Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
Over the past years much has been clarified about mitochondrial pathology. There are several encephalomyopathies related to mitochondrial dysfunction, of which the most important are Kearns-Sayre syndrome (KSS), myoclonus epilepsy and ragged red fibres syndrome (MERRF) as well as the mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes syndrome (MELAS), about which several reviews were published recently.1-3
The clinical picture of MELAS is the result of a respiratory chain defect and involves mainly the CNS and the skeletal muscles, which are especially vulnerable to mitochondrial dysfunction because of their dependency on the oxidative metabolism.4 5 The histopathological presentation in the skeletal muscles is ragged red fibres which are caused by impaired intramitochondrial protein synthesis. The clinical expression of MELAS is highly variable, in that different mutations can lead to a similar clinical syndrome and a given mutation may be responsible for an inconstant phenotypical expression.6 7 In most cases, the enzymatic defect in MELAS is a complex I deficiency and, to a lesser degree, a complex IV deficiency. The enzyme abnormality is associated with a point mutation at np3243 in the tRNA Leu(UUR) region, which accounts for 80% of the patients with MELAS.5
The MELAS syndrome was first described in 1984 by Pavlakis et al.8 Later, Hirano and Pavakis7described the target symptoms and additional clinical manifestations, based on 110 reported patients with MELAS. The six target symptoms include clinical stroke, seizures, lactic acidosis, ragged red fibres, exercise intolerance, and onset of symptoms before the age of 40. Additional clinical manifestations comprise dementia, limb weakness, short stature, hearing loss, and recurrent migraine-like headaches. Lactic acidosis is the most common finding from laboratory investigations. In 12% of patients the ECG discloses Wolff-Parkinson-White syndrome. Protein and lactate in CSF is raised in most patients.9 In about 80% of the patients lucencies consistent with infarction, mostly localised in one of the cerebral hemispheres, can be shown by brain CT.
Psychiatric symptoms in patients with MELAS are rarely reported. Suzukiet al 10 described one patient with schizophrenia-like symptoms such as auditory hallucinations, delusions of persecution and disorganised behaviour.
Here we report on a female patient with MELAS in whom psychiatric symptoms preceded the establishment of the clinical diagnosis for several years.
She was admitted in December 1987 to the Vincent van Gogh Institute for Psychiatry in Venray, The Netherlands, because of aggressive and paranoid behaviour and neglect of body care. She was born from non-consanguinous parents and had a normal psychomotor development. Family history did not disclose any neurological or psychiatric disorder. At the age of 14 she had been evaluated medically for the first time because of short stature. No abnormalities were found. The medical history comprised two previous neurological admissions to hospital. The first, at the age of 18, was mandated because of severe headaches, a confusional state, aphasia and apraxia. Hemiparesis or hemianopsia could not be shown. Routine hematological and blood chemical tests showed no abnormal values. The CSF, obtained by lumbar puncture, disclosed no abnormalities (lactate and pyruvate concentrations were not measured). An EEG disclosed severe hypofunctional disturbances over the left hemisphere and CT showed a hypodensity in the left temporo-occipital area. Angiography of the carotid and vertebrobasilar system was without abnormalities. Her neurological condition improved and she continued school activities. Some months later, however, she was readmitted, again with headaches, vomiting, and a confusional state without neurological deficits or other accompanying psychiatric symptoms. This time body temperature was raised (38.9°C) without any sign of meningism. There was no leucocytosis, but the erythrocyte sedimentation rate was slightly increased. Creatine phosphokinase was slightly increased to 344U/l (reference values 15–110 U/l). Serum concentrations of lactate and pyruvate were raised, with values of 2.23 mmol/l (reference values 0.66–1.8 mmol/l) and 191 μmol/l (reference values 30–90 μmol/l) respectively. Analysis of lumbar CSF showed 80/3 polynuclear leucocytes, a slightly increased protein concentration of 0.58 mg/l, and enhanced concentrations of lactate (3.3 mmol/l; reference values <2.8 mmol/l) and pyruvate (224 μmol/l; reference values 8–150 μmol/l). An EEG disclosed severe slowing, especially over the right hemisphere and CT showed a hypodensity in the right temporo-occipital region. Cardiovascular examination did not disclose abnormalities apart from a Wolff-Parkinson-White syndrome. At audiometric examination a decreased perception of high tones was found, compatible with retrocochlear deafness. Moreover, focal epileptic seizures were found for the first time and the patient was treated consequently with phenytoin. About four years later, at the age of 22, she was referred to our hospital because of persistent temper tantrums and paranoid ideation. Psychiatric examination disclosed predominantly symptoms of behavioural disinhibition without the presence of clear psychopathology except vague ideas of reference. During subsequent years, the patient developed a gradual deterioration of behaviour, complete retrocochleair deafness, progressive aphasia and apraxia, bradyphrenia, and an increase in focal temporal epileptic seizures and absences, despite maintenance therapy with phenytoin, necessitating addition of vigabatrine. She never developed manifest symptoms of muscle weakness. In addition, fluctuating psychiatric symptoms occurred, in particular paranoid delusions, affective instability, and disturbed impulse control with aggressive incidents, for which treatment with haloperidol in dosages varying between 10 and 20 mg daily was given chronically.
At the age of 27, she was referred for diagnostic re-evaluation to the Department of Psychiatry of the University Hospital Dijkzigt in Rotterdam. Ragged red fibres were found by muscle biopsy (Professor HFM Busch, neurologist), suggestive of a mitochondrial disorder. Subsequent analysis showed a point mutation 3243 A-G in the muscle biopsy with a mDNA mutation percentage of 60 (Dr BA van Oost, University Hospital, Nijmegen) that was compatible therefore with the clinical diagnosis of MELAS. At that time symptomatic treatment with riboflavine and vitamin B complex was started.
Over subsequent years, her condition deteriorated both physically and psychiatrically. The psychiatric picture was characterised by psychotic episodes, including delusions of reference and influence, paranoid ideation, and auditory hallucinations, and sometimes suicidal behaviour necessitating a closed ward. At the age of 31, she was unexpectedly found dead, probably because of acute heart failure.
Postmortem examination of the CNS disclosed pseudolaminar cortical necrosis in the occipital region with many so-called fossilated neurons as well as “etat vermoulu” with a gliotic but non-broken molecular layer (Dr P Wesseling, neuropathologist, University Hospital, Nijmegen). These abnormalities were found particularly in the superficial part and not, as in classic anoxia, in the depths of the gyri. The neostriatum, pallidus, and thalamus were normal. The optic tract was somewhat pale and gliotic. The lateral geniculate body, the optic radiation, and the striate area were not or almost not affected.
This report describes a young female patient in whom, after a psychiatric and neurological history of almost 10 years, the diagnosis of MELAS was established by showing ragged red fibres and subsequently a point mutation 3243 A-G in muscle biopsy. Somatic, neurological, and biochemical abnormalities as described in this case, such as incidents of stroke-like symptoms, retrocochlear deafness, disturbances of consciousness, focal epileptic seizures, cognitive deterioration, and increases of lactate and pyruvate in both serum and CSF, are in agreement with those reported by other investigators.7 So far, only one report in the literature could be found describing additional psychiatric symptomatology such as schizophrenia-like symptoms,10 that were present also in this particular patient, especially delusions of reference and influence, auditory hallucinations, and paranoid ideation.
Concerning the pathophysiology of the schizophrenic-like disorder in this patient, it cannot be excluded that the site and laterality of the lesion were involved, as it has been shown in epileptic patients that left side temporal lobe foci increase substantially the risk for the development of a schizophrenia-like psychosis.11 12Moreover, traumatic or ischaemic hemispheric lesions may be associated with psychotic episodes.13 Thus a direct relation between MELAS and schizophrenia-like psychosis is questionable as both the epileptic disorder and the vascular pathology are known to provoke vulnerability to neuropsychiatric morbidity.
The reasons for the delay in establishing the correct diagnosis are most probably not only lack of familiarity with this disorder, but also the complex symptomatology with both neurological, cognitive, and psychiatric features. Moreover, no systematic integrative diagnostic assessment was performed trying to relate objective neurovascular and biochemical abnormalities with behavioural disturbances.
We conclude that in patients with complex and intermittent or progressive mixed neurological and psychiatric disorders, the diagnostic possibility of mitochondrial encephalomyopathy should be considered.
We are indebted to Drs A Verrips and CWGW Frenken, neurologists, for their critical comments.