Continuing Education Activity

Holmes tremor can present at rest or with movement, usually with a sustained posture. It is slow (less than 4.5 Hz) but with a large amplitude. It has also been referred to as rubral tremor, midbrain tremor, thalamic tremor, post-traumatic tremor, or complex tremor in view of the affected areas in the brain. This activity describes the evaluation and treatment of Holmes tremor and reviews the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Identify the etiology of Holmes tremor.
• Review the evaluation of Holmes tremor.
• Outline the anagement options available for Holmes tremor.

Introduction

Gordon Holmes reported in 1904 a series of patients with focal brain damage presenting tremors. Holmes tremor can present at rest or with movement (intention), usually with a sustained posture. It is slow (< 4.5 Hz) but with a large amplitude.[1] It has also been referred to as rubral tremor, midbrain tremor, thalamic tremor, post-traumatic tremor, or complex tremor because of the affected areas in the brain. The tremor was mostly associated with lesions in the midbrain, but now many other regions have been recognized.[2]

Etiology

Holmes tremors can be caused by a number of conditions:

• Stroke (ischemic and hemorrhagic)
• Trauma
• Neurodegenerative (multiple sclerosis)
• Tumors
• Infectious
• Progressive multifocal leukoencephalopathy
• Vascular lesions (cavernoma, arteriovenous malformations)

Epidemiology

There are few reports in the literature for Holmes tremor. This could be because due to misdiagnosis as it can be categorized as another type of tremor or because single case reports have not been published. A study in 2016 identified only 155 patients reported since the original 1904 description until 2016.[3] This small amount of cased proves that Holmes tremor is a rare manifestation.

In a series of twenty patients, the average age at diagnosis is 30.6 years (range 8-64), with a female to male ratio of 2:1.[3] The median time from the lesion occurrence and the tremor is 3.6 months, but it can range from one month until two years.[3] Another series of 23 patients found that the median time from the lesion occurrence and the tremor is 29 days, with a range of 2 days to 20 months.[4]

Pathophysiology

Neuroimaging techniques had helped to uncover the pathophysiology of many tremors.[5] In Holmes tremor, functional MRI has pointed to lesions in a commonly connected brain circuit involving the cerebellum (vermis, lateral cerebellar cortex, and flocculonodular areas), globus pallidus pars internus (GPi), thalamus (ventralis oralis posterior (VOP) and pulvinar nucleus), red nucleus, and pontomedullary junction.[6][7]

Several other circuits have been associated with the tremor, including the dopaminergic nigrostriatal system, dentatorubro-olivary pathways, and the cerebellothalamic system. Physician-scientists propose that a "two-hit" lesion that includes the nigrostriatal and other regions, as mentioned, is necessary to produce the symptoms.[1][8][9][10][11] The involvement of the GPi and VOP implies a pallidal–thalamic circuit.[12][13] The involvement of the pulvinar nucleus suggests posterior thalamic lesions involved in the tremor.[14][15] The presence of a combination of tremors is explained by the multiple regions involved, thus producing a resting, intention, and postural tremor. The GPi influences the pedunculopontine nucleus via the descending reticulospinal tract, controlling posture by acting on the axial and proximal appendicular musculature.[16] The thalamostriatal connections are involved in the interaction of basal ganglia pathways with cerebellar pathways making the GPi one of the targets for treatment.[1][17][18][19]

Most injuries are irreversible, but reversible cases of Holmes tremor had been reported after the resolution of spontaneous intracranial hypotension[20] or nonketotic hyperglycemia[21]. Distortion and swelling of the midbrain can produce functional disruption of the connected brain circuits.

History and Physical

Tremor diagnosis is based on a careful clinical examination, neurophysiological studies, and radiological assessment.

A neurological examination will show a unilateral resting, intention, and postural tremor affecting the extremity symmetrically, which is usually greater proximally than distally. It has a high amplitude at resting, which may worsen with intention. The frequency is generally below 4.5 Hz. Prolong or sustain posture will accentuate the tremor.

The Fahn-Tolosa-Marin tremor rating scale is used to measure tremor severity.[22] The pre-treatment score will be used to assess the results of medical/surgical treatment if there is evidence of a change in the post-treatment score.

Evaluation

Laboratories are usually nondiagnostic. An electromyogram is used to measure the frequency of tremor activity.

A Head computed tomographic (CT) scan will be useful for acute cases in which hemorrhage is identified. The gold standard study is a brain magnetic resonance imaging (MRI) with and without contrast, which will show ischemic lesions, neurodegenerative/inflammatory lesions, traumatic sequela, and tumoral/vascular pathologies. The brain MRI will also be used for the treatment coordination when fused to the head CT scan.

Treatment / Management

Medical

The most commonly used drugs are levetiracetam, trihexyphenidyl, levodopa, dopamine agonists, anticholinergics, and topiramate.[23][24] Very good results have been shown with levetiracetam. Also, the anticholinergics drug trihexyphenidyl has shown good results. Response to levodopa has been approximately 54%.[3][25] Second-line drugs that may help with some of the symptoms include clonazepam, bromocriptine, amantadine, biperiden, or botulinum toxin injections.[4][23][26]

Surgical

Stereotactic lesions (radiofrequency, thermal), principally at the thalamus, have produced partial improvement.[27][28][29] The effect may also wane with time.[1][29]

Gamma knife thalamotomy at Vim nucleus with a 130 Gy dose at the 100% isodose line; the 30% isodose line was kept lateral to the medial margin of the internal capsule with partial results.[30]

Classical targets for deep brain stimulation (DBS) in the VIM produced a good clinical response with partial results in only 31% of patients with Holmes tremor.[31] DBS to the GPi or VOP has been thought of as a target given the areas involved in Holmes tremor.[6] Areas located slightly more medial to the GPi target provide good results. DBS to the thalamic ventralis intermedius nucleus (VIM) in 57.8% of the patients and the GPi 32.8% of the patients provided better tremor suppression than medical treatment.[10] DBS to the GPi provides better control of the resting tremor component and overall tremor improvement.[1][23][32] Some consider that stimulation of the GPi is more effective than thalamic stimulation when there is a midbrain lesion.[2] The postural tremor component had better surgical results, but rest tremor and intention tremor results are similar.[23] GPi stimulation improves the proximal tremor while the Vim stimulation improves the distal tremor.[10] Results have been sustained after several years of follow up.[32] Sometimes a planned target can not be used as it is seriously affected by the etiology.[32]

Other areas of DBS have provided good single case improvement, including the prelemniscal radiations (inferior to the caudal zona incerta)[33] and the posterior subthalamic (three patients)[34]. The ventralis oralis anterior (VOA) and posterior (VOP)  produces sustained improvement.[12] Other areas include zona incerta, lenticular fasciculus, subthalamic nucleus, sometimes bilateral with a variable degree of improvement.[31][35] Because of the multiple structures involved, a combination of two targets for DBS can be considered.[31][36] Other studies have not found benefits among patients treated with multiple targets.[10][23] A patient with a midbrain hemorrhage who had stimulation of Vim, GPi, and VOA was found that only the GPi stimulation improved the tremor; none of the other two did not result in further tremor reduction.[1] The presurgical planning of two targets provides the surgeon to choose the best target with optimal results.[32] Stimulation is probably a life-long requirement as a report in which the system was removed after four years produced the tremor's reappearance similar to the preimplantation status.[37]

Focused ultrasound in deep brain targets for movement disorders and some types of tremors have been used and are now under clinical trials for Holmes tremor.[38][39][40][41][42]

Differential Diagnosis

Several tremors disorders are included in the differential diagnosis.[43][44]

• Essential tremor (most common action tremor, usually bilateral with a frequency of 4 Hz to 12 Hz, the onset is typically 60–70 years)
• Intention tremor
• Parkinson's disease tremor (most common resting tremor)
• Orthostatic tremor (middle-aged or older adults, unsteadiness on standing, 16 Hz tremor in the lower extremities)
• Physiological tremor (does not interfere with activities of daily living, 8 to 12 Hz)
• Cerebellar tremor (typically of low frequency below 5 Hz, rest tremor is usually absent)
• Functional tremor (no underlying physical cause can be found, and can have different manifestations, unresponsive to medication, frequency variability, suppression during attention distraction)[45]

Prognosis

DBS offers a more significant improvement in overall tremor control, especially in postural tremor.[23] This effect is better with GPi, VOP, or VOA stimulation compared to the classic Vim stimulation.

Complications

Here are a few complications:

• Problems with functional activities of daily living
• Surgical complications of thalamotomy (intracerebral bleeding, weakness, dystonia, and speech disturbance)
• Surgical complications of DBS (intracerebral bleeding, weakness, foreign body implant infections, and hardware maintenance)

Consultations

The consultations from the following departments:

• Neurology
• Neurosurgery
• Physical medicine and rehabilitation
• Physical therapist
• Occupational therapist
• Social workers

Deterrence and Patient Education

Holmes tremor is significantly incapacitating as the patient presents tremor in resting and intention activities, as with posture. This is in addition to the primary insult producing the tremor. There is no specific treatment. Medication and DBS have been the mainstay to control it. However, results can be incomplete. Initial treatment with levetiracetam, trihexyphenidyl, or levodopa should be tested for an adequate response. Those unresponsive patients should be offered DBS, understanding that results may be incomplete and that multiple targets may be required. Patients have to understand that the original neurological deficits will not benefit from the DBS procedure. This is important, so they do not have false expectations from the procedure.

Pearls and Other Issues

• Holmes tremors are resting, kinetic tremors worsened by sustained posture, with slow frequency (< 4.5 Hz) and large amplitude.
• Etiology can be classified as vascular, traumatic, neoplastic, infectious, neuroimmunological, neuroinflammatory, or neurodegenerative.
• It is an extremely rare condition, with only 155 patients reported between 1904-2016.
• This tremor's pathophysiology is complex and requires multiple subcortical regions within the basal ganglia to be lesioned, including the dopaminergic nigrostriatal system, dentatorubro-olivary pathways, and the cerebellothalamic system.
• Clinical evaluation includes a thorough history, screening of risk factors, and a physical examination that shows a unilateral resting, intention, and postural tremor with low frequency and high amplitude affecting the extremity symmetrically, proximally more than distally.
• The Fahn-Tolosa-Marin tremor rating scale measures tremor severity. This scale is useful to determine appropriate medical or surgical treatment and measure the effectiveness of treatment through time.
• Differential diagnosis includes essential tremors, intention tremor, Parkinson's disease tremor (most common resting tremor), orthostatic tremor, physiological tremor, cerebellar tremor (typically of low frequency below 5 Hz, rest tremor is usually absent), and functional tremor.
• Pharmacological treatments include anti-epileptics (levetiracetam, topiramate), dopamine agonists, anticholinergics (trihexyphenidyl), benzodiazepines, and botulinum toxin injections.
• Surgical options for refractory cases include thalamic stereotactic ablation, gamma knife thalamotomy, deep brain stimulation to the GPi or thalamic VOP, VOA, or Vim.
• Prognosis depends on the Holmes tremor's etiology, with pharmacoresistant tremors responding relatively well to deep brain stimulation in multiple areas in the basal ganglia circuit.

Enhancing Healthcare Team Outcomes

Management of Holmes tremor is particularly challenging as it involves resting, intention, and postural tremors. The quality of life of patients is very affected in those untreated or unresponsive. Collaboration shared decision making, and communication is a crucial element for a good outcome. The interprofessional care provided to the patient by the neurologist, neurosurgeons, and nurses must use an integrated care pathway combined with an evidence-based approach for the evaluation, diagnosis, and treatment planning. This will improve patient satisfaction and provide better outcomes.

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Disclosure: Franklyn Rocha Cabrero declares no relevant financial relationships with ineligible companies.

Disclosure: Orlando De Jesus declares no relevant financial relationships with ineligible companies.