We demonstrate that patients with inflammatory neuropathy and tremor differ from patients without tremor with regard to cerebellar function and sensorimotor plasticity. We found very low rates of EBCC in patients with inflammatory neuropathy and tremor compared to nontremulous patients and healthy controls, suggesting abnormal associative learning in the cerebellum that segregates with tremor. We also describe an absence of normal facilitation in TMS-evoked EMG potentials after PAS in patients with tremor, suggesting abnormal sensorimotor cortex plasticity. In nontremulous patients, sensorimotor plasticity, demonstrated by facilitation of TMS-evoked EMG potentials after PAS, occurred in neighboring muscles but without a normal facilitatory response in the target muscle, suggesting a lack of topographic specificity of sensorimotor plasticity.
Tremor in our patients with inflammatory neuropathies was invariably present during posture and action. Five patients had additional rest tremor. When present in all 3 conditions, tremor was worst during posture or action, which is in concordance with previous reports.8,22
Previously, a lower tremor frequency in distal compared to proximal hand muscles in 2 out of 6 patients with paraproteinemic neuropathy was described.8
This was also observed in 3 of our patients. However, on a group level, the peak tremor frequency did not differ between proximal and distal muscles.
EBCC is a form of simple associative learning that is well-studied and for which the cerebellum is both necessary and sufficient. Structural or functional impairments of the cerebellum lead to abnormalities in acquisition of this conditioned response.17,18,23,24
We demonstrate abnormal EBCC in tremulous neuropathy patients that clearly differentiates them from the normal rates of conditioning in nontremulous neuropathy patients and controls. Mean R1 and R2 latencies and latency variability did not differ between groups, making it unlikely that desynchronization of the afferent volley alone may be a factor in the lack of conditioned responses in the tremulous patients. The degree of impairment of acquisition of conditioned responses reported here is in line with the degree of impairment reported in patients with cerebellar degeneration or cerebellar lesions. A previous study showed a delayed second agonist burst25
in patients with IgMPN and tremor, suggesting that the cerebellum, although intact, would be a likely candidate for a central processor “tricked” into generating tremor in the context of distorted mistimed peripheral signals.8
Our data instead provide evidence that the cerebellum is not functioning normally in those patients who develop tremor.
We were able to record somatosensory evoked potentials, albeit delayed, in all CIDP or IgMPN patients with tremor. This is in line with the assertion that tremor occurs in the presence of distorted rather than absent sensory input.8
All patients, tremulous and nontremulous, had normal SAI as compared with normal controls. This suggests that despite the peripheral sensory-motor delay due to the demyelinating neuropathies, central processes have, remarkably, been able to adapt to such delays to reset to the new latency of the N20.
In healthy subjects, PAS causes a facilitation of motor evoked potentials in the “target muscle” only, lasting for 15–30 minutes. This response shares a number of features with long-term potentiation.19
Patients with tremor showed no response to PAS. The normal SAI in patients with tremor argues against afferent dysfunction and associated changes in the sensory motor cortex as sole explanation for the abnormal PAS response. This is supported by the findings in one tremulous CIDP patient with normal N20 and absent PAS response. In recent work, we have demonstrated that cerebellar suppression in healthy subjects by transcranial direct current stimulation impairs subsequent motor cortical facilitation by PAS.26
We therefore speculate that the absent PAS response in tremulous neuropathy patients may reflect cerebellar dysfunction that is also responsible for their impaired EBCC.
In patients without tremor, PAS response was also abnormal. Facilitatory changes were seen but these occurred in neighboring ulnar-innervated muscles but not in the APB. This latter finding has not, to our knowledge, previously been described in any other group of subjects. It is conceivable that altered topographic representation triggered by the neuropathy may affect sensory-motor integration required to mediate changes associated with PAS.27,28
An additional speculation is that this unusual response to PAS may be explained by a peripheral phenomenon such as ephaptic transmission between peripheral nerve fibers.
We present evidence that tremor in patients with inflammatory neuropathy is associated with cerebellar dysfunction. We acknowledge that generalizability is limited by our relatively small sample size. Also, this study does not answer the question whether the cerebellar abnormalities in tremulous patients are secondary to the presence of tremor or primary. Regarding the latter, one possibility is that in those with tremor, the specific antibody involved in causing the peripheral neuropathy is capable of crossing the blood–brain barrier and binding to the cerebellum. There is indirect evidence for this in IgMPN, in which tremor is typical. It would be of interest to look for evidence of antibodies that bind to cerebellum in tremulous patients with CIDP: they may share a common causative antibody for their neuropathy and the cerebellar dysfunction that drives the development of tremor.