Is nigrostriatal dopaminergic deficit necessary for Holmes tremor to develop? The DaTSCAN and IBZM SPECT study

Abstract

Holmes’s tremor (HT) is assumed to be the result of coexistence of nigrostriatal dopaminergic system impairment and the lesion of cerebello-thalamic pathways. It was suggested that dopaminergic deficiency is responsible for rest tremor, and lack of compensatory cerebellar function leads to spill of tremor into voluntary movements. Cases of HT with and without abnormalities of the presynaptic part of dopaminergic nigrostriatal were published and these findings raised the question of possibility of the postsynaptic lesion. Three patients with HT diagnosed according to criteria of Consensus Statement on Tremor were studied. In all of them SPECT imaging with ligands of presynaptic (I 123-FP CIT—DaTSCAN) and postsynaptic (I 123-iodobenzamide—IBZM) nigrostriatal dopaminergic neurons was performed. Indices of uptake in caudate and putamen normalized to nonspecific uptake in occipital cortex and indices of asymmetry for each whole striatum as well as for putamen and caudate separately were calculated. SPECT studies did not reveal asymmetry of DaTSCAN and IBZM binding in striatum in all studied subjects. The current clinical diagnostic criteria of HT are presumably insufficiently specific and when using them we identify patients both with and without the involvement of dopaminergic system. These two groups may represent tremor disorders of similar phenomenology but of different pathomechanism.

Mapping holmes tremor circuit using the human brain connectome

“…The nigrostriatal tract was also not a key part of our Holmes tremor circuit, despite dopaminergic medication being a first line treatment for Holmes tremor . This result aligns with other data suggesting that nigrostriatal tract involvement is not necessary for development of Holmes tremor . Specifically, many patients with Holmes tremor have normal dopamine neuroimaging and only half of patients respond to dopaminergic medication …”

“…4 This result aligns with other data suggesting that nigrostriatal tract involvement is not necessary for development of Holmes tremor. 32 Specifically, many patients with Holmes tremor have normal dopamine neuroimaging and only half of patients respond to dopaminergic medication. 4,5,[32][33][34] Given that all 36 lesion locations causing Holmes tremor were connected to a common circuit, this connectivity could be considered necessary for a lesion to cause Holmes tremor.…”

Damage to the central nucleus of the thalamus via atypical Holmes tremor: a case report

“… 6 Current research shows that involvement of the substantia nigra and striatum is not necessary for the occurrence of HT. 7 Specifically, many patients with HT have normal dopamine levels as measured via neuroimaging, and only half of such patients respond to dopaminergic medication. 4 , 8 …”

The Molecular Neuroimaging of Tremor

“…Another study revealed tremor amplitude-related activity in the sensorimotor cortex and cerebellar vermis in a patient with Holmes tremor caused by a microbleed near the right red nucleus that caused ipsilateral nigrostriatal dopaminergic denervation [85]. Nigrostriatal dopaminergic denervation is a variable finding in Holmes tremor and does not always correspond to a good levodopa responsiveness [83,[85][86][87]. Therefore, it has been suggested that lesions causing Holmes tremor do not localize to any single region, but instead localize to a functionally connected network [84].…”