A Transcranial Doppler Ultrasonography Study of Cerebrovascular CO2 Reactivity in Mitochondrial Encephalomyopathy
Background and Purpose To elucidate the pathogenic role of vascular involvement such as mitochondrial angiopathy in patients with mitochondrial encephalomyopathy (MEM), we used the transcranial Doppler sonography (TCD) method to detect impairment of cerebrovascular CO2 reactivity.
Methods The cerebral perfusion reserve in 13 MEM patients, including 6 with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) was studied by TCD for different CO2 partial pressures. For the parameter of mean flow velocity, the mean spatial Doppler frequency (fm) was obtained from the right and left middle cerebral arteries and basilar artery under conditions of normocapnia, hypercapnia, and hypocapnia in cases in which hyperventilation was possible. By fitting the obtained fm and the end-tidal CO2 partial pressure (Petco2) to the exponential formula fm=a×e(K×Petco2), where a is the theoretical fm at a Petco2 of 0 mm Hg, the parameter K, an index of CO2 reactivity, was calculated.
Results The K value was lower than control values at at least one site of the middle cerebral arteries and basilar artery of all patients with MELAS as well as the other MEM patients except for one patient with myoclonic epilepsy with ragged-red fiber and one with Kearns-Sayer syndrome.
Conclusions Our results suggest that there is a high incidence of impairment of cerebrovascular CO2 reactivity in MEM patients. Moreover, the noninvasive TCD method was found useful for evaluation of cerebral hemodynamics in MEM patients.
Recent clinical and histopathologic reports concerning MELAS suggest that certain cerebral circulatory and/or metabolic disorders refer to manifestations of strokelike episodes.1 2 3 4 However, few studies have used SPECT and PET to examine the functional aspects of cerebral hemodynamics for MELAS, and none have done so for the other types of MEM.5 6 7 8 9 10
A TCD CO2 reactivity assessment has been reported to be a valuable and noninvasive method for evaluation of cerebral hemodynamics. The usefulness of this method for examining cerebrovascular disorders in adults, but not yet in children, has recently been confirmed.11 12 13 14 15 16 17
The purpose of the present study was to evaluate cerebral hemodynamics and the vascular reserve in patients with MEM, including children.
Subjects and Methods
We examined 13 patients with MEM (8 males and 5 females) followed up at the Department of Pediatrics, Osaka University Medical School (age at examination, 5 to 23 years). Six patients were diagnosed with MELAS, 4 with CCOD, 1 with MERRF, 1 with KSS, and 1 was unclassified. Profiles of the patients are presented in Table 1⇓.
As pediatric patient control subjects, 6 patients (4 males and 2 females) were registered (age at examination, 5 to 12 years). Five of them had congenital heart diseases with almost normal to slightly low cardiac output (single ventricle and translocation of great arteries after an operation such as Fontan's procedure), and 1 had migraine without aura in the interictal state. None of these subjects showed either permanent neurological deficits or abnormal neuroradiological findings.
After demonstrative explanations of method, informed consent was obtained from the examinees or from their parents in the case of children.
The examination was performed when the clinical condition of both MEM patients and control patients was relatively stable. The examinees were made to relax and, in two cases, sedated mildly to moderately with oral sodium trichloroethylphosphate and intravenous thiopental sodium.
Blood flow velocity of the right and left MCAs and BA was obtained with the use of a pulse-gated TCD device (TC2-64B, 2 MHz, EME). Previously reported methods (Aaslid18 and Arnolds and von Reutern19 ) were used, in which the ultrasonic transducer was placed manually or attached to the head belt on the examinee's temporal bone (temporal approach) or below the occipital bone (transbasal approach). Sampling position and measurement depth were determined according to the location at which a maximal value with minimal noise and a typical laminal flow pattern were obtained.
Blood flow velocities were measured under the following conditions for each vessel: normocapnia, hypercapnia by inhalation of 5% CO2 gas (CO2 5%, O2 20%, N2 balance), and hypocapnia by hyperventilation in six cases (Table 2⇓). Petco2 was continuously monitored by an expired gas analyzer (1H21B, San-ei). The data sampling was started after Petco2 had stabilized under each condition (usually after 1 to 2 minutes) and continued for 1 to 2 minutes until at least three consecutive readings were obtained for each condition. After inhalation of CO2 gas or hyperventilation, breathing ambient air for 5 minutes was sufficient for subjects to return to their normal basal state. The frequency spectrum of the signals was analyzed by a fast Fourier transform wave-analyzing system (Echospec, Diagnostic Electronics Corp), after which the mean spatial Doppler frequency (fm, expressed in hertz) was calculated on-line.
In general, cerebral blood flow at a given Paco2 ranging from 25 to 60 mm Hg has been found to change along an exponential curve, as reported by Markwalder et al20 and other authors.12 13 21 22 Petco2 is convertible to Paco2 except for particular cardiorespiratory disorders.23 Therefore, by fitting fm and Petco2 to the exponential formula fm=a×e(K×Petco2) (Fig 1⇓), where a is the theoretical fm at a Petco2 of 0 mm Hg, the parameter K (per millimeter of mercury) could be calculated as an index of CO2 reactivity. Curves for the various K values are also illustrated in Fig 1⇓.
Blood pressure monitored intermittently during these examinations showed no significant fluctuation more than ±10% on average.
The results of routine TCD, SPECT, CT, and MRI of the 13 MEM patients are listed in Table 1⇑, and K values are presented in Table 2⇑. SPECT, CT, and MRI were performed less than 1 year before or after this study when the patients' clinical states were almost the same. The electroencephalographic study did not show any localization of epileptic discharge for any of the examinees.
Mean(±SD) K values for the MEM group were statistically smaller than those for the patient control group (P<.05, Wilcoxon unpaired t test): 21.8(±15.5)×10−3 versus 32.6(±4.7)×10−3 in MCAs and 24.8(±11.6)×10−3 versus 36.8(±7.4)×10−3 in the BA, although there was considerable variety among individual data in the MEM group. The distribution of the K values is shown in Fig 2⇓. The cutoff for K values in the control group was set at −1.5 SD, resulting in lower limits of 25.5×10−3 in MCAs and 26.2×10−3 in the BA, respectively. These were slightly lower than those of adult volunteers (mean[±SD] values in MCAs were 35[±5]×10−3 as obtained by Markwalder et al20 and 33[±5]×10−3 as obtained by Maeda et al12 ). For the MEM group, on the other hand, the mean K values were 21.1×10−3 in MCAs and 24.8×10−3 in the BA, and 16 of 24 (MCAs) and 6 of 13 (BA) of these data were below the lower limit.
No relationship could be established between the decrease in K values and abnormalities in either routine TCD or other neuroradiological findings.
MELAS Patients (Patients 1 to 6)
K values for patients 1, 2, 4, and 6 were clearly low, particularly in patient 2, the most severe case of early onset with diffuse brain atrophy and severe neurological deficits consequent to recurrent and intractable strokelike episodes. Examinations of SPECT and routine TCD in this case revealed marked and diffuse low perfusion. Patient 5, who had developed repeated strokelike episodes localized to the occipital lobe on either side with homonymous hemianopsia, atrophic changes on CT and MRI, and low-flow velocity in the bilateral posterior cerebral arteries on routine TCD, showed a slight decrease in K value in BA but not in bilateral MCAs. In patient 3, “total” K values, calculated from all the data including those for both hypercapnic and hypocapnic conditions, were within normal limits. However, under hypercapnic conditions she showed a poor increase in fm (Fig 3A⇓), which suggests a definite abnormality in CO2 reactivity. This patient was thought to have discrepant reactivities to hypercapnia and hypocapnia; a similar discrepancy was seen in the left MCA of patient 5 but for the other vessels. K values calculated separately for each condition were as follows (hypercapnia/hypocapnia, ×10−3): right MCA, 0.1/89.6; left MCA, 3.0/68.2; BA, 12.0/50.0 in patient 3; and right MCA, 31.2/54.0; left MCA, 1.5/68.8; BA, 35.4/21.6 in patient 5.
Other Patients (Patients 7 to 13)
Three patients with CCOD and one unclassified patient showed clearly decreased K values in at least one vessel. In particular, patient 7, a female with severe CCOD with onset at 5 years of age, showed markedly low K values in the bilateral MCAs. In patient 10, a woman with relatively mild CCOD accompanied by muscle weakness and hearing impairment but no mental retardation, K values were slightly lower than control values for adults. In patient 11, although data for the bilateral MCAs were not available because of the thick cranium, K values in the right cervical internal carotid artery and BA were only slightly above the lower limit of control values. No discrepancy between the reactivities to hypercapnia and hypocapnia was seen in patients 10, 11, and 13.
The usefulness of the CO2 reactivity method has been well established11 12 for adult patients with brain infarction, chronic hypertension, and cerebrovascular obstructive diseases but not for children. In the present study a decrease in K values was found in all six MELAS patients and most of the other MEM patients, suggesting a high incidence of abnormal cerebrovascular reactivity in MEM patients. “Normal” control data were not available because it was difficult to obtain a normal volunteer, and therefore we chose six subjects who had no neurological signs or symptoms as “patient” controls. We supposed that their K values would not be larger than those of normal control subjects and that overestimation of our results could be avoided. Indeed, the mean K value for control patients was almost equal to that for normal adult volunteers regardless of their age. We established a cutoff of −1.5 SD for patient control data because the normal variance in children is generally wider than in adults, even though our data showed relatively small variance.
The decrease in K value seemed to correlate more with the clinical severity of the patient's disease rather than its diagnostic entity. It was difficult to establish a correlation between the K value and routine TCD, SPECT, CT, or MRI, suggesting that the K value may be unique as a physiological parameter.
We found that there are at least two patterns of marked abnormality in CO2 reactivity: One is extremely low reactivity under both hypercapnic and hypocapnic conditions (Fig 3B⇑), such as in patient 4 and the right MCA and BA of patient 5, and the other is extremely low reactivity under only hypercapnic conditions (Fig 3A⇑), such as in patient 3 and the left MCA of patient 5. The former is likely to indicate severe impairment of reactivity involving vasomotor function of the smooth muscle or endothelium. It is probably a typical finding in the most severe MEM cases.
A possible explanation of the latter is an altered “set point” or threshold in reactivity due to continuous or frequent exposure of regional cerebral tissues to sustained acidosis. Additionally, it may relate to the vulnerability to additional stress and metabolic demand in the central nervous system beyond the compensation for insufficient mitochondrial function, in other words, decreased cerebrovascular reserve. This pattern was seen in only two patients with MELAS, but whether it was unique to MELAS patients is thus far unclear.
Whether the primary cause of strokelike episodes is either mitochondrial cytopathy or angiopathy is still controversial. “Mitochondrial angiopathy,” characterized by a degenerative change with increased abnormal mitochondria in the endothelial cells of intramuscular and intracerebral small arteries and arterioles, has been reported in an autopsied MELAS case.3 A similar change was also reported as strongly succinate dehydrogenase-reactive blood vessels in most MELAS and MERRF patients and in some CCOD patients, suggesting a high incidence of vascular involvement in MEM patients.4
On the other hand, a phenomenon similar to “luxury perfusion”24 was identified in a MELAS patient by a PET study, indicating tissue metabolic abnormality rather than mitochondrial angiopathy as a cause of strokelike episodes.6 7 8 9 10
As stated above, the present data suggest that there are at least two factors in abnormal cerebrovascular reactivity. It is therefore suggested that disorders of cerebral metabolism and circulation, in various combinations and various degrees and mutually influencing each other, cause clinical central nervous system involvement in MEM.
The TCD CO2 reactivity method used in this study can be used repeatedly and noninvasively and is useful for evaluation of cerebrovascular reactivity in MEM patients. Furthermore, it should be useful as one of the parameters for evaluation of clinical status and therapeutic effect.
Selected Abbreviations and Acronyms
|CCOD||=||cytochrome C oxidase deficiency|
|fm||=||mean spatial Doppler frequency|
|K||=||index of CO2 reactivity|
|MCA||=||middle cerebral artery|
|MELAS||=||mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes|
|MERRF||=||myoclonic epilepsy with ragged-red fiber|
|PET||=||positron emission tomography|
|Petco2||=||end-tidal CO2 partial pressure|
|SPECT||=||single-photon emission computed tomography|
|TCD||=||transcranial Doppler sonography|
We thank Nobuo Handa, MD, and Hiroaki Maeda, MD (First Department of Internal Medicine, Osaka University Medical School), for helpful reviews, technical advice, and equipment support and Tetsuzo Tagawa, MD, Koji Inui, MD, Jiro Ono, MD, and Hiroshi Arai, MD (Department of Pediatrics, Osaka University Medical School), for helpful comments and technical assistance.
- Received January 29, 1996.
- Revision received April 15, 1996.
- Accepted May 3, 1996.
- Copyright © 1996 by American Heart Association
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