J Neurol Neurosurg Psychiatry 65:951-952 doi:10.1136/jnnp.65.6.951
  • Letters to the editor

Multifocal cortical myoclonus and cerebral amyloid β-peptide angiopathy

  1. A J LARNER,
  1. Department of Neurology
  2. Department of Neuropathology
  3. Department of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
  1. Dr AJ Larner, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK. Fax 0044 171 829 8720.
  1. Department of Neurology
  2. Department of Neuropathology
  3. Department of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
  1. Dr AJ Larner, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK. Fax 0044 171 829 8720.
  1. Department of Neurology
  2. Department of Neuropathology
  3. Department of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
  1. Dr AJ Larner, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK. Fax 0044 171 829 8720.

    The commonest clinical presentations of the sporadic cerebral amyloid angiopathies are with either recurrent lobar haemorrhages or with dementia.1 In addition, transient focal neurological syndromes have occasionally been reported in association with cerebral amyloid angiopathies. These may represent transient ischaemic events or possibly focal seizures related to petechial intraparenchymal haemorrhages which are not associated with neuroimaging abnormalities; large haemorrhages may follow the onset of transient symptoms by weeks or months.2 3 We report on a patient with multifocal cortical myoclonus who subsequently proved to have amyloid β-peptide cerebral amyloid angiopathy, an association not previously described. We consider possible pathogenetic interrelations of these findings.

    A 65 year old woman presented with a 4 year history of involuntary movements. She had been noted to have abnormal jerking movements of her legs—for example, when climbing the stairs— which, on occasion had caused her to fall. Using an electric vacuum cleaner or hearing the telephone ring had been noted to trigger these involuntary movements. There was no history of cognitive impairment. Her medical history was unremarkable aside from treated hypothyroidism. Family history was positive for sudden death, all three of her elder siblings (one sister, two brothers) dying in their mid-60s. One had previously had angina, the other two had been healthy until the time of their deaths, which were ascribed to a “heart attack” and a “clot on the brain”, respectively.

    Examination of the patient disclosed a pronounced startle response, and action myoclonus in all limbs. There was no consistent stimulus sensitivity of the jerks. Otherwise, neurological examination was within normal limits.

    Investigations, which proved either normal or negative, included standard tests of haematological and biochemical indices, thyroid function tests, serum vitamin B12, red cell folate, serum electrophoresis, quantitative immunoglobulins, angiotensin converting enzyme (ACE) concentrations, autoantibodies (including ANCA, anti-endomysial antibodies, and anti-GAD antibodies), and anti-neuronal antibodies (Hu, Purkinje). Blood film was negative for acanthocytes. Analysis of CSF showed a raised protein (0.82 g/l) but normal glucose concentration, cytology, and ACE; oligoclonal bands were not present. T2 weighted brain MRI showed a few small foci of high signal in the periventricular white matter, thought to represent age related small vessel disease. Carotid angiography was normal. Small bowel biopsy showed a normal mucosa with no evidence of coeliac disease. Analysis of mitochondrial DNA for common mutations (positions 3243, 3271, 8344, and 8356) proved negative. Psychometric assessment showed the patient to have a verbal IQ of 94, performance IQ of 95, indicative of functioning in the lower half of the average range but within the patient’s estimated average optimal level of ability. She was noted to show signs of inefficiency and slowness, particularly in word retrieval and frontal lobe tasks, but there was no unequivocal evidence of focal deficits.

    Peripheral, cervical, and cortical somatosensory evoked potentials after electrical stimulation of the median nerve at either wrist were of normal latency and morphology. However, although the amplitude of peripheral and cervical potentials was normal, the cortical responses were abnormally large, particularly from the right arm (22 μV; left 15 μV). Hence, on clinical and neurophysiological grounds, a diagnosis of multifocal cortical myoclonus of unknown cause was made. The patient was treated with clonazepam (0.25 mg twice daily), with marked symptomatic benefit at follow up.

    Ten months after these investigations, the patient presented to an ophthalmologist with episodes of metamorphopsia for which no ocular cause was found. A further 3 months later she presented with a sudden onset of right parietal headache associated with vomiting and left sided pyramidal signs. Brain CT disclosed a large right sided parieto-occipital intracerebral haematoma with mass effect. At surgical drainage of the haematoma, a small piece of brain tissue was removed from the right parieto-occipital region. Histological examination showed small, irregular fragments of cortical grey and minimal amounts of white matter. The first included vessels, some of which were in obvious continuity with meningeal vessels. Most of them had thickened hyaline walls which stained with Congo red, showing the characteristic apple green birefringence under polarised illumination, and were positive with immunostaining for βA4. This immunostaining also showed diffuse plaques, a few containing cores most of which could not be seen on routine staining. No abnormalities were seen in the white matter. Silver impregnation (Bielschowsky) and tau immunohistochemistry did not show neurofibrillary tangles, neuritic plaques, or cortical dystrophic neurites. According to the criteria of the Boston Cerebral Amyloid Angiopathy Group,3 the histological findings and clinical data indicated a diagnosis of “probable cerebral amyloid angiopathy with supporting pathological evidence”. DNA was screened by polymerase chain reaction amplification for the presence of mutations in the amyloid precursor protein (APP) gene, which are known to cosegregate with hereditary cerebral haemorrhage with amyloidosis Dutch type (HCHWA-D; codons 670/671 of exon 16 and in codons 692, 693, 713, and 717 of exon 17). No mutation was found.

    The patient underwent psychometric reassessment 1 month after the intracerebral haemorrhage and surgical drainage, from which she had made a good physical recovery. In keeping with the location of the haemorrhage, she was found to have significantly impaired visual perceptual functions, with left unilateral neglect, an inability to discriminate shapes, and a severe deterioration in her performance on the visual version of the recognition memory test (verbal version remained within the average range). Additionally, a mild degree of verbal intellectual deterioration was noted (verbal IQ 83).

    A wide variety of disorders may produce cortical myoclonus: the differential diagnosis includes anoxic injury, focal CNS damage (vascular or neoplastic lesions of sensorimotor cortex), encephalopathies (metabolic, mitochondrial, viral, paraneoplastic, toxic), degenerations (basal ganglia, spinocerebellar), malabsorption syndromes (coeliac disease, Whipple’s disease), storage disorders, and dementias (Creutzfeldt-Jakob disease). Myoclonus may also be encountered in Alzheimer’s disease, in which it is associated with increasing severity of dementia. We are not aware of previous reports of cortical myoclonus as a clinical feature of sporadic cerebral amyloid angiopathy. Although this could be a chance concurrence, it is possible that recurrent small intraparenchymal bleeds from angiopathic vessels may have been causal, as vascular lesions are a recognised cause for cortical myoclonus. Another possibility which may be worth considering relates to the effects of amyloid β-peptide (Aβ) and its metabolic fragments on neuronal membrane ion channels and their associated currents.4 Because the pathophysiology of cortical myoclonus is thought to reflect both increased excitability and deficiency of inhibitory processes in the cortex,5 the effects of Aβ on a variety of ion currents, both excitatory and inhibitory, might theoretically produce such an imbalance and hence contribute to the development of cortical myoclonus.


    Thanks are due to Mr W Harkness for performing the cerebral biopsy; Dr Lisa Cipolotti and Professor CD Frith for neuropsychological assessment; Professor C Van Broeckhoven (Antwerp) for DNA analysis; and Drs Peter Brown, Martin Rossor, and Dafydd Thomas for constructive criticisms of the manuscript.


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