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J Neurol Neurosurg Psychiatry. 2007 April; 78(4): 438–439.
PMCID: PMC2077771

Dramatic response to levetiracetam in post‐ischaemic Holmes' tremor

Holmes' tremor refers to an unusual combination of rest, postural and kinetic tremor of extremities. Common causes of Holmes' tremor include stroke, trauma, vascular malformations and multiple sclerosis, with lesions involving the thalamus, brain stem or cerebellum.1 Although some drugs (eg, levodopa and dopaminergic drugs, clonazepam and propranolol) have been occasionally reported to give some benefit, medical treatment of Holmes' tremor is unsatisfactory, and many patients require thalamic surgery to achieve satisfactory control.2

We report a patient in whom post‐ischaemic Holmes' tremor dramatically responded to levetiracetam treatment.

A 61‐year‐old right‐handed man with a history of polycythaemia vera suddenly developed dizziness, diplopia and ataxia in February 2006. A CT scan showed a left cerebellar haemorrhagic infarction. Within a few days, his neurological state gradually improved. However, in March 2006, a coarse, slowly progressive tremor arose in his left upper extremity. On admission to our hospital, the man was alert and orientated. His blood pressure was 130/85 mm Hg and pulse 80/min. Serum electrolytes, urea, creatinine, bicarbonate, liver transaminases, thyroxine, triiodothyronine, and thyroid‐stimulating hormone were normal. Blood analysis showed 5.8×103 cells/mm3 of red blood cells, 17 g/dl of haemoglobin and 49.5% of haematocrit. On examination, a severe‐intensity, mainly proximal, slow, large‐amplitude resting tremor was observed on the left upper limb (fig 1A1A).). Tremor was also present during posture and intentional movements, and was worsened by emotional distress and any attempts to inhibit it. No associated rigidity was observed. Tremor was exhausting and rendered the arm useless, preventing the patient from feeding and caring for himself. However, it stopped during sleep. No associated palatal tremor, nystagmus, signs of brain stem dysfunction, chorea, dystonia, bradykinesia or rigidity was present. Finger‐to‐nose test showed both dysmetria and incoordination on the left side. No deficits of position, vibratory sense, and superficial sensation of light touch and pain were observed. EEG was unremarkable. Surface electromyograms showed rhythmic grouping discharges of 3.5 Hz in the left proximal forearm muscles (fig 1C1C).). Jerk‐locked averaging analysis failed to show a cortical origin of the tremor. Brain MRI showed left cerebellar infarction with involvement of the superior and inferior semilunar lobules, left cerebellar tonsil and of the vermis (further details are provided in the supplementary figure available online at http://jnnp.bmj.com/supplemental). No evidence of other brain abnormalities was observed. The tremor was nearly incessant during wakefulness and disappeared during sleep. Diagnosis of Holmes' tremor was made, but initial treatment with clonazepan and propranolol was ineffective. The patient refused to take dopaminergic agents and levetiracetam was started, 1000 mg three times daily. After 24 h, the tremor was markedly reduced and the man was able to carry out most daily activities by himself. One day later, the tremor completely disappeared, with complete alleviation of all components (fig 1B1B).). The drug was well tolerated. The patient was discharged, but 2 weeks later he was readmitted, owing to the reappearence of the tremor 2 days after levetiracetam self‐discontinuation. Levetiracetam was reintroduced (1000 mg twice daily) and the patient promptly regained the functional use of the arm. At the last visit in August 2006, he maintained his improvement with no sign of toxicity.

figure jn103275.f1
Figure 1 Graphic tasks before (A) and at day 2 (B) of levetiracetam treatment. Surface electromyogram (EMG) (C) showing 3.5/sec tremor mostly involving proximal muscles of the left upper limb and absent at the right upper limb (EMG1: left triceps; ...

The movement disorder shown by this patient fullfilled the criteria of Holmes' tremor1: predominantly unilateral tremor; occurring not only at rest but also in posture and during movement, and disappearing during sleep; low frequency (3–5 Hz); and exacerbation by goal‐directed movements. Although brain stem lesions are usually found in patients with Holmes' tremor, lesions involving the thalamus or the cerebellum may also cause this movement disorder as they probably interrupt the neighbouring cerebellothalamic and nigrostriatal fibres.1

Holmes' tremor usually begins weeks to months after the insult, but the reasons for this delayed onset are not fully understood. Compensatory or secondary changes in nervous system function may contribute to tremor genesis. However, both the dopaminergic nigrostriatal fibres and the cerebellothalamic systems must be lesioned to produce the combination of rest and kinetic tremors characteristic of this condition.1 This mechanism may account for the response variability of Holmes' tremor to pharmacotherapy. No definitive treatment is available for Holmes' tremor. Isolated cases of partial or complete relief have been reported with different drugs such as propranolol, clonazepam, levodopa and dopaminergic agents.1,2 Our patient showed a dramatic and rapid effect at levetiracetam discontinuation and reinstitution on postischaemic Holmes' tremor . No previous report on levetiracetam used for symptomatic treatment of Holmes' tremor is available.

Levetiracetam is a new antiepileptic drug with a mechanism of action distinct from that of other anticonvulsants, and the synaptic vesicle protein SVA2 was found as its main binding site in the brain.3 The mechanism by which this drug improved tremor in our patient remains speculative. Interestingly, levetiracetam reduces neuronal synchronisation in animal models of epilepsy and may act by limiting the high‐frequency repetitive firing of neuronal cells or by a depressant action on the corticopontocerebellar pathways.4 Furthermore, levetiracetam has been reported to have improved different kinds of movement disorders (eg, essential and cerebellar tremor, myoclonus, L‐dopa‐induced dyskinesia) and changes in γ‐aminobutyric acid transmission and chloride influx are suggested as potential mechanisms.4,5

In conclusion, levetiracetam is an easy‐to‐test drug that may improve considerably the disability in patients with Holmes' tremor. Further studies will clarify its long‐term efficacy and its mechanism of action in movement disorders.

Supplementary figure is available online at http://jnnp.bmj.com/supplemental

Supplementary Material

[web only media]

Footnotes

Competing interests: None declared.

Consent was obtained for publication of the patient's details described in this report.

Supplementary figure is available online at http://jnnp.bmj.com/supplemental

References

1. Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder Society on Tremor: Ad Hoc Scientific Committee. Mov Disord 1998. 13(Suppl 3)2–23.23 [PubMed]
2. Kim M C, Son B C, Miyagi Y. et al Vim thalamotomy for Holmes' tremor secondary to midbrain tumour. J Neurol Neurosurg Psychiatry 2002. 73453–455.455 [PMC free article] [PubMed]
3. Lynch B A, Lambeng N, Nocka K. et al The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA 2004. 1019861–9866.9866 [PubMed]
4. Striano P, Coppola A, Vacca G. et al Levetiracetam for cerebellar tremor in multiple sclerosis: an open‐label pilot tolerability and efficacy study. J Neurol 2006. 253762–766.766 [PubMed]
5. Bushara K O, Malik T, Exconde R E. The effect of levetiracetam on essential tremor. Neurology 2005. 641078–1080.1080 [PubMed]

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