- Email: [email protected]
Progressive degenerative disorder of the central nervous system
Progressive Degenerative Disorder of the Central Nervous System Enrique Chaves-Carballo The child with a deteriorating course is a regular if not common clinical problem for the child neurologist. An apparent plateau in the course can often be confusing if the focus is limited to the current visit. With the explosion of information and understanding of molecular genetics, failure to recognize the presence of a degenerative disease may have significant consequences for the family of the patient and possibly the patient as well. Copyright 9 1996 by W.B. Saunders Company
A
6-YEAR-OLD boy was referred for evaluation of cerebral palsy. He was product of an uncomplicated, fullterm pregnancy, labor, and delivery. Birth weight was 9 lb 11 oz. Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. Pendular nystagmus was noted shortly after birth and an ophthalmologic examination showed bilateral optic atrophy. A diagnosis of cerebral palsy was made at 7 months and multiple tests (including head computed tomography) failed to provide any explanation for this. Psychomotor development was slow and at 6 years of age he was unable to sit or walk without support. He could read and communicate to a certain extent with computer-assisted speech. His general health had been good except for chronic otitis that required ear tubes, esophageal candidiasis, and reflux. A younger brother also had been diagnosed as having cerebral palsy with similar features. On examination he measured 103.7 cm, weighed 14.8 kg and head circumference was 49.5 cm; these measurements were at below the 3rd percentile for height and weight and at the 25th percentile for head. Eye examination showed slow, pendular nystagmus and small, pale optic discs. Axial muscle groups and upper extremities were hypotonic whereas lower extremities showed increased tone and spontaneous upgoing plantar responses. Voluntary movements were described as athetoid. He was unable to walk without assistance.
From the Section of Neurology, Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO. Address reprint requests to Enrique Chaves-Carballo, MD, Section of Neurology, Department of Pediatrics, Children's Mercy Hospital, 2401 Gillham Rd, Kansas City, 114064108. Copyright 9 1996 by W.B. Saunders Company 1071-9091/96/0303-001255.00/0 212
NEUROPHYSIOLOGICAL AND NEUROIMAGING DATA
Brainstem auditory-evoked responses showed wave I at normal latencies bilaterally but with poor wave morphology so that later components could not be identified. A magnetic resonance imaging (MRI) study showed severe, diffuse abnormalities of the white matter. On Tl-weighed images myelin was markedly decreased with only a faint signal noted in the thalami- and thalamo-occipital tracts (Fig 1), while on T2-weighed images high-intensity signal changes were most severe in the centrum semiovale (Figs 2 and 3). The cortex appeared intact with normal gyral and sulcal markings. DIFFERENTIAL DIAGNOSIS
The presence of severe motor involvement with disproportionate preservation of cognitive function is unusual and may result from predominantly white matter injury or degeneration. This differs from the more common situation where both gray and white matter are comparably affected as occurs in hypoxicischemic or neonatal encephalopathy because of birth injury (cerebral palsy). The absence of perinatal risk factors in this case is also against this possibility. A more likely explanation for the clinical presentation of mainly motor dysfunction is a leukodystrophy.1 Loss of white matter may be caused by breakdown of already formed myelin (demyelination) or by failure to develop myelin (dysmyelination). The presence of myelin degradation products favors the process of demyelination but this can only be confirmed pathologically. The early onset of symptoms and lack of myelin evident in neuroimaging studies suggest that there was a failure of myelin development or dysmyelination in this case. Even more unusual is the association of
Seminars in Pediatric Neurology, Vol 3, No 3 (September), 1996: pp 212-215
PROGRESSIVE CEREBRAL PALSY
Fig 1. Tl-weighted MRI axial image of brain in 6-year-old boy with delayed motor development and nystagmus shows almost complete absence of myelin except for minimal signal in thalami and thalamo-occipital fibers. There is also mild ventricular enlargement.
motor and visual impairment, the latter manifested by early pendular nystagmus as seen in macular degeneration, albinism or optic atrophy. Cerebromacular degeneration (as these disorders were called in the past) is evident in Tay-Sachs disease and Batten disease or neuronal ceroid-lipofuscinosis. However, eye examination in this case failed to show a cherry-red spot, macular degeneration or retinitis pigmentosa. Instead, funduscopic examination revealed small, pale optic discs consistent with optic atrophy. Congenital malformations associated with optic atrophy include septo-optic dysplasia, which can be excluded easily with computed tomography or MRI. Another important feature in this case is the mode of inheritance. This could be either because of autosomal recessive or sex-linked recessive transmission. The majority of leucodystrophies are inherited as autosomal recessive; however, sex-linked inheritance is present in Fabry disease (ceramide trihexosidosis) and in Pelizaeus-Merzbacher disease (PMD). Finally, neuroimaging studies, particularly MRI, may be helpful in sorting out the various possibilities. A paucity of myelin on Tl-weighted
213
Fig 2. T2-weighted MRI axial image in same case shows diffuse, bilateral markedly high-intensity signal (because of the absence) of white matter consistent with abnormal myelin in the centrum semiovale. Note that the cortical ribbon signal remains intact.
images and a corresponding high-intensity signal on T2-weighted images have been described in PMD. 2,3 The combination of developmental delay,
Fig 3. T2-weighted MRI image shows similar changes in coronal view.
214
ENRIQUE CHAVES-CARBALLO
optic atrophy, and a failure of myelin formation in two male siblings is consistent with P M D . DISCUSSION
P M D is an X-linked recessive, progressive degenerative disorder of the central nervous system with distinctive clinical, genetic, neuroimaging, and molecular diagnostic features. 4 Onset is usually in the neonatal or infantile period with a b n o r m a l eye m o v e m e n t s described as p e n d u l a r or jerk-type nystagmus. Associated h e a d m o v e m e n t s suggest a clinical diagnosis of spasmus nutans. However, ophthalmoscopic examination reveals small, pale optic discs compatible with optic atrophy. By the third m o n t h of age p s y c h o m o t o r development comes to a standstill or regresses and choreoathetosis may appear. T h e m o t o r progress is affected so that sitting or ambulation without support may never be achieved. Spasticity and ataxia develop and seizures m a y a p p e a r later. O n the other hand, cognitive function may be spared for some time and mental deterioration may not b e c o m e apparent until the terminal stages. H e a d circumference is r e d u c e d in some cases. D e a t h ensues within a decade, although survival has b e e n r e p o r t e d to the third decade. Until the advent of neuroimaging studies, a clinical suspicion of P M D could be confirmed only by brain biopsy or autopsy. Neuropathological studies of the brain showed d e g e n e r a t i o n of myelin in a patchy ("tigroid") distribution with minimal (if any) degradation products. Thus, small patches of preserved myelin are f o u n d a m o n g areas of demyelination in P M D . N e u rons and axons are usually spared. T h e most affected region is the c e n t r u m semiovale but lesions m a y be f o u n d also in the brainstem, internal capsule, and cerebellum. N e u r o p h y s i o l o g i c a l studies, p a r t i c u l a r l y evoked responses, usually are markedly abnormal. M R I studies have b e c o m e increasingly helpful in sorting out the various leucodystrophies. A l t h o u g h the M R I findings in P M D are not diagnostic, these are sufficiently distinctive that, in Conjunction with typical clinical findings, a diagnosis can be m a d e confidently. Molecular studies have redefined P M D as an inborn error of myelin f o r m a t i o n , localized in
the gene responsible for proteolipid protein ( P L P ) p r o d u c t i o n in the X - c h r o m o s o m e . 5 P L P is the main c o m p o n e n t of myelin protein and comprises half of the protein of the myelin sheath. In about one third of patients with P M D studied, a m u t a t i o n in the gene encoding for P L P m a y be demonstrable using the polymerase chain reaction. T h e majority of the mutations described to date have b e e n " u n i q u e " to each family studied, indicating that looking for " o l d " mutations may not be fruitful in new cases. However, once a m u t a t i o n is shown, this can be used to diagnose both affected and carrier m e m b e r s of the family and even for prenatal diagnosis. O n the other hand, in two thirds of cases no evidence of a m u t a t i o n for the P L P gene can be f o u n d by present techniques (M.E. Hodes, personal communication, 1995). COMMENT
Recent advances have shown that PMD is a genetically determined disorder of proteolipid protein production which disrupts normal central nervous system myelin formation. The best known and most common is the early infantile form, which is sex-linked recessive and has a chronic, almost stable clinical course for a decade or more. The condition has now been subdivided into a variety of types, some of which can be inherited differently so that females may also be affected. The classic infantile type of PMD is suspected by the presence in the early months of life of nystagmus and peculiar head movements along with stagnation of normal motor development. This has led to the analogy with the curious state referred to as spasmus nutans, which in some cases remains just that, a curious state, whereas in others, neuroimages show the ocular and head motions to be symptomatic of an optic chiasmhypothalamic glioma. The illness described above by Dr. Chaves-Carballo is one of many disorders in which neurological abnormalities are identified early in life and followed by a seemingly stable course, bringing forth a diagnosis of "cerebral palsy." Because many of these conditions are genetic, their lack of recognition precludes genetic counseling with the danger of further affected children by the unsuspecting parents. Arginase deficiency and glutaric acidemia type I are inherited metabolic diseases characterized by neurological abnormalities of early onset that can remain stable for long periods of time. The carbohydrate-deficient glycoprotein syndrome, identified by the presence in serum of abnormal isotransferfins, can be added to this list. Mannosidosis and SjogrenLarsen syndrome also share with PMD the chronic persistence of neurological dysfunction that seem to be stable year after year. Likewise, chronic stable long tract signs without obvious brain dysfunction can be seen with anomalies at the skull base and upper cervical spine and can easily be mislabeled "cerebral palsy." The same is true of benign
PROGRESSIVE CEREBRAL PALSY
215
cervicomedullary astrocytomas which can on occasion appear in early infancy. Among the genetically determined white matter diseases of infancy and childhood, PMD is the prototype of the dysmyelinating, as opposed to the demyelinating, disorders. The most common of the "classical" forms of these collective diseases each have certain reasonably common clinical features which aids in their diagnostic recognition. For example, infantile Krabbe's disease usually has onset between 4 and 7 months after birth with irritability, hypertonicity, seizures, elevated cerebrospinal fluid (CSF) protein, and progressive demyelination seen on MRI. Infantile metachromatic leukodystrophy usually begins between 16 and 24 months of age with gait disturbance, combinations of long tract and peripheral nerve signs, and retained cognitive skills in the early phase. Sex-linked adrenoleukodystrophy has onset of symptoms later in childhood, is usually manifested by progressive ataxia, dementia, and characteristic skin discoloration secondary to primary adrenal insufficiency. Other disorders of early onset but not among the primary white matter diseases are Canavan's disease and Alex-
ander's disease, which are notable for the combination of hypotonia, developmental delay, and progressive macrocephaly. Infantile Gaucher's disease is first symptomatic at 3 to 6 months of age and combines hepatosplenomegaly with increasing irritability, hypertonicity with head retraction, ophthalmoparesis, and lower cranial nerve dysfunction leading to facial paresis and bulbar dysfunction. The infantile type of hexosaminidase A deficiency, Tay-Sach's disease, is characterized by a rather striking startle response to various forms of auditory and tactile stimuli in addition to myoclonus, gelastic seizures, and macular cherry red spots. Pompe's disease can be suspected clinically by the presence of cardiomegaly or cardiac failure, hypotonia, reflex loss, and in approximately a third of the cases, enlargement of the tongue. The clinical hallmarks found in the most prevalent form of these disorders along with laboratory evaluations of lysosomal enzymes and very long chain fatty acids in addition to the findings on MRI, provides a high degree of accuracy in their clinic~aldifferentiation. William E. Bell, M D
REFERENCES
1. Aicardi J: The inherited leukodystrophies: A clinical overview. J Inherit Metab Dis 16:733-743, 1993 2. Kendall BE: Inborn errors and demyelination: MRI and the diagnosis of white matter disease. J Inherit Metab Dis 16:771-786, 1993 3. Lee BCP: Magnetic resonance imaging of metabolic and primary white matter disorders in children. Neuroimag Clin NA 3:267-289, 1993
4. Powers JM, Rubio A: Selected leukodystrophies. Sere Pediatr Neurol 2:200-210, 1995 5. Gencic S, Abuelo D, Ambler M, et al: PelizaeusMerzbacher disease: An X-linked neurologic disorder of myelin metabolism with a novel mutation in the gene encoding proteolipid protein. Am J Hum Genet 45:435-442, 1989
A
6-YEAR-OLD boy was referred for evaluation of cerebral palsy. He was product of an uncomplicated, fullterm pregnancy, labor, and delivery. Birth weight was 9 lb 11 oz. Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. Pendular nystagmus was noted shortly after birth and an ophthalmologic examination showed bilateral optic atrophy. A diagnosis of cerebral palsy was made at 7 months and multiple tests (including head computed tomography) failed to provide any explanation for this. Psychomotor development was slow and at 6 years of age he was unable to sit or walk without support. He could read and communicate to a certain extent with computer-assisted speech. His general health had been good except for chronic otitis that required ear tubes, esophageal candidiasis, and reflux. A younger brother also had been diagnosed as having cerebral palsy with similar features. On examination he measured 103.7 cm, weighed 14.8 kg and head circumference was 49.5 cm; these measurements were at below the 3rd percentile for height and weight and at the 25th percentile for head. Eye examination showed slow, pendular nystagmus and small, pale optic discs. Axial muscle groups and upper extremities were hypotonic whereas lower extremities showed increased tone and spontaneous upgoing plantar responses. Voluntary movements were described as athetoid. He was unable to walk without assistance.
From the Section of Neurology, Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO. Address reprint requests to Enrique Chaves-Carballo, MD, Section of Neurology, Department of Pediatrics, Children's Mercy Hospital, 2401 Gillham Rd, Kansas City, 114064108. Copyright 9 1996 by W.B. Saunders Company 1071-9091/96/0303-001255.00/0 212
NEUROPHYSIOLOGICAL AND NEUROIMAGING DATA
Brainstem auditory-evoked responses showed wave I at normal latencies bilaterally but with poor wave morphology so that later components could not be identified. A magnetic resonance imaging (MRI) study showed severe, diffuse abnormalities of the white matter. On Tl-weighed images myelin was markedly decreased with only a faint signal noted in the thalami- and thalamo-occipital tracts (Fig 1), while on T2-weighed images high-intensity signal changes were most severe in the centrum semiovale (Figs 2 and 3). The cortex appeared intact with normal gyral and sulcal markings. DIFFERENTIAL DIAGNOSIS
The presence of severe motor involvement with disproportionate preservation of cognitive function is unusual and may result from predominantly white matter injury or degeneration. This differs from the more common situation where both gray and white matter are comparably affected as occurs in hypoxicischemic or neonatal encephalopathy because of birth injury (cerebral palsy). The absence of perinatal risk factors in this case is also against this possibility. A more likely explanation for the clinical presentation of mainly motor dysfunction is a leukodystrophy.1 Loss of white matter may be caused by breakdown of already formed myelin (demyelination) or by failure to develop myelin (dysmyelination). The presence of myelin degradation products favors the process of demyelination but this can only be confirmed pathologically. The early onset of symptoms and lack of myelin evident in neuroimaging studies suggest that there was a failure of myelin development or dysmyelination in this case. Even more unusual is the association of
Seminars in Pediatric Neurology, Vol 3, No 3 (September), 1996: pp 212-215
PROGRESSIVE CEREBRAL PALSY
Fig 1. Tl-weighted MRI axial image of brain in 6-year-old boy with delayed motor development and nystagmus shows almost complete absence of myelin except for minimal signal in thalami and thalamo-occipital fibers. There is also mild ventricular enlargement.
motor and visual impairment, the latter manifested by early pendular nystagmus as seen in macular degeneration, albinism or optic atrophy. Cerebromacular degeneration (as these disorders were called in the past) is evident in Tay-Sachs disease and Batten disease or neuronal ceroid-lipofuscinosis. However, eye examination in this case failed to show a cherry-red spot, macular degeneration or retinitis pigmentosa. Instead, funduscopic examination revealed small, pale optic discs consistent with optic atrophy. Congenital malformations associated with optic atrophy include septo-optic dysplasia, which can be excluded easily with computed tomography or MRI. Another important feature in this case is the mode of inheritance. This could be either because of autosomal recessive or sex-linked recessive transmission. The majority of leucodystrophies are inherited as autosomal recessive; however, sex-linked inheritance is present in Fabry disease (ceramide trihexosidosis) and in Pelizaeus-Merzbacher disease (PMD). Finally, neuroimaging studies, particularly MRI, may be helpful in sorting out the various possibilities. A paucity of myelin on Tl-weighted
213
Fig 2. T2-weighted MRI axial image in same case shows diffuse, bilateral markedly high-intensity signal (because of the absence) of white matter consistent with abnormal myelin in the centrum semiovale. Note that the cortical ribbon signal remains intact.
images and a corresponding high-intensity signal on T2-weighted images have been described in PMD. 2,3 The combination of developmental delay,
Fig 3. T2-weighted MRI image shows similar changes in coronal view.
214
ENRIQUE CHAVES-CARBALLO
optic atrophy, and a failure of myelin formation in two male siblings is consistent with P M D . DISCUSSION
P M D is an X-linked recessive, progressive degenerative disorder of the central nervous system with distinctive clinical, genetic, neuroimaging, and molecular diagnostic features. 4 Onset is usually in the neonatal or infantile period with a b n o r m a l eye m o v e m e n t s described as p e n d u l a r or jerk-type nystagmus. Associated h e a d m o v e m e n t s suggest a clinical diagnosis of spasmus nutans. However, ophthalmoscopic examination reveals small, pale optic discs compatible with optic atrophy. By the third m o n t h of age p s y c h o m o t o r development comes to a standstill or regresses and choreoathetosis may appear. T h e m o t o r progress is affected so that sitting or ambulation without support may never be achieved. Spasticity and ataxia develop and seizures m a y a p p e a r later. O n the other hand, cognitive function may be spared for some time and mental deterioration may not b e c o m e apparent until the terminal stages. H e a d circumference is r e d u c e d in some cases. D e a t h ensues within a decade, although survival has b e e n r e p o r t e d to the third decade. Until the advent of neuroimaging studies, a clinical suspicion of P M D could be confirmed only by brain biopsy or autopsy. Neuropathological studies of the brain showed d e g e n e r a t i o n of myelin in a patchy ("tigroid") distribution with minimal (if any) degradation products. Thus, small patches of preserved myelin are f o u n d a m o n g areas of demyelination in P M D . N e u rons and axons are usually spared. T h e most affected region is the c e n t r u m semiovale but lesions m a y be f o u n d also in the brainstem, internal capsule, and cerebellum. N e u r o p h y s i o l o g i c a l studies, p a r t i c u l a r l y evoked responses, usually are markedly abnormal. M R I studies have b e c o m e increasingly helpful in sorting out the various leucodystrophies. A l t h o u g h the M R I findings in P M D are not diagnostic, these are sufficiently distinctive that, in Conjunction with typical clinical findings, a diagnosis can be m a d e confidently. Molecular studies have redefined P M D as an inborn error of myelin f o r m a t i o n , localized in
the gene responsible for proteolipid protein ( P L P ) p r o d u c t i o n in the X - c h r o m o s o m e . 5 P L P is the main c o m p o n e n t of myelin protein and comprises half of the protein of the myelin sheath. In about one third of patients with P M D studied, a m u t a t i o n in the gene encoding for P L P m a y be demonstrable using the polymerase chain reaction. T h e majority of the mutations described to date have b e e n " u n i q u e " to each family studied, indicating that looking for " o l d " mutations may not be fruitful in new cases. However, once a m u t a t i o n is shown, this can be used to diagnose both affected and carrier m e m b e r s of the family and even for prenatal diagnosis. O n the other hand, in two thirds of cases no evidence of a m u t a t i o n for the P L P gene can be f o u n d by present techniques (M.E. Hodes, personal communication, 1995). COMMENT
Recent advances have shown that PMD is a genetically determined disorder of proteolipid protein production which disrupts normal central nervous system myelin formation. The best known and most common is the early infantile form, which is sex-linked recessive and has a chronic, almost stable clinical course for a decade or more. The condition has now been subdivided into a variety of types, some of which can be inherited differently so that females may also be affected. The classic infantile type of PMD is suspected by the presence in the early months of life of nystagmus and peculiar head movements along with stagnation of normal motor development. This has led to the analogy with the curious state referred to as spasmus nutans, which in some cases remains just that, a curious state, whereas in others, neuroimages show the ocular and head motions to be symptomatic of an optic chiasmhypothalamic glioma. The illness described above by Dr. Chaves-Carballo is one of many disorders in which neurological abnormalities are identified early in life and followed by a seemingly stable course, bringing forth a diagnosis of "cerebral palsy." Because many of these conditions are genetic, their lack of recognition precludes genetic counseling with the danger of further affected children by the unsuspecting parents. Arginase deficiency and glutaric acidemia type I are inherited metabolic diseases characterized by neurological abnormalities of early onset that can remain stable for long periods of time. The carbohydrate-deficient glycoprotein syndrome, identified by the presence in serum of abnormal isotransferfins, can be added to this list. Mannosidosis and SjogrenLarsen syndrome also share with PMD the chronic persistence of neurological dysfunction that seem to be stable year after year. Likewise, chronic stable long tract signs without obvious brain dysfunction can be seen with anomalies at the skull base and upper cervical spine and can easily be mislabeled "cerebral palsy." The same is true of benign
PROGRESSIVE CEREBRAL PALSY
215
cervicomedullary astrocytomas which can on occasion appear in early infancy. Among the genetically determined white matter diseases of infancy and childhood, PMD is the prototype of the dysmyelinating, as opposed to the demyelinating, disorders. The most common of the "classical" forms of these collective diseases each have certain reasonably common clinical features which aids in their diagnostic recognition. For example, infantile Krabbe's disease usually has onset between 4 and 7 months after birth with irritability, hypertonicity, seizures, elevated cerebrospinal fluid (CSF) protein, and progressive demyelination seen on MRI. Infantile metachromatic leukodystrophy usually begins between 16 and 24 months of age with gait disturbance, combinations of long tract and peripheral nerve signs, and retained cognitive skills in the early phase. Sex-linked adrenoleukodystrophy has onset of symptoms later in childhood, is usually manifested by progressive ataxia, dementia, and characteristic skin discoloration secondary to primary adrenal insufficiency. Other disorders of early onset but not among the primary white matter diseases are Canavan's disease and Alex-
ander's disease, which are notable for the combination of hypotonia, developmental delay, and progressive macrocephaly. Infantile Gaucher's disease is first symptomatic at 3 to 6 months of age and combines hepatosplenomegaly with increasing irritability, hypertonicity with head retraction, ophthalmoparesis, and lower cranial nerve dysfunction leading to facial paresis and bulbar dysfunction. The infantile type of hexosaminidase A deficiency, Tay-Sach's disease, is characterized by a rather striking startle response to various forms of auditory and tactile stimuli in addition to myoclonus, gelastic seizures, and macular cherry red spots. Pompe's disease can be suspected clinically by the presence of cardiomegaly or cardiac failure, hypotonia, reflex loss, and in approximately a third of the cases, enlargement of the tongue. The clinical hallmarks found in the most prevalent form of these disorders along with laboratory evaluations of lysosomal enzymes and very long chain fatty acids in addition to the findings on MRI, provides a high degree of accuracy in their clinic~aldifferentiation. William E. Bell, M D
REFERENCES
1. Aicardi J: The inherited leukodystrophies: A clinical overview. J Inherit Metab Dis 16:733-743, 1993 2. Kendall BE: Inborn errors and demyelination: MRI and the diagnosis of white matter disease. J Inherit Metab Dis 16:771-786, 1993 3. Lee BCP: Magnetic resonance imaging of metabolic and primary white matter disorders in children. Neuroimag Clin NA 3:267-289, 1993
4. Powers JM, Rubio A: Selected leukodystrophies. Sere Pediatr Neurol 2:200-210, 1995 5. Gencic S, Abuelo D, Ambler M, et al: PelizaeusMerzbacher disease: An X-linked neurologic disorder of myelin metabolism with a novel mutation in the gene encoding proteolipid protein. Am J Hum Genet 45:435-442, 1989