What is the appropriate management and treatment for a patient with rubral tremor, potentially with a history of multiple sclerosis?

Rubral Tremor Management

Rubral tremor requires a stepwise pharmacological approach starting with high-dose anticholinergics (trihexyphenidyl up to 38 mg/day), followed by combination therapy with dopaminergic agents if monotherapy fails, with surgical intervention (deep brain stimulation or MRgFUS thalamotomy) reserved for medically refractory cases that significantly impair quality of life. 1

Understanding Rubral Tremor

Rubral tremor is a rare, disabling movement disorder characterized by:

• Low-frequency (2-3 Hz) coarse oscillation present at rest, with sustained posture, and during movement 1
• Action tremor component that is typically more predominant than resting tremor 1
• Most commonly results from midbrain lesions affecting the red nucleus and surrounding structures, including cavernous angiomas, stroke, or traumatic brain injury 1, 2
• Can occur in multiple sclerosis patients, though this represents cerebellar/intention tremor rather than pure rubral tremor 3

Critical Diagnostic Pitfall

Drug-induced rubral tremor can occur in patients with pre-existing midbrain lesions when exposed to antipsychotics (risperidone) or neuroleptics, and will resolve with medication discontinuation 2, 4. Always obtain medication history before initiating treatment.

First-Line Pharmacotherapy

High-Dose Anticholinergics

Trihexyphenidyl is the most effective first-line agent for rubral tremor:

• Start at low doses (2-5 mg/day) and titrate upward to 30-40 mg/day as tolerated 1
• Doses up to 38 mg/day have demonstrated successful tremor control without severe side effects 1
• This represents significantly higher dosing than typically used for Parkinson's disease tremor 1
• Monitor for anticholinergic side effects: dry mouth, urinary retention, confusion, blurred vision 1

Combination Therapy if Monotherapy Fails

If anticholinergics alone are insufficient:

• Add bromocriptine (dopamine agonist) to anticholinergic therapy 4
• Benztropine combined with bromocriptine has shown dramatic response in neuroleptic-induced rubral tremor 4
• Glutethimide may provide functional benefit in 75% of patients with action tremor from multiple sclerosis or traumatic brain injury 5

Medications with Limited or No Efficacy

The following agents are typically ineffective and should not be first-line choices:

• Valproate, clonazepam, and verapamil show minimal benefit 1
• Botulinum toxin is contraindicated in multiple sclerosis-related tremor due to pre-existing corticospinal weakness that becomes dose-limiting 3

Surgical Intervention for Refractory Cases

When pharmacotherapy fails and tremor significantly impairs quality of life:

Deep Brain Stimulation (DBS)

• Preferred for bilateral tremor or younger patients requiring adjustable, reversible treatment 6
• Complication rate of 21.1% at 1 year 7
• Allows for programming adjustments post-operatively 7

MRgFUS Thalamotomy

• Lower complication rate (4.4%) compared to DBS (21.1%) and radiofrequency thalamotomy (11.8%) 7
• Sustained tremor improvement of 56% at 4 years with 63% disability improvement 7
• Contraindicated for bilateral treatment or contralateral to previous thalamotomy 7
• Requires skull density ratio ≥0.40 and MRI compatibility 7
• Most adverse events (gait disturbance, paresthesias) are mild-moderate and resolve by 1 year 7

Special Considerations for Multiple Sclerosis

In MS patients with tremor:

• Distinguish between cerebellar intention tremor versus true rubral tremor, as treatment approaches differ 3
• Botulinum toxin should be avoided due to pre-existing corticospinal weakness 3
• Glutethimide may provide functional benefit in MS-related action tremor 5
• Consider that BPPV can coexist with MS and may respond to conventional particle repositioning maneuvers 7

Treatment Algorithm

1. Exclude drug-induced causes (antipsychotics, neuroleptics) and discontinue if present 2, 4
2. Initiate trihexyphenidyl 2-5 mg/day, titrate to 30-40 mg/day over weeks to months 1
3. If inadequate response, add bromocriptine or benztropine 4
4. Consider glutethimide trial if anticholinergic/dopaminergic combination fails 5
5. Refer for surgical evaluation (DBS or MRgFUS) if medically refractory and functionally disabling 7, 6