- Email: [email protected]
An adult case of Leigh disease
Clinical Neurology and Neurosurgery 106 (2004) 237–240
An adult case of Leigh disease Branko Malojcic a , Vesna Brinar a,∗ , Charles Poser b , Visnja Djakovic a a
Department of Neurology, University Hospital Centre Zagreb, Kispaticeva 12, 10 000 Zagreb, Croatia b Department of Neurology, Harvard Medical School, Boston, MA 02215, USA
Abstract Leigh’s disease is a mitochondrial disease of infancy and early childhood, and is rare in adults. Following a febrile illness, a 21-year-old woman developed ataxic paraparesis and was originally diagnosed as multiple sclerosis. Her illness progressed to somnolence and quadriparesis. The unusual MR images, the discovery of elevated blood lactate and pyruvate levels, the results of muscle biopsy and the lack of response to corticosteroid treatment, led to the correct diagnosis of Leigh disease. Initiation of a ketogenic diet resulted in a rapid partial response. She recovered sufficiently to be able to walk after 6 months. © 2004 Elsevier B.V. All rights reserved. Keywords: Leigh disease; MRI; Lactate; Pyruvate; Differential diagnosis; Ketogenic diet
1. Introduction Subacute necrotizing encephalomyelopathy was first described by Leigh in 1951 [1] and has since been referred to as Leigh disease (LD). This mitochondrial disease usually begins in infancy or early childhood and is characterized by psychomotor retardation, feeding difficulties, respiratory problems, cranial nerve palsies and ataxia. There is also a juvenile and an adult form, the latter more benign and with a better prognosis. Because the clinical picture is not specific, it may be difficult to diagnose. The differential diagnosis includes a long list of conditions. It is due to a deficiency of cytochrome c oxidase and thus the oxidation of pyruvates, but abnormalities of pyruvate dehydrogenase and rarely of the NADH-Co-Q reductase system have also been reported. The present case initially proved to be a diagnostic dilemma the solution of which led to appropriate therapy and clinical improvement.
2. Case report A 21-year old woman developed a fever of 39 ◦ C, headache and vomiting 7 days prior to admission to an outside hospital. Two days later she became unable to walk due
∗
Corresponding author. Fax: +385-1-46-14-713. E-mail address: [email protected] (V. Brinar).
0303-8467/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2004.02.028
to severe paraparesis and ataxia. Her past medical history revealed that she had always had difficulty doing physical exercises and that her gait was considered inappropriate by her parents. She had a younger sister with Down syndrome and another sister had died at age 13 due to encephalitis, diagnosed at autopsy. The parents were healthy and not consanguineous. Her initial neurological examination revealed a spastic paraparesis, limb dysmetria and slurred speech. A CT scan was performed which revealed symmetrical hypodensities in the basal ganglia (Fig. 1). The diagnosis of multiple sclerosis (MS) was suspected. Her general condition deteriorated and she was transferred to our service. On admission, she was deeply somnolent and unresponsive to voice stimuli; cranial nerve functions were intact except for horizontal nystagmus; she had severe spastic paraparesis with bilateral Babinski signs; superficial and deep sensations were preserved; cerebellar functions could not be tested. After 1 day, the muscle weakness spread to the upper extremities and the lower cranial nerves, and she developed bowel and bladder incontinence. The diagnosis of acute disseminated encephalomyelitis (ADEM) was entertained on the basis of her clinical signs, and she was started on intravenous methylprednisolone; her condition worsened, her stupor deepened and her tetraparesis increased. Visual evoked potentials, nerve conduction times, electromyography were all normal. EKG was non- specific. EEG showed dysrhythmia with a right fronto-parieto-occipital lateralization. There were no traces of neurotropic viruses or borreliosis, and no oligoclonal bands in the CSF.The first
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B. Malojcic et al. / Clinical Neurology and Neurosurgery 106 (2004) 237–240
Fig. 1. CT showing bilateral hypodensities in the basal ganglia.
Fig. 2. T2-weighted images showing bilateral high intensity lesions in basal ganglia.
MRI which could not be obtained until 3 days after admission, showed bilateral high intensity areas in the caudate and lentiform nuclei, and in the subcortical white matter in T2-weighted images, none of which enhanced with gadolinium (Fig. 2). The MR images suggestive of LD led to the measurement of serum lactate and pyruvate levels which were found to be quite elevated and confirmed the diagnosis (Table 1). A muscle biopsy was performed that showed normal muscle fiber architecture and morphology but electronmicroscopy revealed subsarcolemmal aggregations of abnormal mitochondria (Table 2). Genetic testing of mitochondrial and genomic DNA failed to reveal point mutations in T8993G and T8993C which are characteristic for maternal Leigh syndrome, or a T3243 mutation which is characteristic for MELAS. Testing of the parents could not be carried out for technical reasons. A ketogenic diet was started on the 11th hospital day, with a fat/protein ratio of 4:1 and energy content at 40 kcal/kg. The second MRI, performed 3 days later showed additional symmetrical lesions in the cerebellar white matter (Fig. 3). MRI of the entire spinal cord was normal. Eight days after
the initiation of the ketogenic diet, her level of consciousness returned to near normal. At the end of her first month in hospital, muscle strength in the arms had increased to 3/5. Another brain MRI was performed which demonstrated no new lesions, while the old lesions in centrum semiovale, basal ganglia and the cerebellum were smaller in diameter and without surrounding edema. She was discharged on the 49th hopsital day still paraparetic and incontinent of stool and urine. Serum lactate and pyruvate levels were obtained at follow-up visits at 3, 6, and 16 months (Table 2). Additional brain MRIs were also performed (Fig. 4). Except for minor fluctuations in muscle strength, which reflected her dietary compliance, she continued to improve. Incontinence had disappeared by the third month, and she was able to walk unaided by the sixth month, although mild paraparesis with bilateral Babinski signs, and truncal ataxia, along with impaired short-term memory and attention, have persisted to the present time. MR spectroscopy revealed normal brain lactate levels (Fig. 5). She has not resumed work as a cook.
Table 1 Lactate and pyruvate levels during hospitalization
Table 2 Lactate and pyruvate levels during follow up
Lactate (mmol/l)
Pyruvate (mmol/l)
Lactate/pyruvate ratio
Days
Lactate (mmol/l)
Pyruvate (mmol/l)
Lactate/pyruvate ratio
Months after hospitalization
11.9 9.1 3.3
0.03 0.10 0.31
440.0 89.2 10.8
Admission 7th hospital day 14th hospital day
1.01 0.60 0.90
0.06 0.05 0.07
16.83 12.76 13.04
3 6 16
B. Malojcic et al. / Clinical Neurology and Neurosurgery 106 (2004) 237–240
239
Fig. 3. T2-weighted images showing bilateral high intensity lesions in cerebellar white matter.
in the mitochondria, 40 to 60% of patients, including our patient, have no definite metabolic derangement [2]. Point mutations in the mitochondrial genome are found at base pairs 8527-9207 but genetic testing of mitochondrial and genomic DNA in our patient failed to reveal the characteristic point mutations in T8993G or T8993C. Other diseases/syndromes that result from OXOPHOS defects are the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy with ragged red fibers (MERF), Leber’s hereditary optic neuropathy (LHON), Alpers disease (AD), infantile mitochondrial myopathy
Fig. 4. T2-weighted images 16 months after onset of the disease: minor changes in the size of the lesions.
3. Discussion LD belongs to the group of mitochondrial encephalomyelopathies. It is caused by a defect in the oxidative phosphorylation (OXOPHOS) pathway or by a deficiency of the pyruvate dehydrogenase complex (PHD). Although several biochemical or molecular abnormalities have been identified
Fig. 5. MR spectroscopy through the right putamen: the N-acetylaspartate (at 2.0 ppm), creatinine (at 3.0 ppm) and choline (at 3.2 ppm) peaks are normal, there is an inverted lactate peak at 1.32 ppm but no characteristic lactate doublet.
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B. Malojcic et al. / Clinical Neurology and Neurosurgery 106 (2004) 237–240
(IMM), Kearns-Sayre syndrome (KSS) and chronic progressive external ophthalmoplegia (CPEO). OXOPHOS deficiencies are a frequent cause of encephalopathy [3]; there are morphological and lesion distribution characteristics that can help in differentiating mitochondrial encephalopathy, but important overlaps occur [4]. In LD, focal necrosis or spongiform degeneration are found in the brain with partial sparing of neurons, as well as marked capillary proliferation mostly affecting the basal ganglia, thalamus, midbrain and pons, but other brain regions including the cerebral and cerebellar cortices may be involved [5]. The typical age of onset is infancy in AD, LD, and IMM; childhood or adolescence in KSS, MELAS, and MERF; late adolescence or early adulthood in LHON; and CPEO in adults. A number of cases of adult onset LD have been reported. The clinical course of all mitochondrial diseases can be relapsing–remitting with multifocal symptoms. The clinical diagnosis of Leigh syndrome is based on the following criteria: progressive neurological disease with motor and intellectual deterioration, signs and symptoms of brainstem and basal ganglia disease, raised lactate levels in blood and CSF, and hyperintense lesions on T2-weighted MRI [6]. It is therefore not surprising that diseases like MS or ADEM may be included in the differential diagnosis, especially when the age of onset is in the 2nd or 3rd decade [7]. The absence of CSF oligoclonal bands helps in eliminating MS. The neuroimaging features characteristic for LD are symmetrical hypodensities in the basal ganglia on CT scans, that appear as areas of increased signal intensity on T2-weighted MRI, and strongly support the diagnosis of LD [8,9]. Lesions of the brainstem and cerebellum can be found in other mitochondrial encephalomyelopathies, e.g. in MELAS, MERF [10], CPEO and KSS, and may also have lesions in both cerebral grey and white matter [11]. The follow-up MRIs of our patient showed only modest changes compared to the last one performed during her hospital stay and therefore we concluded her disease to be stable.. An increase in the lactate-to-pyruvate ratio (LPR), which is normally in the 10–15:1 range is characteristic for LD. Regular monitoring of the LPR ratio is a sensitive tool for monitoring the effects of therapy and blood lactate and pyruvate levels were measured during the entire course of disease as indicators of disease activity. The improvement of the patient’s clinical condition was accompanied by the normalization of that ratio, and the fact that the disease was inactive was confirmed by MR spectroscopy in the last year of follow-up that showed no abnormal lactate peaks in the basal ganglia [12]. Various therapeutic agents have been known to result in improvement in LD patients but none have been tested in reliable, controlled trials. Because the disease has several distinct clinical phenotypes, only small numbers of patients have been treated with these various agents. The beneficial effects of sodium dichloroacetate [13], flunarazine [14],
soybean oil [15], coenzyme-Q(10) [16] and ketogenic diet [17,18] constitute anecdotal reports. Our decision to use the ketogenic diet was based on the unavailability of these other forms of treatment in Croatia. Despite the fact that LD may be self-limited in adults, the beginning of clinical improvement shortly after the diet was started, and the fluctuations in the symptoms corresponding to failures of compliance, suggest that the treatment has been effective.
References [1] Leigh D. Subacute nectrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry 1951;14:216–21. [2] Rahman S, Blok R, Dahl H, Danks D, Kirby D, Chow C, et al. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol 1996;39:343–51. [3] Schapira A, Cock H. Mitochondrial myopathies and encephalomyopathies. Eur J Clin Invest 1999;29:886–98. [4] Oldfors A, Tulinius M. Mitochondrial encephalomyopathies. J Neuropathol Exp Neurol 2003;62:217–27. [5] Agapitos E, Pavlopoulos P, Patsouris E, Davaris P. Subacute necrotizing encephalomyelopathy (Leigh’s disease): A clinicopathologic study of ten cases. Gen Diagn Pathol 1997;142:335–41. [6] Goldenberg P, Steiner R, Merkens L, Dunaway T, Steiner R, Zimmerman E, et al. Remarkable improvement in adult Leigh syndrome with partial cytochrome c oxidase deficiency. Neurology 2003;60:865–8. [7] Brinar V. The differential diagnosis of multiple sclerosis. Clin Neurol Neurosurg 2002;104:211–20. [8] Greenberg S, Faerber E, Riviello J, Leon G, Capitanio M. Subacute necrotizing encephalomyelopathy (Leigh disease): CT and MRI appearances. Pediatr Radiol 1990;21:5–8. [9] Koch T, Yee M, Hutchinson H, Berg B. Magnetic resonance imaging in subacute necrotizing encephalomyelopathy (Leigh’s disease). Ann Neurol 1986;19:605–7. [10] Cavanagh J, Harding B. Pathogenic factors underlying the lesions in Leigh’s disease. Brain 1994;117:1357–76. [11] Valanne L, Ketonen L, Majander A, Suomalainen A, Pihko H. Neuroradiologic findings in children with mitochondrial disorders. Am J Neuroradiol 1998;19:369–77. [12] Krageloh-Mann I, Grodd W, Niemann G, Haas G, Ruitenbeek W. Assessment and therapy monitoring of Leigh disease by MRI and proton spectroscopy. Pediatr Neurol 1992;8:60–4. [13] Takanashi J, Sugita K, Tanabe Y, Maemoto T, Niimi H. Dichloroacetate treatment in Leigh syndrome caused by mitochondrial DNA mutation. J Neurol Sci 1997;145:83–6. [14] Westarp M, Holzgraefe M, Gallenkamp U, Thomas R, Bechinger D. Diagnosis and treatment in a case of juvenile subacute necrotizing encephalopathy Leigh without cytochrome c oxidase deficiency. Eur Neurol 1992;32:206–11. [15] Kumagai R, Ichikawa K, Yasui T, Kageyama Y, Miyabayashi S. Adult Leigh syndrome: treatment with intravenous soybean oil for acute central respiratory failure. Eur J Neurol 1999;6:613–5. [16] Van Maldergem L, Trijbels F, DiMauro S, Sindelar P, Musumeci O, Janssen A, et al. Coenzyme Q-responsive Leigh’s encephalopathy in two sisters. Ann Neurol 2002;52:750–4. [17] Leung T, Hui J, Yeung W, Goh K. A Chinese girl with Leigh syndrome: effect of botulinum toxin on dystonia. J Paediatr Child Health 1998;34:480–2. [18] Wijburg F, Barth P, Bindoff L, Birch-Machin M, van der Blij J, Ruitenbeek W, et al. Leigh syndrome associated with a deficiency of the pyruvate dehydrogenase complex: results of treatment with a ketogenic diet. Neuropediatrics 1992;23:147–52.
An adult case of Leigh disease Branko Malojcic a , Vesna Brinar a,∗ , Charles Poser b , Visnja Djakovic a a
Department of Neurology, University Hospital Centre Zagreb, Kispaticeva 12, 10 000 Zagreb, Croatia b Department of Neurology, Harvard Medical School, Boston, MA 02215, USA
Abstract Leigh’s disease is a mitochondrial disease of infancy and early childhood, and is rare in adults. Following a febrile illness, a 21-year-old woman developed ataxic paraparesis and was originally diagnosed as multiple sclerosis. Her illness progressed to somnolence and quadriparesis. The unusual MR images, the discovery of elevated blood lactate and pyruvate levels, the results of muscle biopsy and the lack of response to corticosteroid treatment, led to the correct diagnosis of Leigh disease. Initiation of a ketogenic diet resulted in a rapid partial response. She recovered sufficiently to be able to walk after 6 months. © 2004 Elsevier B.V. All rights reserved. Keywords: Leigh disease; MRI; Lactate; Pyruvate; Differential diagnosis; Ketogenic diet
1. Introduction Subacute necrotizing encephalomyelopathy was first described by Leigh in 1951 [1] and has since been referred to as Leigh disease (LD). This mitochondrial disease usually begins in infancy or early childhood and is characterized by psychomotor retardation, feeding difficulties, respiratory problems, cranial nerve palsies and ataxia. There is also a juvenile and an adult form, the latter more benign and with a better prognosis. Because the clinical picture is not specific, it may be difficult to diagnose. The differential diagnosis includes a long list of conditions. It is due to a deficiency of cytochrome c oxidase and thus the oxidation of pyruvates, but abnormalities of pyruvate dehydrogenase and rarely of the NADH-Co-Q reductase system have also been reported. The present case initially proved to be a diagnostic dilemma the solution of which led to appropriate therapy and clinical improvement.
2. Case report A 21-year old woman developed a fever of 39 ◦ C, headache and vomiting 7 days prior to admission to an outside hospital. Two days later she became unable to walk due
∗
Corresponding author. Fax: +385-1-46-14-713. E-mail address: [email protected] (V. Brinar).
0303-8467/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2004.02.028
to severe paraparesis and ataxia. Her past medical history revealed that she had always had difficulty doing physical exercises and that her gait was considered inappropriate by her parents. She had a younger sister with Down syndrome and another sister had died at age 13 due to encephalitis, diagnosed at autopsy. The parents were healthy and not consanguineous. Her initial neurological examination revealed a spastic paraparesis, limb dysmetria and slurred speech. A CT scan was performed which revealed symmetrical hypodensities in the basal ganglia (Fig. 1). The diagnosis of multiple sclerosis (MS) was suspected. Her general condition deteriorated and she was transferred to our service. On admission, she was deeply somnolent and unresponsive to voice stimuli; cranial nerve functions were intact except for horizontal nystagmus; she had severe spastic paraparesis with bilateral Babinski signs; superficial and deep sensations were preserved; cerebellar functions could not be tested. After 1 day, the muscle weakness spread to the upper extremities and the lower cranial nerves, and she developed bowel and bladder incontinence. The diagnosis of acute disseminated encephalomyelitis (ADEM) was entertained on the basis of her clinical signs, and she was started on intravenous methylprednisolone; her condition worsened, her stupor deepened and her tetraparesis increased. Visual evoked potentials, nerve conduction times, electromyography were all normal. EKG was non- specific. EEG showed dysrhythmia with a right fronto-parieto-occipital lateralization. There were no traces of neurotropic viruses or borreliosis, and no oligoclonal bands in the CSF.The first
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B. Malojcic et al. / Clinical Neurology and Neurosurgery 106 (2004) 237–240
Fig. 1. CT showing bilateral hypodensities in the basal ganglia.
Fig. 2. T2-weighted images showing bilateral high intensity lesions in basal ganglia.
MRI which could not be obtained until 3 days after admission, showed bilateral high intensity areas in the caudate and lentiform nuclei, and in the subcortical white matter in T2-weighted images, none of which enhanced with gadolinium (Fig. 2). The MR images suggestive of LD led to the measurement of serum lactate and pyruvate levels which were found to be quite elevated and confirmed the diagnosis (Table 1). A muscle biopsy was performed that showed normal muscle fiber architecture and morphology but electronmicroscopy revealed subsarcolemmal aggregations of abnormal mitochondria (Table 2). Genetic testing of mitochondrial and genomic DNA failed to reveal point mutations in T8993G and T8993C which are characteristic for maternal Leigh syndrome, or a T3243 mutation which is characteristic for MELAS. Testing of the parents could not be carried out for technical reasons. A ketogenic diet was started on the 11th hospital day, with a fat/protein ratio of 4:1 and energy content at 40 kcal/kg. The second MRI, performed 3 days later showed additional symmetrical lesions in the cerebellar white matter (Fig. 3). MRI of the entire spinal cord was normal. Eight days after
the initiation of the ketogenic diet, her level of consciousness returned to near normal. At the end of her first month in hospital, muscle strength in the arms had increased to 3/5. Another brain MRI was performed which demonstrated no new lesions, while the old lesions in centrum semiovale, basal ganglia and the cerebellum were smaller in diameter and without surrounding edema. She was discharged on the 49th hopsital day still paraparetic and incontinent of stool and urine. Serum lactate and pyruvate levels were obtained at follow-up visits at 3, 6, and 16 months (Table 2). Additional brain MRIs were also performed (Fig. 4). Except for minor fluctuations in muscle strength, which reflected her dietary compliance, she continued to improve. Incontinence had disappeared by the third month, and she was able to walk unaided by the sixth month, although mild paraparesis with bilateral Babinski signs, and truncal ataxia, along with impaired short-term memory and attention, have persisted to the present time. MR spectroscopy revealed normal brain lactate levels (Fig. 5). She has not resumed work as a cook.
Table 1 Lactate and pyruvate levels during hospitalization
Table 2 Lactate and pyruvate levels during follow up
Lactate (mmol/l)
Pyruvate (mmol/l)
Lactate/pyruvate ratio
Days
Lactate (mmol/l)
Pyruvate (mmol/l)
Lactate/pyruvate ratio
Months after hospitalization
11.9 9.1 3.3
0.03 0.10 0.31
440.0 89.2 10.8
Admission 7th hospital day 14th hospital day
1.01 0.60 0.90
0.06 0.05 0.07
16.83 12.76 13.04
3 6 16
B. Malojcic et al. / Clinical Neurology and Neurosurgery 106 (2004) 237–240
239
Fig. 3. T2-weighted images showing bilateral high intensity lesions in cerebellar white matter.
in the mitochondria, 40 to 60% of patients, including our patient, have no definite metabolic derangement [2]. Point mutations in the mitochondrial genome are found at base pairs 8527-9207 but genetic testing of mitochondrial and genomic DNA in our patient failed to reveal the characteristic point mutations in T8993G or T8993C. Other diseases/syndromes that result from OXOPHOS defects are the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy with ragged red fibers (MERF), Leber’s hereditary optic neuropathy (LHON), Alpers disease (AD), infantile mitochondrial myopathy
Fig. 4. T2-weighted images 16 months after onset of the disease: minor changes in the size of the lesions.
3. Discussion LD belongs to the group of mitochondrial encephalomyelopathies. It is caused by a defect in the oxidative phosphorylation (OXOPHOS) pathway or by a deficiency of the pyruvate dehydrogenase complex (PHD). Although several biochemical or molecular abnormalities have been identified
Fig. 5. MR spectroscopy through the right putamen: the N-acetylaspartate (at 2.0 ppm), creatinine (at 3.0 ppm) and choline (at 3.2 ppm) peaks are normal, there is an inverted lactate peak at 1.32 ppm but no characteristic lactate doublet.
240
B. Malojcic et al. / Clinical Neurology and Neurosurgery 106 (2004) 237–240
(IMM), Kearns-Sayre syndrome (KSS) and chronic progressive external ophthalmoplegia (CPEO). OXOPHOS deficiencies are a frequent cause of encephalopathy [3]; there are morphological and lesion distribution characteristics that can help in differentiating mitochondrial encephalopathy, but important overlaps occur [4]. In LD, focal necrosis or spongiform degeneration are found in the brain with partial sparing of neurons, as well as marked capillary proliferation mostly affecting the basal ganglia, thalamus, midbrain and pons, but other brain regions including the cerebral and cerebellar cortices may be involved [5]. The typical age of onset is infancy in AD, LD, and IMM; childhood or adolescence in KSS, MELAS, and MERF; late adolescence or early adulthood in LHON; and CPEO in adults. A number of cases of adult onset LD have been reported. The clinical course of all mitochondrial diseases can be relapsing–remitting with multifocal symptoms. The clinical diagnosis of Leigh syndrome is based on the following criteria: progressive neurological disease with motor and intellectual deterioration, signs and symptoms of brainstem and basal ganglia disease, raised lactate levels in blood and CSF, and hyperintense lesions on T2-weighted MRI [6]. It is therefore not surprising that diseases like MS or ADEM may be included in the differential diagnosis, especially when the age of onset is in the 2nd or 3rd decade [7]. The absence of CSF oligoclonal bands helps in eliminating MS. The neuroimaging features characteristic for LD are symmetrical hypodensities in the basal ganglia on CT scans, that appear as areas of increased signal intensity on T2-weighted MRI, and strongly support the diagnosis of LD [8,9]. Lesions of the brainstem and cerebellum can be found in other mitochondrial encephalomyelopathies, e.g. in MELAS, MERF [10], CPEO and KSS, and may also have lesions in both cerebral grey and white matter [11]. The follow-up MRIs of our patient showed only modest changes compared to the last one performed during her hospital stay and therefore we concluded her disease to be stable.. An increase in the lactate-to-pyruvate ratio (LPR), which is normally in the 10–15:1 range is characteristic for LD. Regular monitoring of the LPR ratio is a sensitive tool for monitoring the effects of therapy and blood lactate and pyruvate levels were measured during the entire course of disease as indicators of disease activity. The improvement of the patient’s clinical condition was accompanied by the normalization of that ratio, and the fact that the disease was inactive was confirmed by MR spectroscopy in the last year of follow-up that showed no abnormal lactate peaks in the basal ganglia [12]. Various therapeutic agents have been known to result in improvement in LD patients but none have been tested in reliable, controlled trials. Because the disease has several distinct clinical phenotypes, only small numbers of patients have been treated with these various agents. The beneficial effects of sodium dichloroacetate [13], flunarazine [14],
soybean oil [15], coenzyme-Q(10) [16] and ketogenic diet [17,18] constitute anecdotal reports. Our decision to use the ketogenic diet was based on the unavailability of these other forms of treatment in Croatia. Despite the fact that LD may be self-limited in adults, the beginning of clinical improvement shortly after the diet was started, and the fluctuations in the symptoms corresponding to failures of compliance, suggest that the treatment has been effective.
References [1] Leigh D. Subacute nectrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry 1951;14:216–21. [2] Rahman S, Blok R, Dahl H, Danks D, Kirby D, Chow C, et al. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol 1996;39:343–51. [3] Schapira A, Cock H. Mitochondrial myopathies and encephalomyopathies. Eur J Clin Invest 1999;29:886–98. [4] Oldfors A, Tulinius M. Mitochondrial encephalomyopathies. J Neuropathol Exp Neurol 2003;62:217–27. [5] Agapitos E, Pavlopoulos P, Patsouris E, Davaris P. Subacute necrotizing encephalomyelopathy (Leigh’s disease): A clinicopathologic study of ten cases. Gen Diagn Pathol 1997;142:335–41. [6] Goldenberg P, Steiner R, Merkens L, Dunaway T, Steiner R, Zimmerman E, et al. Remarkable improvement in adult Leigh syndrome with partial cytochrome c oxidase deficiency. Neurology 2003;60:865–8. [7] Brinar V. The differential diagnosis of multiple sclerosis. Clin Neurol Neurosurg 2002;104:211–20. [8] Greenberg S, Faerber E, Riviello J, Leon G, Capitanio M. Subacute necrotizing encephalomyelopathy (Leigh disease): CT and MRI appearances. Pediatr Radiol 1990;21:5–8. [9] Koch T, Yee M, Hutchinson H, Berg B. Magnetic resonance imaging in subacute necrotizing encephalomyelopathy (Leigh’s disease). Ann Neurol 1986;19:605–7. [10] Cavanagh J, Harding B. Pathogenic factors underlying the lesions in Leigh’s disease. Brain 1994;117:1357–76. [11] Valanne L, Ketonen L, Majander A, Suomalainen A, Pihko H. Neuroradiologic findings in children with mitochondrial disorders. Am J Neuroradiol 1998;19:369–77. [12] Krageloh-Mann I, Grodd W, Niemann G, Haas G, Ruitenbeek W. Assessment and therapy monitoring of Leigh disease by MRI and proton spectroscopy. Pediatr Neurol 1992;8:60–4. [13] Takanashi J, Sugita K, Tanabe Y, Maemoto T, Niimi H. Dichloroacetate treatment in Leigh syndrome caused by mitochondrial DNA mutation. J Neurol Sci 1997;145:83–6. [14] Westarp M, Holzgraefe M, Gallenkamp U, Thomas R, Bechinger D. Diagnosis and treatment in a case of juvenile subacute necrotizing encephalopathy Leigh without cytochrome c oxidase deficiency. Eur Neurol 1992;32:206–11. [15] Kumagai R, Ichikawa K, Yasui T, Kageyama Y, Miyabayashi S. Adult Leigh syndrome: treatment with intravenous soybean oil for acute central respiratory failure. Eur J Neurol 1999;6:613–5. [16] Van Maldergem L, Trijbels F, DiMauro S, Sindelar P, Musumeci O, Janssen A, et al. Coenzyme Q-responsive Leigh’s encephalopathy in two sisters. Ann Neurol 2002;52:750–4. [17] Leung T, Hui J, Yeung W, Goh K. A Chinese girl with Leigh syndrome: effect of botulinum toxin on dystonia. J Paediatr Child Health 1998;34:480–2. [18] Wijburg F, Barth P, Bindoff L, Birch-Machin M, van der Blij J, Ruitenbeek W, et al. Leigh syndrome associated with a deficiency of the pyruvate dehydrogenase complex: results of treatment with a ketogenic diet. Neuropediatrics 1992;23:147–52.