J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.43.9.789 on 1 September 1980. Downloaded from

Journal of , Neurosurgery, and Psychiatry, 1980, 43, 789-797

Delayed-onset dystonia in patients with "static" ROBERT E BURKE, STANLEY FAHN, AND ARNOLD P GOLD From the Department of Neurology, Columbia University College ofPhysicians and Surgeons, and The Neurological Institute, New York

SUMMARY Eight cases of persistent dystonia appearing one to 14 years after non-progressive cerebral insults are described. Five were due to perinatal anoxia, one to trauma, and two to cerebral infarction. This phenomenon of delayed-onset dystonia has not been described previously, although review of earlier literature reveals several probable examples. Delayed-onset dystonia due to perinatal anoxia is an important diagnostic alternative to dystonia musculorum deformans for dystonia occurring in childhood.

Abnormal movements he caused in an case of involuntary may ments seen individual cerebral guest. Protected by copyright. by non-progressive cerebral insults. Choreic, palsy can change radically in their character at athetoid and dystonic movements due to peri- later ages.7 Lesny8 documented a change between natal anoxia or kericterus,l and ballistic, choreic the ages of five and 14 years from to and athetoid movements due to cerebral infarc- a "wholly different condition," that is, chorea, tion2 have been documented. In addition, abnor- "tension ," or "tension athetosis," in 45 mal involuntary movements have been reported of 100 cases of athetoid cerebral palsy. These after trauma, anoxia or carbon monoxide poison- cases of dystonic movements, however, occurred ing in the adult.3 in the setting of pre-existing different abnormal In general, the abnormal involuntary move- involuntary movements, which were apparent ments in such cases appear either (1) at the time since early infancy. the insult occurs, (2) when the acute neurologic The abnormal involuntary movements which deficit resolves, or (3) when the patient matures develop after cerebrlal infarction occur acutely neurologically, as in the case of perinatal insults. or as the patient recovers from the initial hemi- In a study of the natural history of choreo- plegia. This temporal sequence is typical of athetoid cerebral palsy, Polanil found that of 56 hemiballism and hemichorea,9 10 and appears to patients, 39 had abnormal involuntary move- hold true in many of the published cases of ments by the age of 21 years, and the other 17 post-hemiplegic athetosis, where information is had abnormal involuntary movements by the age provided as to the onset of the abnormal move- of 3j years. These data are supported by the ments in relation to the initial event.2 11-18 observations of Crothers and Paine5 who noted In contrast to these cases in which the move- http://jnnp.bmj.com/ that the majority of patients with "extrapyra- ments appear soon after the insult or as part of midal" cerebral palsies were first seen between an evolving picture in relation to the insult, we the ages of 10 and 18 months because of abnor- have seen several patients in whom dystonic mal motor development. As these children grew movements appeared and progressed in severity older, abnormal involuntary movements deve- cne or more years after an original insult. In loped. Paine¢ serially evaluated children with the interval between the initial event and the perinatal brain injury and noted that of those subsequent appearance of the movements, these who ultimately developed choreo-athetosis or patients had minimal or no neurological abnor- on September 29, 2021 by dystonia, 92% showed visible chorea or athetosis malities which, most importantly, were entirely by the age of three years. The abnormal move- static until the appearance of the abnormal movements. We considered these movements as Address for reprint requests: Dr Robert E Burke, Neurological dystonic when they were sustained, involuntary Institute, 710 West 168th Street, New York, NY 10032, USA. twisting movements affecting muscles of the Accepted I May 1980 limbs, trunk, neck or face.19 The terms 789 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.43.9.789 on 1 September 1980. Downloaded from

790 Robert E Burke, Stanley Fahn, and Arnold P Gold focal, segmental and generalised dystonia are left was equivocal. Normal or negative tests included used as defined by Marsden.7 Similar cases have complete blood count (CBC), urinalysis, electro- been reported by Hanson, Berenberg and lytes, renal and liver function tests, serum cerulo- They described three children who suf- plasmin, antinuclear antibody (ANA) and skull Byers.20 radiographs. An electroencephalogram (EEG) fered cerebral anoxia in early life, with mild but showed background disorganization, bilateral slow- stable subsequent motor dysfunction, who deve- ing, and intermit-tent sharp waves wit-h a left-sided loped , athetosis, or dystonic movements predominance. Cerebrospinal fluid (CSF) contained at ages five to 15 years, which then progressed no cells, glucose of 3-7 mmol/l, protein of 0*32 g/l, in severity. with a gamma globulin fraction of 16% (normal, This phenomenon of delayed-onset dystonia 12%). A slit-lamp examination was negative. A merits recognition because it represents a pre- computed -tomography (CT) scan showed right cere- viously neglected diagnostic consideration, es- bral hemiatrophy, with enlargement of the right pecially for dystonia occurring in adolescence. frontal horn, right atrium and sulci over the right convexity. She was discharged, but because of pro- Furthermore, the existence of this phenomenon gressive gait difficulty she was readmit-ted after two may shed some light on the pathogenesis and mon-ths. Repeat examination showed marked dys- pathophysiology of dystonic rmtovements. tonic posturing of the left arm an,d leg. Repeat serum ceruloplasmin was normal; serum thyroxine Case histories was normal. CSF contained a protein of 0-21 g/l, and a gamma globulin of 7x3%. A four-vessel cere- Perinatal anoxia bral angiogram was normal. She was referred to the Case I This child developed dystonic movements Neurological Institute and examined by us 10 of the left arm and leg at the age of seven years. months after the onset of the abnormal movements. She was the product of a normal, full-term preg- On examination, there were twisting abnormal in- guest. Protected by copyright. nancy, but delivery was complicated, necessitating volun-tary movements of the left arm and leg when the use of forceps. Apgar Score at one minute was she sat at rest. The left shoulder was elevated and 3. She apparently did well in the early neonatal the arm extended at the elbow. The foot was plantar period and was discharged after four days. Deve- flexed with equinovarous posturing. When she lopmental milestones were acquired normally: she walked, there was abduction of the arm, liftinig the walked at seven months, said words at one year, arm in the air. The right side was not involved. and spoke in sentences at two years. She had no There was no weakness, reflexes were symmetric, problem learning to ride a bicycle or tie shoe laces, and plantar reflexes were flexor. At follow-up exam- but she was considered to be a "clumsy child." ination 18 months after the onset, the affected arm Her speech was indistinct and she received speech and leg were unchanged, but she had developed therapy. Initially there were academic difficulties, a slight head tilt to the left. and for that reason formal psychometry was done, Case 2 This boy developed dystonic movements of which demonstra-ted a "very superior range of in- the right forearm at the age of 14 years. Records of telligence." his birth indicate he was the product of a full term At the age of seven years the child developed pregnancy. There was premature rupture of the progressive difficulty with walking and using her left membranes, and labour was 12 hours in dura- hand. Tlhe parents noted that when the child walked tion. Delivery was complicated by a breech presenta- or climbed stairs, she tended to rotate externally tion with prolapse of the cord, requiring reposition the left leg, the left arm would become pronated of the extremities and forceps. Apgar Score at one with the wrist and fingers flexed. There was no minute was zero. The chiild was resuscitated and

history of head trauma, drug inrgestion, or change placed in an incubator with oxygen. He slowly im- http://jnnp.bmj.com/ in intellect. There was no family history of neuro- proved and was discharged after one week. The logic illness. The mother and father were of Scottish mother was told that tihe child was "probably brain and Irish descent, respectively. Over eight months, damaged." the abnormal posturing became more severe and At the age of two years the child was seen here she was admitted to another ihospital for evaluation in tihe Pediatric Clinic. Th-e mother, who had had at the age of eight years. On examination, the child two previous normal dhildtren, thought this child's was alert and of normal intelligence. Her speech development may have been slow, but the attending was indistinct. Head circumference was normal. pediatrician considered the child to be normal. Skull

W'hen walking, she oircumducted and externally radiographs and an EEG were normal. At the age on September 29, 2021 by rotated -the left leg, and she had at times a "dys- of three years, the child was said to have indistinct tonic posture of the left foot." When running she speech. The child apparently developed normally would flex and markedly pronate the left arm. She thereafter, keeping up with other children athletic- was said to have a mild left affecting ally. Indistinct speech was a persistent problem and distail musculature of arm and leg. Cranial nerves, speech therapy was prescribed until the age of 11 cerebellar testing, deep tendon reflexes, and sensation years. His performance in school otherwise was were normal. The right plantar reflex was flexor, the average. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.43.9.789 on 1 September 1980. Downloaded from

Delayed-onset dystonia in patients with "static" encephalopathy 791 An intermittent of the right haind was and horizontal tremor of the head were noted. observed at the age of 11 years, and at 14 years, The child did well until aged 13 years when the twisting movements of the right hand appeared, parents noted episodes in which his head and trunk whfich necessitated a change to writing with the were pulled to the left. These movements were left hand. There was no history of head trauma, associated wit-h a forward protrusion on the left drug ingestion or change in intellect. Both parents shoulider and extension of the left arm backwards. were of Irish descent, and tihere was no history The movements became more severe, and after of neurological illness in the family. evaluation at two other institutions, he was referred Other than a questionable right hemiparesis, here. examination revealed abn-ormal movements of the On examination, the child had a poor fund of right hand "resembling chorea." Intellect, cerebellar knowledge, and spellinrg and mathematics were at a function and sensation were normal. CBC, urin- third grade level. Graphomotor skills were deficient. alysis, electrolytes, sedimentation rate, skull films, His gait was spastic with slight flexion at the hips serology for syphilis and a CT scan were negative and knees. There was mild weakness of the hands. or normal. CSF contained no cells and a protein of Tone was generally increased, with hyperactive deep 0.27 g/l, and glucose of 3-8 mmol/l. An EEG tendon reflexes and bilateral extensor plantar re- showed bursts of generalised 4-6 Hz spike and slow flexes. Cerebellar testing showed mild . waves. There were no focal abnormalities. Sensation was normal. No Kayser-Fleischer rings Over the next two years, the abnormal involun- were noted. Examination of his abnormal move- tary movements of the right arm remained the ments revealed intermittent torticollis with the chin same. The patient noted occasional "twitching" of pulled left and intermittent scoliotic posturing with the left thumb. NTeurologic evaluation by us at the the thoracic spine being convex to the right. The age of 16 years revealed sustained ulnar deviation left shoulder was elevated and pulled anteriorly.

of the right hand, which fluctuated in severity. The When the patient walked, the left arm was pulled guest. Protected by copyright. fingers of the right hand also had sustained ulnar backwards, with the arm extended at the elbow. deviation and were hyperextended at the metacarpo- Occasional athetotic flexion and extension move- phalangeal joints. There was no detectable weak- ments of the right fingers were noted. Chest x-ra) ness. Intermittent sustained extension at the left showed mild pectus carinatum. CBC, urinalysis, thumb distal interphalangeal joint was noted. The skull radiographs, CSF analysis and a CT scan were abnormal involuntary movements were made more normal. severe by action, such as walking or finger-to-nose After discharge, benzhexol was started and the testinig. Repeat blood count, urinalysis, electrolytes, abnormal movements lessened. At follow-up, 20 CSF analysis, including gamma globulin, liver func- months after the onset of the movements, he re- tion tests, ceruloplasmin, slit-lamp examination, and mained improved with only oocasional dystonic repeat EEG were normal. The patient's mother and movements of the left shoulder, precipitated by three sisters were examined and they were normal. stress, or by missing doses of benzhexol. Case 3 This boy developed dystonic movements of Case 4 This boy developed dystonic movements of the left arm and trunk at the age of 13 years. He the right arm and the neck at age nine years. The was the result of a full term, uncomplicated preg- child was cyanotic at birth with apnoea and no heart nancy. Labour was induced. The child was cyanotic beat. He was examined by us at the age of four at birth and required intubation with oxygen months, and the only abnormal findings were in- therapy for eight hours. Apgar score at one minute creased tone in legs and generalised . was 7. Developmental milestones were slightly de- Re-examination at one year showed that the child layed: he sat allone at eight months, walked was able to walk unassisted, but there was increased unassisted at 15 months, began to speak at two tone in the legs witih poor prehensile function. At years. His gait was awkward in early life and he 17 months, a left hand preference was noted in http://jnnp.bmj.com/ cften fell for no apparent reason. He was not able addition to a right-sided reflex preponderance. At to run until the age of five years. In kindergarten, 21 years, the right hemiparesis was more marked. when five years old his teacher raised the question Language function was well-developed, but speech of and mental retardation. There was no was slurred. Skull radiographs, radionuclide brain fam!ily history of neurologic disease. scan and CSF analysis were normal. An EEG Neurologic examination by us at the age of six showed left focafl spike discharges. Subsequent in- years revealed a co-operative, alert child with mildly tellectual function and motor performance deve- dysarthric speech and a fund of knowledge deficient loped normally, but the parents observed difficulty for chronological age. Reproductions of Bender- with fine movements such as tying shoe laces and on September 29, 2021 by Gestalt patterns were immature and suggestive of buttoning. perceptual difficulty. His gait was s-pastic; the legs At the age of nine years he developed a head were stiff, and there was a tendency towards toe tilt to the right and abnormal involuntary move- walking. Tone was increased, especially in the legs. ments of the right arm. Examination revealed in- Reflexes were generally hyperactive, but plantar distinct speech, moderate head tilt to the right, and responses were flexor. Mild cerebellar dysfunction posturing of the right arm when walking. The was noted. A fine resisting tremor of the extremities abnormal movements involved the shoulder as well

D J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.43.9.789 on 1 September 1980. Downloaded from

792 Robert E Burke, Stanley Fahn, and Arnold P Gold

as the hand. Four months later, the child awoke were sudden myoclonic jerks of the head and arms, and could not walk because of marked in his often in a series, and there were dystonic move- gastrocnemii wit'h equinus posturing of the feet, and ments. On standing, the ohild leaned backward in then these symptoms promptly resolved. Examina- an opisthotonic position. The head would either tion showed normal intellect (full scale IQ 118). turn to the left or be retroflexed. The right arm Gait was characterised by a diminished arm swing was flexed at the elbow and wrists, and abducted on tfhe right, and a tendency to toe walk on the at the shoulder. The right leg would be thrust for- right. The head was tilted to the right, and both ward with flexion at the knee. A CBC, electrolytes, arms had "rapid irregular jerky movements sedimentation rate, liver function tests, acid-base associated with slow writing movements." CBC, studies, serum ceruloplasmin, CT scan, and visual urinalysis, sedimentation rate, CSF analysis, cerulo- evoked responses were normal or negative. An EEG plasmin, radionuclide brain scan, pneumoencephalo- showed epileptiform discharges over the right occi- gram, and slit-lamp examination were normal. An pital region. The movements responded to benz- tEEG showed occasional spike discharges in t1he left hexol. At follow-up examination, two years later central and posterior temporal areas with diffuse while the child remained on benzhexol, there was slowing, more prominent on tihe left. The child was no evidence of progression. treated, with transient success, with levodopa. but it was discontinued after a few weeks when it Craniocerebral trauma seemed no longer effective. Case 6 This girl developed abnormal movements At l1 years of age, two years after the onset of of the right arm and leg six years after craniocere- the movements, repeat examination revealed torti- bral trauma. The child was normal until two years collis with head tilted to the right. The right arm old when, in an automobile accident, she suffered a was intermittently internally rotated and elevated depressed skull fracture on the left. She was admit-

at the shoulder. The right forearm continuously as- ted to another hospital in with a right guest. Protected by copyright. sumed a sustained supination posture. The fingers hemiparesis. The ohild slowly recovered from this of the right hand were flexed. The left arm was injury. Initially she was aphasic, but over two intermittently internally rotated proximally. All months her speech became normal. Function in the abnormal movements were aggravated by action, for right arm and hand improved, but she never re- example, writing or walking. At rest, there were no gained fine dexterity in the right hand, and she abnormal movements of the legs. With walking, the changed to being left-handed. Her gait also im- ri,ght foot plantar flexed and the leg internally proved, and six years after the accident she no rotated. Strength was normal. Repeat psychometrics longer needed a foot brace. Diphenylhydantoin was at that time showed a full scale IQ of 110. At 13 given for six months after the accident and she years of age, benzhexol was begun, with some never had after it was discontinued. improvement. Six years after the accident, the child developed Case S This boy developed dystonic movements of right sided "choreo-athetotic movements" and she the trunk, right arm and leg at the age of 61 years. was referred here. Family history was negative for He was t'he result of a full term, normal pregnancy. neurologic disease. On examination her intellect Delivery was reported to be normal, but the birth was normal. Graphomotor function was performed records were not detailed. The mother was not awkwardly with her right hand. There was a mild aware of any postnatal respiratory difficulty. How- right hemiparesis involving primarily the hand and ever, developmental milestones were abnormal, with foot, with a right reflex preponderance, and an ex- an inability to stand unsupported until 20 months, tensor right plantar response. "Sinuous" movements to walk unassisted until aged two years, and to of the right arm and leg, and right paraspinal speak in phrases until six years old. At the age of muscle spasm were noted. She was treated with 18 months, the child was diagnosed by a familv diazepam and perphenazine. http://jnnp.bmj.com/ physician to have cerebral palsy. Three years after the onset of the movements, When the child was 61 years old, the parents aged II years, she was examined by one of us. noted rapid jerks of the arm and head, and sus- At that time, she did not have any rapid choreic tained abnormal positions of the head. At another movements. At rest, she had occasional writhing, hospital, CSF analysis and a CT scan were normal. athetoid movements of the hand. When she used An EEG showed epileptifo,rm activity over both the arm, for example, for writing or picking up hemispheres. Treatment with clonazepam resulted objects, dystonic movements became apparent. The in worsening of the movements. There was no hand would develop sustained flexion and median family history of neurologic disease. deviation at the wristt. When standing, she had on September 29, 2021 by The child was examined by us at the age of 71 intorsion of the right foot. When she walked or years. Intellect was normal. Speech was dysarthric, ran, she developed marked internal rotation of the with frequent drooling. The gait vas mildly broad- right leg and flexion of the hip. based with a tendency to toe walk. Tone was generally increased, and reflexes were hyperactive. Cerebral infarction The plantar responses were flexor. There were two Case 7 This woman developed dystonic movements types of abnormal involuntary movements. There one year after a probable cerebral infarction. At J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.43.9.789 on 1 September 1980. Downloaded from

Delayed-onset dystonia in patients with "static" encephalopathy 793 t-he age of 65 years, a left hemiparesis occurred At follow-up, one year after onset of the move- abruptly and then resolved completely within 24 ments, the movements were unchanged. hours. She never had sensory complaints. Six months later, a thermogram revealed dense coldness over the Literature review right side of her face. One year after the , she noted a "hard It is often the case that a phenomenon not pre- spot" in her left triceps. She progressively developed viously emphasised in the literature nevertheless is sustained flexion at tihe elbow, wrist and fingers. evident in some prior reports. We reviewed most She had difficulty opening her jaw and had a sensa- of the cases of dystonia reported in the English tion of "tightness" over the left side of her face. literature since the description by Schwalbe.21 The Levodopa, amantadine, propranolol, and carba- very complete literature reviews by Herz22 and mazepine were not effective in treating these Eldridge23 were supplemented by reviews of more movements. recent reports. We summarise briefly cases in which She was examined here two years after the onset adequate data are available and which we feel are of the movements. Intellect and speech were normal, probably representative of delayed-onset dystonia. as were cranial nerves, strength, cerebellar function and sensation. Reflexes were not obtained in the Perinatal anoxia lefit arm, but otherwise were intact and symmetric. Herz22 Case 10 This boy developed dysto-nic move- Plantar responses were flexor. The left arm was ments at the age of eight years. He was born after abducted at the shoulder and it was flexed at the a full term pregnancy. Delivery was by forceps. He elbow and wrist. The first three fingers were flexed had several convulsions in the postnatal period, but at the metacarpophalangeal and proximal inter- none afterwards. Early development was slow, and phalangeal joints. There was a notable limitation he walked at 21 years. His gait was said to be stiff, of jaw opening. CBC, electrolytes, lupus erythema- but he was "able to play ball and get around guest. Protected by copyright. tosis preparation, serum thyroxine, serology for fairly well." He apparently toe-walked and bilateral syphilis, CSF were normal or negative. Skull radio- obturator sections were done at the age of eight years graphs and brain scan were negative. An EEG was to improve this gait. Involuntary movements of the mildly abnormal, showing nonspecific intermittent extremities began before the procedure and became bitemporal slowing. A CT scan showed mild gen- worse afterwards. Examination at the age of 18 years eralised atrophy and a lucency in the right cerebral revealed normal intellect and a scissors gait. The hemisphere consistent with an infarction in the patient's trunk was bent and turned to the left. distribution of the right middle cerebral artery. An Slow, sustained, twisting movements involved the arteriogram showed a complete occlusion of the arms and legs. This patient was diagnosed by Herz right internal carotid artery. An EMG showed to have dystonia musculorum deformans. Family activity at rest in agonist and antagonist muscles history is not mentioned. of the left arm. Ryan24 This girl developed dystonic movements at Case 8 This man developed dystonic movements aged four years. She was born of a normal preg- of the left arm one year after a cerebral infarction. nancy, but delivery extended over a period of two The patient was well until the age of 54 years, when days, oulminating in a forceps extraction with he had sudden onset of bilateral arm and leg cyanosis at birth. Infancy, however, was said to be "heaviness" with a tendency to fall to the left. At normal. The child walked alone at 18 months. Deve- another hospital, examination revealed mild left loprrent continued to be considered normal until Facial, arm and leg weakness. CSF, brain scan, and the age of four when she fell, injuring her left leg. EE'G were normal. The weakness resolved in a few She was hospitalised and said to have "hysterical days, and the patient returned to work. spasm" of the dorsiflexors of the left foot. This One year later, the patient fell and struck his left "spasm" apparently persisted until aged seven years. http://jnnp.bmj.com/ wrist. One month after this injury, he developed when it improved, although the child continued abnormal involuntary movements of the left arm. to walk on the outside of her shoe. At the age of On examination here, the patient was normal, with 10 years, three weeks after a fall, the child deve- the exception of left leg hyperreflexia and an ex- loped retrocollis, arching of the back and dystonic tensor plantar response on that side. There were postures of the limbs. No Kayser-Fleischer rings marked dystonic movements of the left arm: the were noted; liver funnction tests and CSF were nor- shoulder was pulled backwards and upwards; the mal. There was no family history of neurologic

first two fingers were flexed, the third and fourth illness. This patient was reported as a case of dys- on September 29, 2021 by were extended and abducted. The left great toe was tonia musculorum deformans. held in constant dorsiflexion. CBC, urinalysis, Hanson, Berenberg, and Byers20 This boy deve- electrolytes, ESR, protein electrophoresis, cerulo- loped a tremor at the age of 11 years; at the plasmin and CSF analysis were normal or negative age of 14 years he developed "flexion " of as were EEG, CT scan, radionuclide brain scan and the neck. The pregnancy was normal. The child auditory evoked responses. An EMG at was a breech presentation and born with the cord rest showed intermittent, simultaneous activity in looped around his neck. There were no spontaneous the left biceps and triceps. respirations for 25 minutes. Motor development J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.43.9.789 on 1 September 1980. Downloaded from

794 Robert E Burke, Stanley Fahn, and Arnold P Gold

was slow; he sat aged 18 montths and walked alone delayed-onset dystonia in these cases, we must aged 21 years. No neurologic abnormalities were exclude other possible aetiologies of dystonia.27 recognised by the family physician. At the age of In cases 6, 7, and 8, the somatotopic correspon- 11 years he began to develop slurred speech dence between the initial neurologic manifesta- and a tremor of the left arm. At the age of 14 tions and the subsequent dystonic movements years, he developed flexor spasms of the neck which make a causal relationship quite likely. In these were worse when walking. Subsequently, facial grim- acing and choreoathetosis of the arms appeared. patients there was no intellectual decline or other neurologic manifestations to suggest a Craniocerebral trauma central nervous system degenerative or meta- Messimy, Diebler and Metzger25 A 30-year-old man bolic disease, for example Huntington disease, suffered right sided head trauma in an auto ac- Parkinson disease, Wilson disease, Hallervorden- cident. There was no loss of consciousness. Four Spatz disease or a lipidosis. There was no history years later, he developed dystonic movements of of encephalitis or drug ingestion. In cases 7 and the left arm. A CT scan showed calcification of 8, mass lesions were excluded by appropriate the right caudate nucleus. studies, and in case 6 a mass lesion was improb- able on clinical grounds. These three cases are Cerebral infarction examples of the recognized causal relationship Denny-Brown26 A patient was said to have sud- between dystonic movements and prior head denly developed a mild hemiparesis with sensory trauma or but we report them as loss due to a cerebral embolus. The patient re- stroke,27 covered completely except for some mild residual examples of a marked delay between the insult facial numbness. Eleven months after this episode, and the onset of the movements, which has not "there began a progressive flexion of the wrist and previously been emphasized. guest. Protected by copyright. fingers, spreading to the elbow after a further three In Cases 1 to 5, lack of intellectual decline or months, and eventually leading to severe dystonic other neurological signs mitigate against degen- flexion of the arm and neck." erative and metabolic diseases. Wilson disease was excluded in each case. There was no prior Discussion history of drug ingestion or encephalitis and a mass lesion was excluded in each case. It is To summarise in eaoh of the cases presented, more difficult to exclude dystonia musculorum a presumably non-progressive cerebral insult was deformans (hereditary and idiopathic torsion followed by a period of neurologic stability for dystonia) in these cases, because at present one to 14 years. During this period, the patients dystonia musculorum deformans is diagnosable had mild or no neurologic deficit. They then only on the basis of clinical and genetic criteria, developed abnormal dystonic movements which and when known secondary causes of dystonia progressed in severity over a period of months are excluded. The clinical expression of dystonia to years, but then stabilised. The dystonic move- musculorum deformans can be quite variable, ments in each case were persistent. Clinical data with some cases being nonprogressive and mono- for cases of dystonia secondary to perinatal symptomatic.28 A negative family history for anoxia are contained in the table. neurological disease does not exclude a genetic- To make plausible the possibility of a causal ally recessive form of the disease, nor a domi- relationship between the original insult and t-he nant form, because formes frustes exist and may http://jnnp.bmj.com/

Table Delayed-onset dystonia following perinatal anoxia

Case Birth Apgar Motor Age of onset Site of Length of Evidence of complication score developmenit dystonia involvement follow-up after progression at onset most recent follow-up 1 Forceps 3 Normal 7 Left arm and leg 18 months Minimal 2 Breech, cord 0 Normal 14 Right arm 2 years None prolapse, forceps on September 29, 2021 by 3 Cyanosis 7 Abnormal 13 Left arm, neck, 20 months None trunk 4 Cyanosis 0 Abnormal 9 Right arm and 34 years None leg, neck 5 Normal (?) NA Abnormal 64 Right arm and 2 years None leg, neck and trunk NA-Not available J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.43.9.789 on 1 September 1980. Downloaded from

Delayed-onset dystonia in patients with "static" encephalopathy 795

go unrecognized by family members.23 29 How- In the evaluation of dystonia presenting in ever, several features of our cases are against adolescence, a suspected diagnosis of delayed- a diagnosis of dystonia musculorum deformans. onset dystonia does not obviate the need to In Cases 1, 4 and 5, the dystonic movements consider possible structural, metabolic and de- were predominantly unilateral involving the arm generative causes. Where such evaluation has and leg, and apparently stable after 14, 34 and been unrevealing, however, the existence of 2 years follow-up, respectively. In Marsden and delayed-onset dystonia following perinatal Harrison's30 series which specifically excluded anoxia can be an important diagnostic alterna- patients with an abnorm-al perinatal history, 79% tive to dystonia musculorum deformans. Delayed- of children with onset before the age of 11 years onset dystonia is an important alternative not progressed to generalised dystonia. Among only from a clinical point of view in terms of the 21 patients in their total series who did not appropriate prognosis and genetic counseling, progress, that is, who had segmental dystonia, but also from an investigative point of view, in none had unilateral arm and leg involvement. terms of carefully defining a patient population Furthermore, in both cases 1 and 4, there was representative of dystonia musculorum defor- evidence of a structural abnormality of the mans. It is notable, for example, that in hemisphere contralateral to the side of the body Eldridge's review23 of 145 patients considered to affected by movements; an abnormal CT scan have dystonia musculorum deformans (11 of in Case 1, and an abnormal EEG in Case 4. his total of 156 patients were acquired or atypi- These features are inconsistent with dystonia cal cases), a striking number of patients (40, musculorom deformans. In Cases 2 and 3 there or 28%) had an abnormal delivery or develop- was likewise a negative family history, lack of mental history where that information is pro- guest. Protected by copyright. progression, and predominantly focal involve- vided. In his Category IV-A, that of sporadic ment in Case 2 and segmental involvement in cases of typical dystonia in non-Jewish indivi- Case 3. In these cases the ipsilateral leg was not duals, there were two individuals with abnormal involved and there was no evidence of struc- deliveries who each had two offspring (Ref: 23 tural cerebral abnormality, so we cannot defi- table 20; families No 7 and 13). None of these nitely exclude dystonia musculorum deformans. four offspring apparently had dystonia at the However, the similarity to Cases 1, 4 and 5, and time of the study, which would be unlikely if lack of similarity to typical juvenile dystonia the two patients represented cases of spon- musculorum deformans, are against that diagnosis. taneous mutation to a dominant gene as sug- It is probable that our cases of delayed-onset gested. It is conceivable that some of these dystonia subsequent to perinatal anoxia repre- cases may represent examples of delayed-onset sent one end of a spectrum along which lie dystonia. It may be desirable for investigators graduated degrees of neurological impairment of dystonia musculorum deformans to specific- and stability prior to the onset of abnormal ally exclude patients with a history of perinatal movements. At the other end of the spectrum anoxia, as did Marsden and Harrison.30 would be the well recognised cases of severe It is possible that perinatal anoxia can in- neurological impairment noted shortly after fluence the expression of dystonia musculorum birth with development of abnormal movements deformans. Eldridge23 reported a case of identi- 6 in infancy.' 5 8 That such a spectrum exists is cal twins with this disease (Category IV-A, http://jnnp.bmj.com/ suggested by "intermediate" cases such as family 20, fig 18), the second of whom had suf- Herz's22 Case 10. Although details regarding the fered perinatal anoxia and was more severely child's development are lacking, he had a scis- affected with dystonia. The question of whether sors, gait, which required bilateral obturator sec- such a relationship exists between dystonia tion, prior to the onset of dystonia. He was musculorum deformans and perinatal anoxia is considered by Herz to represent a case of dys- in need of further study. Also in need of further tonia musculorum deformans. Our cases 3, 4 and careful epidemiologic study is the question of a

5 also suggest a continuum of neurological im- possible relationship between perinatal anoxia on September 29, 2021 by pairment, as they had neurologic abnormalities and other etiologies of dystonia, such as drug- prior to the onset of the movements, unlike induced dystonias. There are several case re- Cases 1 and 2. The existence of a continuum ports implicating encephalopathy due to peri- does not detract from the significance of the natal anoxia or other aetiologies in the occurence phenomenon of delayed-onset dystonia, es- of drug-induced dystonia. Angle and McIntire31 pecially in relation to the differential diagnosis reported a mentally retarded child, born of a of dystonia presenting in adolescence. precipitous labour at home, who developed per- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.43.9.789 on 1 September 1980. Downloaded from

796 Robert E Burke, Stanley Fahn, and Arnold P Gold sistent dystonia following accidental phenothia- malian central nervous system has been con- zine ingestion. However, the child also had sidered to lack regenerative potential, more previously suffered lead intoxication, and poss- recent work37 indicates that sprouting of intact ibly encephalitis at the age of nine months. neurons takes place after an injury. Central Furthermore, the child -had ingested several nervous system sprouting has been demonstrated other medications, including phenytoin. Angle, for monoaminergic38 and cholinergic39 systems. McIntire and Zetterman32 had previously re- To speculate, it is conceivable that delayed-onset ported an increased incidence of central nervous dystonia is caused by aberrant central nervous system manifestations, including abnormal in- system sprouting subsequent to nonprogressive voluntary movements, in children with an abnor- cerebral insult. However, how much such a pro- mal birth history among 1,033 cases of accidental cess might relate, if at all, to the pathogenesis drug ingestion, including phenothiazines. The of dystonia musculorum deformans is impossible type of abnormal involuntary movements was to suggest without a better understanding of not specified. In addition, abnormal birth history that disease. was assessed as a risk factor only for incidence of central nervous system manifestations over- References all, not for incidence of abnormal involuntary movements specifically, or dystonia in particular. 1 Polani PE. The natural history of choreo-athetoid Simpson33 reported two particularly severe in- "cerebral palsy." Guy's Hospital Reports 1959; stances of butyrophenone-induced dystonia in 108:32-45. two children with minimal brain dysfunction 2 Gowers WR. On "athetosis" and post-hemiplegic

Chalhub, DeVivo and Volpe34 reported pheny- disorders of movement. Medico-Chirurgical guest. Protected by copyright. toin-induced dystonia in an eight-year-old child Transactions 1876; 59:271-325. with a static encephalopathy and dis- 3 Fahn S. Secondary parkinsonism. In: Goldensohn ES, Appel SH, ed Scientific Approaches to order subsequent to diphtheria-pertussis-tetanus Clinical Neurology. Philadelphia: Lea and immunisation at the age of six weeks. They Febiger, 1977: 1159-89. suggested that the prior insult may have pre- 4 Lance JW, Adams RD. The syndrome of disposed the child to the dystonic reaction. intention or action myoclonus as a sequel to There is also a recent report35 of carbamazepine- hypoxic encephalopathy. Brain 1963; 86:111-36. induced dystonia in three children with pre- 5 Crothers B, Paine RS. The Natural History of existing ; two with probable peri- Cerebral Palsy. Cambridge: Harvard University natal anoxia, and a third with agenesis of the Press, 1959: 120. corpus callosum. 6 Paine RS. The evolution of infantile postural The aetiology of dystonia musculorum defor- reflexes in the presence of chronic brain syn- mans and the pathophysiology of the acquired dromes. Dev Med Child Neurol 1964; 5:345-60. dystonias remain unknown. There is no con- 7 Marsden CD. Dystonia: The spectrum of the sistent pathologic abnormality in brains of disease. In: Yahr M, ed The Basal Ganglia. New patients with dystonia musculorum deformans.36 York: Raven Press, 1976: 351-67. 8 Lesny I. The development of athetosis. Dev Med It is generally agreed that clinically similar Child Neurol 1968; 10:441-6. disorders, such as dystonia associated with cere- 9 Meyers R. Ballismus. In: Vinken PJ, Bruyn GW, bral palsy, are associated with basal ganglia

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