potential availability of these medications as intoxicants, in households with a patient who takes anticonvulsant drugs, should always be kept in mind when evaluating ambulatory infants and preschool-age children with acute onset ataxia.
Ticks of the genus Dermacentor may produce a neurotoxin that usually causes a clinical picture of ascending paralysis in children. However, ataxia and nystagmus may occur as initial findings before the onset of motor weakness is present.99 Removal of the tick is curative.
This review of the cerebellum and some of its diseases in pediatric patients was designed to assist the clinician who serves children. The listed references should hopefully permit entrance to a voluminous literature.
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INHERITED METABOLIC AND DEGENERATIVE ATAXIAS
INHERITED METABOLIC AND DEGENERATIVE ATAXIAS
INHERITED METABOLIC AND DEGENERATIVE ATAXIAS
INHERITED METABOLIC AND DEGENERATIVE ATAXIAS\
INHERITED METABOLIC AND DEGENERATIVE ATAXIAS
INHERITED METABOLIC AND DEGENERATIVE ATAXIAS