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Resting tremor only: a variant of Parkinson's disease or of essential tremor
JOURNAL
OF THE
NEUROLOGICAL SCIENCES
ELSEVIER
Journal
of the Neurological
Sciences
130 (1995)
215-219
Case report
Resting tremor only: a variant of Parkinson’s disease or of essential tremor Ming-Hong a Section
Chang a2* , Tso-Wen Chang ‘, Ping-Hong
Lai b, Chern-Guey
of Neurology, Veterans General Hospital-Kaohsiung, No 386, Ta-Chung 1st Road, Kaohsiung, b Department of Radiology, Veterans General Hospital-Kaohsiung, Kaohsiung, Taiwan ’ Department of Neurology, Tzu-Chi Buddhist General Hospital, Hualien, Taiwan
Sy b
Taiwan
Received 18 August 1994;revised 3 January 1995;accepted 22 January 1995
Abstract Resting tremor is one of the characteristic features of Parkinson’s disease. However, there are a number of patients who typically have resting tremor alone for at least 5 years without development of other parkinsonian signs or symptoms. The etiology of an isolated resting tremor is still obscure. Recently, positron emission tomography was used to study these patients with isolated resting tremor, and demonstrated a markedly decreased striatal uptake of fluoro-dopa to the range of Parkinson’s disease. These findings suggested the existence of a separate subtype, namely, tremulous Parkinson’s disease with a manifestation of resting tremor alone. In order to confirm the existence of this subgroup of tremulous Parkinson’s disease and further investigate its morphological changes and the usefulness of magnetic resonance imaging, we collected 5 patients who typically have resting tremor for at least 8 years in the absence of other features of Parkinson’s disease. MRI was performed and the results of the images showed typical findings of Parkinson’s disease with smudging or decreased distance between substantia nigra and red nucleus. Quantitative analysis also demonstrated a significant decrease of the above-noted distance when the resting tremor group was compared to the essential tremor group. Therefore, patients with an isolated resting tremor can have morphological abnormalities in addition to functional disturbances shown by positron emission tomography. To our knowledge, this is the first paper to report that resting tremor is a variant of Parkinson’s disease rather than essential tremor, by using a double-blind method, with magnetic resonance imaging to support. Keywords:
Parkinson’s disease; Essential tremor; Magnetic resonance imaging; Resting tremor; Substantia nigra
1. Introduction Parkinson’s disease (PD) is an idiopathic, relentlessly progressive neurological disorder manifested clinically by resting tremor, bradykinesia, rigidity and postural instability. Within it, there are different subgroups with relatively specific clinical manifestations (Jankovic et al., 1990; Stacy et al., 1992). For example, several investigations have now suggested that patients with tremor as the dominant parkinsonian symptom generally have less bradykinesia and slower progression of disease (Jankovic et al., 1990; Stacy and Jankovic, 1992). One of the intriguing questions is whether the different subgroups represent variations of the same disease, namely PD, or are etiologically distinct entities. Another controversial issue is whether an isolated * Corresponding
author.
Tel.:
07-3461026.
0022-510X/95/$09.50 0 1995 Elsevier SSDI 0022-510X(95)00033-X
Science
B.V. All rights
reserved
resting tremor is etiologically related to PD or essential tremor (ET). Recently, magnetic resonance imaging (MRI) has proved to be a valuable diagnostic tool in the evaluation of PD and Parkinson plus syndrome (Duguid et al., 1986; He&ens and Riederer, 1986; Braffman et al., 1988; Stern et al., 1992; Olanow, 1992). In an attempt to answer the above question, we collected 5 patients who had resting tremor for at least 8 years, without other parkinsonian features, such as rigidity, bradykinesia and postural instability, and evaluated them with MRI.
2. Materials
and methods
Materials Five patients (aged 70, 68, 65, 67, and 6.51 were included in this study. They all presented with a 3-5
216
M.-H.
Chang
et al. /Journal
of the Neurological
Hz resting tremor (RT), with a duration of at least 8 years, most evident when seated or lying relaxed. Upon clinical examinations, they had resting tremor alone, without other parkinsonian features, for example, rigidity and akinesia. Patients with manifestations of more than a tremor were excluded. The selection criteria of patients were described in detail by Brooks et al. (1992). We also studied 10 age-matched patients with essential tremor (ET) for over 10 years. The clinical diagnosis of ET is based on a prolonged history of 4-9 Hz postural or kinetic upper limb or head tremor which could not be attributed to any other neurological or systemic disorders. A positive family history of similar tremor is not essential for the diagnosis. Methods A high field strength (1.5 T) MR system (General Electric Medical Systems) was utilized for all studies. Both Tl- and T2-weighted images of axial views were obtained. Tl-weighted images were obtained using a spin echo sequence with a repetition time (TRl of 500 ms and an echo time of 16 ms (Tl: TR/TE: 500/16). T2-weighted image used a repetition time of 5300 ms and an echo time of 85 ms (T2: TR/TE 5300/85). Each scan represented a 5-mm thick sampling volume. An image matrix of 512 *256 and flow compensation gradients were used. The angle of the scan through the midbrain was O-20 degrees positive to the inferior orbito-meatal line. All scans were interpreted by two neuroradiologists who were blinded to the diagnosis. Qualitatively, two neuroradiologists determined the width of the hypersignal band between the red nucleus (RN) and substantia nigra (SN) pars reticularis and putaminal intensity by direct visualization. Putaminal intensity is graded on a O-3 scale, grade 0 indicating no hypointensity and grade 1 indicating hypointensity limited to the lateral margin of the putamen. Grade 2 for hypointensity extends through part of body of putamen and grade 3 represents hypointensity throughout the entire putamen. Quantitatively, the width of the pars compacta (PC) signal in RT patients and the ET group were measured on the basis of the method described by Braffman et al. (1988) and Stern et al. (1992) and Table 1 Summarized results of physical findings. limb; RL: right lower limb; 4 : decrease; Patient
No.
I: intermediate group; P: pure no: absent; yes: present.
Age (yrs)
Disease duration (yrs)
Progression involvement
1 (I) 2 (I)
70 68
10 13
3 (P) 4 (P) 5 (P)
65 67 65
9 8 10
LU-LL-tRU LU-LL-tRU +RL RL-LL RL-tLL both legs
and limb
Sciences 130 (1995)
215-219
each side was independently determined. Student’s t test was applied to compare the difference in width of pars compacta (PC) between the RT and ET groups.
3. Results Physical findings All 5 patients had a typical resting tremor, either confined to the lower limbs or involving both upper and lower limbs. They did not fulfil the diagnostic criteria, described by Brooks et al., for clinical diagnosis of PD (Brooks et al., 19921, although additional soft signs of parkinsonism, for example, reduced arm swing, were present in patient 1 and 2. However, in spite of the decreased associative movement, none had evidence of bradykinesia on detailed bedside testing. Furthermore, the above 2 patients also had a low-amplitude 4-9 Hz postural tremor of the affected limbs. Consequently, in contrast to the pure resting tremor group, these 2 patients were put into an intermediate group with prominent resting tremor and minimal postural component. Asymmetry in manifestations and severity were another prominent features. Patient 1 and 3 had response to L-dopa but neither of them responded to propranolol. In spite of the long duration of RT, there was, however, no development of other parkinsonian features. The results are summarized in Table 1. MRI findings Qualitative analysis MRI of all 5 patients, including the pure resting tremor and intermediate groups, demonstrated a reduction of the high signal area separating the red nucleus (RN) and substantia nigra (SN), shown in Fig. 1 and Table 2. In addition, MRI of patient 1 and 3 showed abnormally decreased signal intensity in the lateral substantia nigra. However, the MRI findings were normal in 9 patients with essential tremor except for a patient whose MRI findings were interpreted as parkinsonian patient. Furthermore, quantitative analysis of this patient were also classified
resting
group;
LU:
left upper
limb;
LL: left lower
limb;
RU:
Associative movement
Froment
J left -1 left
no yes
response to madopar no response to both
normal normal normal
no no no
response to madopar no response to both no response to both
sign
response to madopar propranolol
right or
upper
M.-H.
Chang
et al./Joumal
of the Neurological
Sciences I30 (1995)
215-219
217
with left (p < 0.05) and right (p < 0.005) and the summarized results were shown in Table 2.
4. Discussion Rapoport et al. (1990a,, 1990b) first reported a patient with combined resting-postural tremor of lower limbs and concluded that the resting tremor in this patient represented an as yet undescribed manifestation of essential tremor. Then, Rajput and Rozdilsky (1990) argued that this resting tremor is consequent to coexisting PD in essential tremor. Therefore, the etiology of this resting tremor is still a confused issue. Recently, several studies demonstrated that variable expressions of PD exist (Jankovic et al., 1990; Stacy and Jankovic, 1992). The study by Jankovic et al. (1990) supported the existence of at least 2 clinical subtypes of PD, the tremor-dominant and the postural instability and gait difficulty subtype. The tremor-dominant subtype may have mild parkinsonian features, such as bradykinesia or rigidity appearing in his clinical course. However, in clinical practice, patients manifesting as isolated resting tremor with or without other soft parkinsonian signs are not uncommonly seen. Hallett (1986) described a number of patients who have typically appearing tremor at rest for as long as 20 or 30 years without the development of other parkinsonian signs or symptoms and the etiology of this tremor in these patients is still obscure and debatable. To date, no patients with isolated resting tremor have had autopsy, so it remains unclear whether these subjects have the Lewy body nigral degeneration that is the pathological hallmark of sporadic PD. Therefore, whether the etiology of isolated resting tremor is best ascribed to PD or ET is still in dispute. The diagnosis of PD is traditionally made on clinical examination. Computed tomography (CT) scans appear normal or show mild, non-specific enlargement of the ventricles or sulci. Recently, MRI allows in vivo brain imaging and biochemical analysis and has been used to evaluate patients with parkinsonism and has become to be a reliable laboratory marker available in the sugges-
Fig. 1. TZ-weighted image (TR/TE: 5300,435 ms) of patient 2 (intermediate group) demonstrates markedly decreased distance between substantia nigra and red nucleus (arrow). The measured width is left 1.73 and right 1.68.
in the parkinsonian range with a mean width, right 2.10 and left 2.04. Putaminal intensity were all graded as 0 in pure resting tremor, intermediate and ET patients.
Quantitative
analysis
The means and standard deviations of pure resting tremor patients were 2.08 k 0.035 on the left side and 1.997 * 0.023 on the right and in the intermediate group, 1.82 + 0.127 on the left and 1.715 k 0.049 on the right. In contrast to the above two groups, the means and standard deviations of the ET group are 2.732 & 0.291 on the left and 2.747 + 0.254 on the right. When comparing the width of PC between pure RT and ET group, significant decrease was found on both sides in the pure RT group (r-l < 0.0001 on the left side and p < 0.00005 on the right side). A significant decrease was also found when comparing the intermediate with the ET group (p < 0.00005 on the left side and p < 0.00001 on the right side). In a comparison between the pure RT and the intermediate group, there was also a significant decrease in the intermediate group
Table 2 MRI findings. I: intermediate group; nigra and red nucleus; b: hypointensity Qualitative Patient 1 (I)
2 (I) 3 (PI 4 (P) 5(P)
P: pure resting in the lateral
group; grade 0: normal substantia nigra.
putaminal
analysis No.
density;
a: narrowing Quantitative
Images (a orb) a and b a a and b a a
findings
of the distance analysis:
between
Width
Putaminal intensity (grade O-3)
left
right
grade grade grade grade grade
1.91 1.73 2.04 2.10 2.10
1.75 1.68 2.01 1.97 2.01
0 0 0 0 0
substantia
of pars compacta
218
M.-H.
Chang
et al. /Journal
of the Neurological
tion of PD (Duguid et al., 1986; Herfkens and Riederer, 1986; Braffman et al., 1988; Stern et al., 1992; Olanow, 1992). The important role of MRI in assessing patients with parkinsonism relates to its capacity to detect iron (He&ens and Riederer, 1986; Olanow, 1992). Iron can decrease T2 relaxation time, which appears as a hypointense signal on high-field strength MRI when performed with heavy T2-weighted technique. In normal adults, MRI shows well-defined areas of signal hypointensity in the globus pallidus, substantia nigra pars reticularis, red nucleus and dentate nucleus of the cerebellum. These areas correlates well with regions of ferric iron deposition as determined by Perls’ stain (He&ens and Riederer, 1986; Olanow, 1992). Because the alteration in iron deposition might contribute to the pathogenesis of PD, MRI may possibly be useful in evaluating PD. Based on previous reports, typical features of PD on MRI include: consistent smudging or narrowing of the area of high signal separating the red nucleus and the substantia nigra (Duguid et al., 1986; He&ens and Riederer, 1986; Braffman et al., 1988; Stern et al., 1992; Olanow, 1992). The above characteristic findings are well demonstrated in our study by qualitative and quantitative analysis. The possible explanation for the above features is that iron abnormally accumulates in the pars compacta of substantia nigra, causing a signal attenuation in the region that formerly had a high signal. Our patients had a typical resting tremor, with or without milder postural component, in the absence of other parkinsonian features. Images studies are consistent with the MRI features of PD, in both pure resting tremor and intermediate groups. Therefore, we postulate that isolated resting tremor is a subgroup of PD, rather than a variant of ET. Currently, we are unable to predict whether our patients with resting tremor will eventually develop the full clinical pictures of PD. However, the duration of the tremor in our patients was over 8 years without development of bradykinesia, implying that the clinical course is more benign and has a manifestation limited to the tremor only. Taking into account the low mortality and slow progression of patients with RT, autopsy is not easily available and furthermore, it is difficult to determine whether its etiology is due to PD or ET, simply based on clinical feature. From our study, MRI possibly becomes to be a sensitive and useful technique in premortal differentiation between PD and ET. In addition, the resting tremor group was clinically divided into pure resting tremor and intermediate groups. The width of PC in the intermediate group was significantly decreased compared with that in the pure resting tremor patients. This finding is possibly related to the long duration of the tremor and disease severity resulting in a further decrease of the width of PC. In any case, the scans of the intermediate group are similar to those of PD than are those of the ET group.
Sciences 130 (1995)
215-219
The only ET patient to show a reduced width of PC to the PD range developed bradykinesic finger movement in a recent follow-up. However, no other parkinsonian features became apparent. It is therefore necessary to closely observe the subsequent clinical features suggestive of PD occur. Recently positron emission tomography (PET) has enabled the functional integrity of nigrostriatal dopaminergic terminals to be assessed in vivo by measuring striatal 6-[i8F]fluorodopa uptake (Brooks et al., 1990). In patients with clinically diagnosed PD, putamen fluorodopa uptake is reduced, on average to around 50% of normal levels. Therefore, measurement of putamen fluorodopa uptake provides a sensitive means of detecting the presence of dysfunction of the nigrostriatal dopaminergic system. Brooks et al. utilized the above method and studied patients with isolated rest tremor (Brooks et al., 1992). Their finding of a selective reduction in putamen fluorodopa uptake to the PD level in patients with isolated rest tremor would favor the existence of the entity “tremulous parkinsonian disease”. PET scans are less popular than MRI, which is easily available in many countries now. We today use MRI to study our resting tremor patients. The results also demonstrate that MRI is sensitive enough to detect PD and is a useful technique in confirming the existence of benign tremulous PD. Therefore, we conclude that an isolated resting tremor is confirmed to be a variant of PD and furthermore, has morphological abnormalities in addition to the functional disturbances documented by PET scans. Despite the presence of laboratory evidences supporting isolated resting tremor as a variant of PD, it remains, however, to be seen whether our resting tremor patients will prove to have the Lewy body nigral degeneration at autopsy that characterizes sporadic PD.
References Braffman, B.H., Grossman, R.I., Goldberg, HI., Stern, M.B., Hurtig, H.I., Hackney, D.B. et al. (1988) MR imaging of Parkinson disease with spin-echo and gradient-echo sequences. AJNR, 9: 1093-1099. Brooks, D.J., Ibanez, V., Sawle, G.V. et al. (1990) Differing patterns of striatal F-dopa uptake in Parkinson disease, multiple system atrophy and progressive supranuclear palsy. Ann. Neurol., 28: 547-555. Brooks, D.J., Playford, E.D., Ibanez, V., Sawle, G.V., Thompson, P.D., Findley, L.J. and Marsden, C.D. (1992) Isolated tremor and disruption of the nigrostriatal dopaminergic system: a F-dopa PET study. Neurology, 42: 1.554-1560. Duguid, J.R., De La Paz, R. and DeGroot, J. (1986) Magnetic resonance imaging of the midbrain in Parkinson’s disease. Ann. Neurol., 20: 744-747. Hallett, M. (1986) Differential diagnosis of tremor. In: Vinken, P.J., Bruyn, G.W. and Klawans, H.L. (Eds.), Handbook of Clinical Neurology: Extrapyramidal Disorders, revised series 5, Elsevier, Amsterdam, pp. 583-595.
M.-H.
Chang
et al. /Journal
of the Neurological
Herfkens, R. and Riederer, S. (1986) Parkinson plus syndrome: diagnosis using high field MR imaging of brain iron. Radiology, 159: 493-498. Jankovic, J., McDermott, M., Carter, J., Gauthier, S., Goetz, C., Golbe, L. et al. (1990) Variable expression of Parkinson’s disease: a base-line analysis of DATATOP cohort. Neurology, 40: 15291534. Olanow, C.W. (1992) Magnetic resonance imaging in parkinsonism. Neural. Clin., 10: 405-420. Rajput, A.H. and Rozdilsky, B. (1990) Essential leg tremor. Neurology, 40: 1909.
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219
Rapoport, A., Sarova, I. and Braun, H. (1990a) Combined restingpostural tremor of lower limbs: another essential tremor variant. Neurology, 40: 1006. Rapoport, A., Sarova, I. and Braun, H. (1990b) Reply to essential leg tremor. Neurology, 40: 1909-1910. Stacy, M. and Jankovic, J. (1992) Differential diagnosis of parkioson’s disease and the parkinsonism plus syndrome. Neural. Clin., 10: 341-359. Stern, M.B., Braffman, B.H., Skolnick, B.E., Hartig, H.I. and Grossman, R.I. (1992) Magnetic resonance imaging in Parkinson’s disease and parkinsonian syndrome. Neurology, 39: 1524-1526.
OF THE
NEUROLOGICAL SCIENCES
ELSEVIER
Journal
of the Neurological
Sciences
130 (1995)
215-219
Case report
Resting tremor only: a variant of Parkinson’s disease or of essential tremor Ming-Hong a Section
Chang a2* , Tso-Wen Chang ‘, Ping-Hong
Lai b, Chern-Guey
of Neurology, Veterans General Hospital-Kaohsiung, No 386, Ta-Chung 1st Road, Kaohsiung, b Department of Radiology, Veterans General Hospital-Kaohsiung, Kaohsiung, Taiwan ’ Department of Neurology, Tzu-Chi Buddhist General Hospital, Hualien, Taiwan
Sy b
Taiwan
Received 18 August 1994;revised 3 January 1995;accepted 22 January 1995
Abstract Resting tremor is one of the characteristic features of Parkinson’s disease. However, there are a number of patients who typically have resting tremor alone for at least 5 years without development of other parkinsonian signs or symptoms. The etiology of an isolated resting tremor is still obscure. Recently, positron emission tomography was used to study these patients with isolated resting tremor, and demonstrated a markedly decreased striatal uptake of fluoro-dopa to the range of Parkinson’s disease. These findings suggested the existence of a separate subtype, namely, tremulous Parkinson’s disease with a manifestation of resting tremor alone. In order to confirm the existence of this subgroup of tremulous Parkinson’s disease and further investigate its morphological changes and the usefulness of magnetic resonance imaging, we collected 5 patients who typically have resting tremor for at least 8 years in the absence of other features of Parkinson’s disease. MRI was performed and the results of the images showed typical findings of Parkinson’s disease with smudging or decreased distance between substantia nigra and red nucleus. Quantitative analysis also demonstrated a significant decrease of the above-noted distance when the resting tremor group was compared to the essential tremor group. Therefore, patients with an isolated resting tremor can have morphological abnormalities in addition to functional disturbances shown by positron emission tomography. To our knowledge, this is the first paper to report that resting tremor is a variant of Parkinson’s disease rather than essential tremor, by using a double-blind method, with magnetic resonance imaging to support. Keywords:
Parkinson’s disease; Essential tremor; Magnetic resonance imaging; Resting tremor; Substantia nigra
1. Introduction Parkinson’s disease (PD) is an idiopathic, relentlessly progressive neurological disorder manifested clinically by resting tremor, bradykinesia, rigidity and postural instability. Within it, there are different subgroups with relatively specific clinical manifestations (Jankovic et al., 1990; Stacy et al., 1992). For example, several investigations have now suggested that patients with tremor as the dominant parkinsonian symptom generally have less bradykinesia and slower progression of disease (Jankovic et al., 1990; Stacy and Jankovic, 1992). One of the intriguing questions is whether the different subgroups represent variations of the same disease, namely PD, or are etiologically distinct entities. Another controversial issue is whether an isolated * Corresponding
author.
Tel.:
07-3461026.
0022-510X/95/$09.50 0 1995 Elsevier SSDI 0022-510X(95)00033-X
Science
B.V. All rights
reserved
resting tremor is etiologically related to PD or essential tremor (ET). Recently, magnetic resonance imaging (MRI) has proved to be a valuable diagnostic tool in the evaluation of PD and Parkinson plus syndrome (Duguid et al., 1986; He&ens and Riederer, 1986; Braffman et al., 1988; Stern et al., 1992; Olanow, 1992). In an attempt to answer the above question, we collected 5 patients who had resting tremor for at least 8 years, without other parkinsonian features, such as rigidity, bradykinesia and postural instability, and evaluated them with MRI.
2. Materials
and methods
Materials Five patients (aged 70, 68, 65, 67, and 6.51 were included in this study. They all presented with a 3-5
216
M.-H.
Chang
et al. /Journal
of the Neurological
Hz resting tremor (RT), with a duration of at least 8 years, most evident when seated or lying relaxed. Upon clinical examinations, they had resting tremor alone, without other parkinsonian features, for example, rigidity and akinesia. Patients with manifestations of more than a tremor were excluded. The selection criteria of patients were described in detail by Brooks et al. (1992). We also studied 10 age-matched patients with essential tremor (ET) for over 10 years. The clinical diagnosis of ET is based on a prolonged history of 4-9 Hz postural or kinetic upper limb or head tremor which could not be attributed to any other neurological or systemic disorders. A positive family history of similar tremor is not essential for the diagnosis. Methods A high field strength (1.5 T) MR system (General Electric Medical Systems) was utilized for all studies. Both Tl- and T2-weighted images of axial views were obtained. Tl-weighted images were obtained using a spin echo sequence with a repetition time (TRl of 500 ms and an echo time of 16 ms (Tl: TR/TE: 500/16). T2-weighted image used a repetition time of 5300 ms and an echo time of 85 ms (T2: TR/TE 5300/85). Each scan represented a 5-mm thick sampling volume. An image matrix of 512 *256 and flow compensation gradients were used. The angle of the scan through the midbrain was O-20 degrees positive to the inferior orbito-meatal line. All scans were interpreted by two neuroradiologists who were blinded to the diagnosis. Qualitatively, two neuroradiologists determined the width of the hypersignal band between the red nucleus (RN) and substantia nigra (SN) pars reticularis and putaminal intensity by direct visualization. Putaminal intensity is graded on a O-3 scale, grade 0 indicating no hypointensity and grade 1 indicating hypointensity limited to the lateral margin of the putamen. Grade 2 for hypointensity extends through part of body of putamen and grade 3 represents hypointensity throughout the entire putamen. Quantitatively, the width of the pars compacta (PC) signal in RT patients and the ET group were measured on the basis of the method described by Braffman et al. (1988) and Stern et al. (1992) and Table 1 Summarized results of physical findings. limb; RL: right lower limb; 4 : decrease; Patient
No.
I: intermediate group; P: pure no: absent; yes: present.
Age (yrs)
Disease duration (yrs)
Progression involvement
1 (I) 2 (I)
70 68
10 13
3 (P) 4 (P) 5 (P)
65 67 65
9 8 10
LU-LL-tRU LU-LL-tRU +RL RL-LL RL-tLL both legs
and limb
Sciences 130 (1995)
215-219
each side was independently determined. Student’s t test was applied to compare the difference in width of pars compacta (PC) between the RT and ET groups.
3. Results Physical findings All 5 patients had a typical resting tremor, either confined to the lower limbs or involving both upper and lower limbs. They did not fulfil the diagnostic criteria, described by Brooks et al., for clinical diagnosis of PD (Brooks et al., 19921, although additional soft signs of parkinsonism, for example, reduced arm swing, were present in patient 1 and 2. However, in spite of the decreased associative movement, none had evidence of bradykinesia on detailed bedside testing. Furthermore, the above 2 patients also had a low-amplitude 4-9 Hz postural tremor of the affected limbs. Consequently, in contrast to the pure resting tremor group, these 2 patients were put into an intermediate group with prominent resting tremor and minimal postural component. Asymmetry in manifestations and severity were another prominent features. Patient 1 and 3 had response to L-dopa but neither of them responded to propranolol. In spite of the long duration of RT, there was, however, no development of other parkinsonian features. The results are summarized in Table 1. MRI findings Qualitative analysis MRI of all 5 patients, including the pure resting tremor and intermediate groups, demonstrated a reduction of the high signal area separating the red nucleus (RN) and substantia nigra (SN), shown in Fig. 1 and Table 2. In addition, MRI of patient 1 and 3 showed abnormally decreased signal intensity in the lateral substantia nigra. However, the MRI findings were normal in 9 patients with essential tremor except for a patient whose MRI findings were interpreted as parkinsonian patient. Furthermore, quantitative analysis of this patient were also classified
resting
group;
LU:
left upper
limb;
LL: left lower
limb;
RU:
Associative movement
Froment
J left -1 left
no yes
response to madopar no response to both
normal normal normal
no no no
response to madopar no response to both no response to both
sign
response to madopar propranolol
right or
upper
M.-H.
Chang
et al./Joumal
of the Neurological
Sciences I30 (1995)
215-219
217
with left (p < 0.05) and right (p < 0.005) and the summarized results were shown in Table 2.
4. Discussion Rapoport et al. (1990a,, 1990b) first reported a patient with combined resting-postural tremor of lower limbs and concluded that the resting tremor in this patient represented an as yet undescribed manifestation of essential tremor. Then, Rajput and Rozdilsky (1990) argued that this resting tremor is consequent to coexisting PD in essential tremor. Therefore, the etiology of this resting tremor is still a confused issue. Recently, several studies demonstrated that variable expressions of PD exist (Jankovic et al., 1990; Stacy and Jankovic, 1992). The study by Jankovic et al. (1990) supported the existence of at least 2 clinical subtypes of PD, the tremor-dominant and the postural instability and gait difficulty subtype. The tremor-dominant subtype may have mild parkinsonian features, such as bradykinesia or rigidity appearing in his clinical course. However, in clinical practice, patients manifesting as isolated resting tremor with or without other soft parkinsonian signs are not uncommonly seen. Hallett (1986) described a number of patients who have typically appearing tremor at rest for as long as 20 or 30 years without the development of other parkinsonian signs or symptoms and the etiology of this tremor in these patients is still obscure and debatable. To date, no patients with isolated resting tremor have had autopsy, so it remains unclear whether these subjects have the Lewy body nigral degeneration that is the pathological hallmark of sporadic PD. Therefore, whether the etiology of isolated resting tremor is best ascribed to PD or ET is still in dispute. The diagnosis of PD is traditionally made on clinical examination. Computed tomography (CT) scans appear normal or show mild, non-specific enlargement of the ventricles or sulci. Recently, MRI allows in vivo brain imaging and biochemical analysis and has been used to evaluate patients with parkinsonism and has become to be a reliable laboratory marker available in the sugges-
Fig. 1. TZ-weighted image (TR/TE: 5300,435 ms) of patient 2 (intermediate group) demonstrates markedly decreased distance between substantia nigra and red nucleus (arrow). The measured width is left 1.73 and right 1.68.
in the parkinsonian range with a mean width, right 2.10 and left 2.04. Putaminal intensity were all graded as 0 in pure resting tremor, intermediate and ET patients.
Quantitative
analysis
The means and standard deviations of pure resting tremor patients were 2.08 k 0.035 on the left side and 1.997 * 0.023 on the right and in the intermediate group, 1.82 + 0.127 on the left and 1.715 k 0.049 on the right. In contrast to the above two groups, the means and standard deviations of the ET group are 2.732 & 0.291 on the left and 2.747 + 0.254 on the right. When comparing the width of PC between pure RT and ET group, significant decrease was found on both sides in the pure RT group (r-l < 0.0001 on the left side and p < 0.00005 on the right side). A significant decrease was also found when comparing the intermediate with the ET group (p < 0.00005 on the left side and p < 0.00001 on the right side). In a comparison between the pure RT and the intermediate group, there was also a significant decrease in the intermediate group
Table 2 MRI findings. I: intermediate group; nigra and red nucleus; b: hypointensity Qualitative Patient 1 (I)
2 (I) 3 (PI 4 (P) 5(P)
P: pure resting in the lateral
group; grade 0: normal substantia nigra.
putaminal
analysis No.
density;
a: narrowing Quantitative
Images (a orb) a and b a a and b a a
findings
of the distance analysis:
between
Width
Putaminal intensity (grade O-3)
left
right
grade grade grade grade grade
1.91 1.73 2.04 2.10 2.10
1.75 1.68 2.01 1.97 2.01
0 0 0 0 0
substantia
of pars compacta
218
M.-H.
Chang
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tion of PD (Duguid et al., 1986; Herfkens and Riederer, 1986; Braffman et al., 1988; Stern et al., 1992; Olanow, 1992). The important role of MRI in assessing patients with parkinsonism relates to its capacity to detect iron (He&ens and Riederer, 1986; Olanow, 1992). Iron can decrease T2 relaxation time, which appears as a hypointense signal on high-field strength MRI when performed with heavy T2-weighted technique. In normal adults, MRI shows well-defined areas of signal hypointensity in the globus pallidus, substantia nigra pars reticularis, red nucleus and dentate nucleus of the cerebellum. These areas correlates well with regions of ferric iron deposition as determined by Perls’ stain (He&ens and Riederer, 1986; Olanow, 1992). Because the alteration in iron deposition might contribute to the pathogenesis of PD, MRI may possibly be useful in evaluating PD. Based on previous reports, typical features of PD on MRI include: consistent smudging or narrowing of the area of high signal separating the red nucleus and the substantia nigra (Duguid et al., 1986; He&ens and Riederer, 1986; Braffman et al., 1988; Stern et al., 1992; Olanow, 1992). The above characteristic findings are well demonstrated in our study by qualitative and quantitative analysis. The possible explanation for the above features is that iron abnormally accumulates in the pars compacta of substantia nigra, causing a signal attenuation in the region that formerly had a high signal. Our patients had a typical resting tremor, with or without milder postural component, in the absence of other parkinsonian features. Images studies are consistent with the MRI features of PD, in both pure resting tremor and intermediate groups. Therefore, we postulate that isolated resting tremor is a subgroup of PD, rather than a variant of ET. Currently, we are unable to predict whether our patients with resting tremor will eventually develop the full clinical pictures of PD. However, the duration of the tremor in our patients was over 8 years without development of bradykinesia, implying that the clinical course is more benign and has a manifestation limited to the tremor only. Taking into account the low mortality and slow progression of patients with RT, autopsy is not easily available and furthermore, it is difficult to determine whether its etiology is due to PD or ET, simply based on clinical feature. From our study, MRI possibly becomes to be a sensitive and useful technique in premortal differentiation between PD and ET. In addition, the resting tremor group was clinically divided into pure resting tremor and intermediate groups. The width of PC in the intermediate group was significantly decreased compared with that in the pure resting tremor patients. This finding is possibly related to the long duration of the tremor and disease severity resulting in a further decrease of the width of PC. In any case, the scans of the intermediate group are similar to those of PD than are those of the ET group.
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The only ET patient to show a reduced width of PC to the PD range developed bradykinesic finger movement in a recent follow-up. However, no other parkinsonian features became apparent. It is therefore necessary to closely observe the subsequent clinical features suggestive of PD occur. Recently positron emission tomography (PET) has enabled the functional integrity of nigrostriatal dopaminergic terminals to be assessed in vivo by measuring striatal 6-[i8F]fluorodopa uptake (Brooks et al., 1990). In patients with clinically diagnosed PD, putamen fluorodopa uptake is reduced, on average to around 50% of normal levels. Therefore, measurement of putamen fluorodopa uptake provides a sensitive means of detecting the presence of dysfunction of the nigrostriatal dopaminergic system. Brooks et al. utilized the above method and studied patients with isolated rest tremor (Brooks et al., 1992). Their finding of a selective reduction in putamen fluorodopa uptake to the PD level in patients with isolated rest tremor would favor the existence of the entity “tremulous parkinsonian disease”. PET scans are less popular than MRI, which is easily available in many countries now. We today use MRI to study our resting tremor patients. The results also demonstrate that MRI is sensitive enough to detect PD and is a useful technique in confirming the existence of benign tremulous PD. Therefore, we conclude that an isolated resting tremor is confirmed to be a variant of PD and furthermore, has morphological abnormalities in addition to the functional disturbances documented by PET scans. Despite the presence of laboratory evidences supporting isolated resting tremor as a variant of PD, it remains, however, to be seen whether our resting tremor patients will prove to have the Lewy body nigral degeneration at autopsy that characterizes sporadic PD.
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