Cerebral Blood Flow Deficits in Hereditary Essential Myoclonus Florence Delecluse, MD; Gunhild Waldemar, MD; Svein Vestermark, MD; Olaf B. Paulson, MD, PhD Hereditary essential myoclonus is a dissegmental myoclonus is the sole clinical abnormality and whose cause is unknown. It is characterized by an early onset, a benign course, an autosomal dominant pattern of inheritance, the absence of any other neurologic dysfunction, and normal results of auxiliary tests. Cerebral blood flow single-photon emission computed to¬ mography (SPECT) and xenon 133 or [technetium 99m]-d, ¿-hexamethylpropyleneamineoxime (HMPAO), which revealed pertinent focal cerebral blood flow asymmetries. studies of a father and son with this disease showed a cortical blood flow reduction contralateral to the myoclonus symptoms. We postulate the cause to be a focal unilateral subcortical cerebral lesion, either in the basal ganglia or in the brain stem, with subsequent cortical deafferentation. (Arch Neurol. 1992 ;49:179-182) CASE 1.—A 6-year-old boy had exhibited normal psychomotor development until his third year, when he developed muscle twitches and jerks affecting his right arm. These twitches and jerks were particularly pronounced during carefully controlled mo¬ tor activity, such as drinking from a glass. Everyday activities, such as writing, draw¬ ing, and playing with toys, were difficult to perform. These sudden, uncontrollable arm jerks could be suppressed by strong volun¬ tary muscle activity. They occurred neither during sleep nor at rest and did not interfere with standing or walking. Computed tomog¬ raphy and physical, mental, and neurologic examinations otherwise yielded normal find¬ ings. There has been no disease progression since age 5 years. CASE 2. —The 40-year-old father of patient 1 has had muscle twitches and jerks since childhood. Jerks of his right upper limb have rendered the manipulation of small objects and drinking glasses difficult. His jerks also could be suppressed by strong muscular ac¬ tivity and disappeared during sleep and rest. The ingestion of small quantities of alcohol, however, had no effect. No other signs of neurologic involvement were noted. His computed tomographic scan was normal. Be¬ cause of these jerks during controlled activi¬ ty, this patient has abandoned social con¬ tacts, other than those that involve his ease in which XT ereditary essential myoclonus (HEM) is a rare but well-defined syndrome1'6 of unknown origin. It has an autosomal dominant pattern of trans¬ mission with incomplete penetrance7 and onset during childhood. It consists of myoclonic jerks in a proximal distri¬ bution, with no other signs of central nervous system involvement. All ancil¬ lary tests, such as electroencephalog¬ raphy (EEG), computed tomography, visual evoked potentials, and polymyography, yield normal results. To our knowledge, this is the first report of cerebral blood flow studies in HEM. Two members of a Scandinavian family with benign HEM spanning three generations were examined with Accepted for publication June 10,1991. From the Department of Neurology, Hopital Erasme, Brussels, Belgium (Dr Delecluse), and the Department of Neurology, Rigshospitalet (Drs Waldemar and Paulson), and the Department of Pediatrics, Glostrup Hospital (Dr Vestermark), Copenhagen, Denmark. Reprint requests to the Department of Neurology, Rigshospitalet, 9, Blegdamsveg, DK-2100 Copenhagen, Denmark (Dr Waldemar). REPORT OF CASES family. CASE 3.—The paternal grandfather of pa¬ tient 1 reportedly has the same problems. He was never able to write a letter because of these same right-sided jerks. This patient could not be included in our study, however, as all attempts at personal contact or exami¬ nation were refused. Downloaded From: http://archneur.jamanetwork.com/ by a UQ Library User on 06/16/2015 MATERIALS AND METHODS Regional cerebral blood flow (rCBF) was studied with a three-section brain-dedicated high-resolution SPECT system (Tomomatie 64, Medimatic, Hellerup, Denmark)" in the Department of Neurology, Rigshospitalet, Copenhagen, Denmark. In the father, rCBF was studied twice on the same day by two different techniques: the 133Xe-inhalation method and the ["Tcl-d.i-HMPAO tech¬ nique. Both studies were performed during rest without myoclonic activity. The 1S3Xeinhalation study was performed to obtain quantitative data, and the ["mTc]-(i,ZHMPAO study was performed to obtain high-resolution images of the distribution of rCBF. First, two 133Xe-inhalation studies were performed to obtain six horizontal sec¬ tions parallel to the canthomeatal plane. Each study lasted 4.5 minutes, during which Xe was inhaled from a closed system with an initial concentration of 740 mBq/L, during the first 1.5 minutes. The arterial input to the brain was estimated from the lung curve pro¬ file obtained from a single stationary scintil¬ lation detector placed above the apex of the right lung. The calculation of absolute cere¬ bral blood flow values from the distribution of the 1,í,íXe in the brain has been described in detail previously.'1 With this technique, the final in-plane resolution is 17 to 20 mm (full width at half maximum), and the section thickness is 20 mm. In addition, SPECT was used to study the isotope distribution after the intravenous injection of 1.1 Gega-Bequerel of [99"Tc]-d,¡-HMPAO (Ceretec, Amersham, London, England). First, 60second data acquisitions were performed in six different positions with the use of a lowresolution collimator. Then, three high-reso¬ lution data acquisitions were performed to obtain nine sections parallel to the cantho¬ meatal plane. These high-resolution images were normalized to the cerebellum and cor¬ rected for back-diffusion of the tracer by a linearization procedure that has been de¬ scribed in detail previously.10 With the ["Tcl-oy-HMPAO technique, the final in- Fig 1.—Xenon Xe 133-inhalation single-photon emission computed tomographic scan of a 40-year-old man (patient 2) with essential myoclonus. Four sections parallel to the canthomeatal (CM) plane are shown. The left hemisphere is shown at left. The color scale indicates absolute blood flow values in milliliters per 100 g per minute. Fig 3.—Technetium Tc 99m-d,/-hexamethylpropyleneamineoxime (HMPAO) and low-resolution single-photon emission computed tomo¬ graphic scans of a 40-year-old man (patient 2, left) and his 6-year-old son (patient 1, right). The left hemisphere is shown at left. One section located approximately 5 cm above the canthomeatal plane Is shown. Fig 2.— Technetium Tc 99m-d,/-hexamethylpropyleneamineoxime (HMPAO) and high-resolution single-photon emission computed tomo¬ graphic scans of a 40-year-old man (patient 2) with essential myoclonus. The left hemisphere is shown at left. Three sections 5, 7, and 9 cm above the canthomeatal (CM) plane are shown. The color scale indicates regional cerebral blood flow given in percent relative to the cerebellum. plane resolution is 9 to 10 mm (full width at half maximum), and the section thickness is 10 mm. In the case of the 6-year-old son, only a low-resolution [99nTcl-d,Z-HMPAO study was technically possible. Regional cerebral blood flow, or mean count rates, was calculat¬ ed in several regions of interest, as described elsewhere.11 The side-to-side asymmetry ra¬ tio for blood flow in a region of interest was defined as the difference in count rate or rCBF between the right and left regions of interest taken as a percent of the higher of the two. A side-to-side asymmetry ratio de¬ viating more than 2 SDs from that of control subjects of the same age11 was considered abnormal. RESULTS The results of the 133Xe-inhalation study in the father are shown in the Table and in Fig 1. The mean cerebral blood flow values were 56 and 60 mL/ 100 g per minute in the left and right hemispheres, respectively. A marked reduction of rCBF was seen in the left frontal and temporal lobes. This reduc¬ tion of blood flow was associated with a crossed cerebellar diaschisis. The SPECT images from the highresolution rmTc]-(J,Z-HMPAO study are shown in Fig 2. These [*>mTc]-d,l- Downloaded From: http://archneur.jamanetwork.com/ by a UQ Library User on 06/16/2015 HMPAO images showed that the frontotemporal low-flow region extended into the parietal lobe as well. The iso¬ tope distribution in the basal ganglia and occipital lobes was normal (Table). An image section from the low-reso¬ lution study performed in the son is compared with that of the father in Fig 3. The isotope uptake was reduced in the left hemisphere in both patients. COMMENT Until the present, although a number of studies have been conducted about HEM, to our knowledge no biochemical, spheric cerebral lesion.12 The mecha¬ Regional Cerebral Blood Flow in a Father and Son With Essential Myoclonus* SAI, % Section Father CM + 1 cm -4.0 Region Xenon Xe133 study Cerebellum Cerebral hemisphere Superior frontal cortex Inferior frontal cortex CM + 7 cm CM + 5 cm CM + 5 cm CM + 7 cm Temporal cortex Superior occipital cortex CM + 5 cm Basal ganglia CM + 3 cm Frontotemporal ROI CM + 5 cm Frontotemporal ROI CM + 7 cm Frontotemporal ROI High-resolution [technetium Tc 99m]-d,/-HMPAO study CM + 5, 7 cm Midinferior temporal cortex Frontal ROI Parietal ROI CM + 5 cm Low-resolution [technetium Tc 99m]-d,/-HMPAO study CM + 5 cm Frontal ROI CM + 5 cm Temporal ROI CM + 5 cm Frontotemporal ROI Son 6.7t e.n 6.7f 11.Ot Huntington's disease,17 progressive su¬ pranuclear palsy,1819 neuroacanthocythosis,2" and even depression.21 Clinically, 13.Ot 11.Ot 15.Ot 8.3t 14.Ot 13.2t 4.9 3.6 8.2t 9.3t 5.8t Regional side-to-side asymmetry ratios (SAI) are given for cerebral blood flow values in selected regions of interest (ROI) from sections shown in Figs 1 through 3. HMPAO indicates hexamethylpropyleneamineoxime, * CM, canthomeatal. tSlgnificantly abnormal SAI (ie, deviating >2 SDs from mean SAI for control subjects of the same age)." pharmacologie, or clinical study has elu¬ cidated the pathophysiologic mecha¬ nism underlying this disease.4 To our knowledge, there are no published anatomopathologic correlates in this dis¬ ease with a benign course, and neither electrophysiologic nor radiologie stud¬ ies have disclosed any abnormalities. Only by certain clinical similarities with more common types of action myoclonus have some authors suspected a "bulbopontocerebellar dysfunction" to be a possible cause of HEM.'3 To our knowledge, this blood flow study is the first to provide a direct clue toward an understanding HEM. Both patients described herein had a clinical syndrome limited to right arm jerks, and both showed a relative hypoperfu¬ sion of the left cerebral hemisphere as¬ sociated with a crossed cerebellar diaschisis. In the father, this result was confirmed with two different tech¬ niques for the measurement of rCBF Both patients were studied during rest only, as the jerks were too short-lasting for an ictal study to be performed. These data would at first suggest that the underlying lesion causing these right arm jerks is an extensive contralateral cerebral hemispheric lesion, of perhaps a degenerative nature, as the flow deficit is not of a vascular distribu¬ tion. However, in our cases of HEM, as in other published cases,4,,i no focal le¬ sions or atrophy were demonstrated on a computed tomographic scan, nor were there any abnormalities on EEGs or VEPs. Logically, one would expect such an anatomic lesion of such vast cor- tical extent to have some kind of radiologic or electrophysiologic repercus¬ sion. Therefore, the unilateral hemispheric cerebral blood flow hypo¬ perfusion we observed cannot be attrib¬ uted to a vast cortical lesion. A more plausible explanation for this finding would be the existence of a small subcor¬ tical lesion in the midbrain, with a sec¬ ondary deafferentation of the ipsilateral frontal lobe as well as of the contralater¬ al cerebellar lobe. In our patients, the rCBF pattern in the midbrain was con¬ sidered normal. With the [""TcW.ZHMPAO technique, the resolution is sufficiently high to calculate side-toside differences in rCBF in many mid¬ brain structures. However, for statisti¬ cal reasons, a flow reduction in these areas must be severe to be significant.11 Therefore, although we found normal rCBF in the subcortical structures, a very mild flow reduction in these areas, in addition to the marked cortical flow reduction, could not be excluded. Deafferentation is a hypothetical mechanism that has mainly evolved from the study of diaschisis on cerebral blood flow and metabolism studies when acute hemispheric cerebral infarction was discovered to be linked with a de¬ crease of regional flow and metabolism in areas of the brain remote from the infarcted tissue. Diaschisis is defined as the temporary depression of function in an area remote from the site of the pri¬ mary injury. One of the first such de¬ scribed was the "crossed cerebellar diaschisis" with hypoperfusion of a cere¬ bellar lobe due to a contralateral hemi- Downloaded From: http://archneur.jamanetwork.com/ by a UQ Library User on 06/16/2015 nism invoked is of deafferentation, a functional transneural depression by deactivation of connecting neural path¬ 13 ways. This same mechanism has been used to explain other types of diaschisis, such as the ipsilateral parietal hypoper¬ fusion seen with thalamic14 or internal capsule10 lesions and the frontal hypo¬ perfusion that has been described in some cases of Parkinson's disease,16 frontal deafferentation has been the postulated cause of the multiple cogni¬ tive deficits described in association with these later diseases. It must be noted, however, that frontal hypoperfu¬ sion or hypometabolism can coexist with normal cognition,11 particularly in the healthy elderly person. In keeping with this hypothesis of a primary subcortical lesion as the origin of HEM, an analogy can be attempted between HEM and other types of subcortical myoclonic disease, such as seg¬ mentai myoclonus, which involves mus¬ cles or groups of muscle supplied by contiguous segments of the brain stem without EEG abnormalities. In their study of 18 cases of segmental branchial myoclonus, Jankovic and Pardo22 ob¬ served many possible causes and sus¬ pected that the underlying mechanism was abnormal discharges in the interneurons and motor neurons due to focal lesions of the inhibitory pathways, par¬ ticularly in the midbrain. Other central nervous system regions implicated in the pathophysiologic features of other types of subcortical myoclonus include the Guillain-Mollaret triangle in palatal myoclonus22 and other types of segmen¬ tal myoclonus,22,23 the substantia nigra and the dentate nucleus in progressive familial myoclonic epilepsy,24 the medul¬ lary reticular formation in reticular re¬ flex myoclonus,2" and the central pons in a case associated with ocular bobbing.26 In contrast, cortical myoclonus is usual¬ ly multifocal and associated with either an abnormal EEG or giant somatosensory visual evoked potentials.27,28 In conclusion, in these cases of HEM characterized by one-sided myoclonus, we have shown the existence of a con¬ tralateral cerebral blood flow hemi¬ spheric hypoperfusion. We believe that this finding can be best explained by a secondary deafferentation due to a small primary subcortical lesion, locat¬ ed in the brain stem or in the basal gan¬ glia, with this lesion being the funda¬ mental cause of HEM. This study was supported by grants from the Danish Medical Research Council and the Lundbeck Foundation, Copenhagen, Denmark. References 1. Daube JR, Peters HA. Hereditary essential myoclonus. Arch Neurol. 1966;15:587-591. 2. Mahloudji M, Pikielny RT. Hereditary essential myoclonus. Brain. 1967;90:669-674. 3. Korten JJ, Notermans SLH, Frenken CWGM, Gabreels FJM, Joosten EMG. Familial essential myoclonus. Brain. 1974;97:131-138. 4. Bressman S, Fahn S. Essential myoclonus. In: Fahn S, Marsden CD, Van Woert MH, eds. Advances in Neurology, Vol 43: Myoclonus. New York, NY: Raven Press; 1986:287-294. 5. Przuntek H, Muhr H. Essential familial myoclonus. J Neurol. 1983;230:153-162. 6. Lundemo G, Persson HE. Hereditary essential myoclonus. 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