Figure 1
Flow diagram of literature search. Summary of steps involved in the literature search leading to final number of articles included.
Table 1
Demographic, Clinical, Treatment, and Imaging Characteristics of Slow OT (Listed in Order of EMG Frequency) (N = 70 cases)
| Case | Author | EMG Frequency, Hz | Age, years | Sex | Duration, years | Family History | Other Tremor | Other Neurologic Disorder | Treatment Helpful | Treatment Failure | Imaging |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Kang54 | 3–4 | NA | F | Parkinsonism | Levodopa | |||||
| 2 | Hegde33 | 3–4 | 69 | M | NA | None | None | Cerebellar ataxia; novel CSF and serum Abs | IVIg | Valproate, Clonazepam, Gabapentin, Thiamine, B12, Methylprednisolone | MRI brain normal |
| 3 | Bonnet49 | 3.2–3.5 | 45 | M | 10 | NA | Rest arms and legs, and postural arms and legs, L>R, 3.2–3.5 Hz | Cerebellar ataxia, SCA3 | Levodopa | ||
| 4 | Oda14 | 4 | 79 | F | NA | NA | NA | Parkinsonism, dementia, L Babinski sign | Levodopa | Haloperidol | MRI brain vascular pathology |
| 5 | Yoo30 | 4 | 48 | M | 3 | None | Rest hand and foot, crossed, 4–6 Hz | PD | None reported | Dopamine agonist, Propranolol, Anticholinergic, Clonazepam | PET DAT asymmetric decreased uptake posterior putamen caudate, L>R |
| 6 | Baker36 | 4 | 38 | F | NA | NA | None | MS, spasticity, ataxia | Clonazepam, Leviracetam, Levodopa Gabapentin | MRI brain L brachium pontis enhancing lesion, periventricular lesions | |
| 7 | Stitt46 | 4–4.5 | 79 | F | 3 | None | None | Alexander disease; asymmetric spastic quadriparesis | None tried | None tried | MRI brain medulla atrophy, hyperintensitiy pons, medulla, upper cervical cord; MRA head and neck normal |
| 8 | Yokota32 | 4.4–4.8 | 67 | F | 5 | Head tremor | Voice 4.8–8.8 Hz, head, postural hand | Perpherazine, Propranolol, Trihexiphenidyl, Levodopa, Clonazepam, Apomorphine | MRI brain generalized atrophy | ||
| 9 | Kim55 | 4–5 | 68 | F | Alprazolam, Propranolol, Clonazepam | ||||||
| 10 | Kim16 | 4–5 | 45 | F | 2 | None | Rest hand and legs 4–5 Hz | Parkinsonism | Trihexiphenidyl | Propranolol | MRI brain normal |
| 11 | Setta48 | 4–5 (coexistent 14 Hz) | 63 | F | 7 | None | Postural arm 4 Hz | Cerebellar ataxia | Propranolol, Primidone, Clonazepam | CT brain – cerebellar atrophy | |
| 12 | Kang54 | 4–5 | ^ | F | Parkinsonism | Clonazepam | Benztropine | ||||
| 13 | Kobylecki31 | 4–5 | 53 | F | 4 | # | Postural arms, head | Dystonia | Alcohol, SSRI, Metoprolol, Trihexyphenidyl | ||
| 14 | Leu-Semenescu17 | 4.3–5.0 | 54 | F | 6 | NA | Rest arm L | PD | Clonazepam, Levodopa | NA | NA |
| 15 | Setta48 | 4–6 (coexistent 15 Hz) | 61 | F | 5 | None | Postural arm 4–5 Hz | Cerebellar ataxia | Propranolol, Primidone, Isoniazid, Valproic acid, Clonazepam | MRI brain cerebellar atrophy | |
| 16 | Lee56 | 4–6 | 81 | F | 0 | NA | None | PD | Levodopa | MRI brain atrophy, periventricular ischemia | |
| 17 | Bonnet49 | 4.2–6.5 | 45 | F | 12 | NA | Postural tremor legs bilateral 8 Hz, Rest tremor arms and legs bilateral 4.3–5 Hz, neck tremor | Parkinsonism, dystonia (SCA3), without ataxia | Levodopa, piribedil, pramipexole | MRI brain mild vermis atrophy | |
| 18 | Leu-Semenescu17 | 5 | 85 | F | 0 | NA | Rest arm L, 6 Hz | PD | Clonazepam, Levodopa | NA | NA |
| 19 | Infante57 | 5 | 62 | M | 32 | Parkin PD | Rest leg bilateral, L>R | Parkinsonism ( Parkin homozygous mutation) | Levodopa | Trihexiphenidyl, Alprazolam | SPECT bilateral symmetric decreased striatal binding |
| 20 | Kobylecki31 | 5.3 | 43 | M | 8 | # | Postural arm, head | Dystonia | Primidone, Alcohol | Clonazepam, Propranolol, Levodopa, Topiramate, Trihexyphenidyl | |
| 21 | Kobylecki31 | 5.8 | 70 | F | 6 | # | Rest arm 4.6 Hz, rest leg 5.2 Hz, jaw tremor | None | Gabapentin, Clonazepam | Levodopa | SPECT normal |
| 22 | Alonso-Navarro35 | 5–6 | 80 | F | 1 | Metoclopramide-induced | MRI brain normal | ||||
| 23 | Leu-Semenescu17 | 5–6 | 57 | F | 0 | NA | Rest arm L | PD | Clonazepam, Levodopa | NA | NA |
| 24 | Kobylecki31 | 5–6 | 50 | F | 6 | # | Rest + postural arms, head | Dystonia | Propranolol, Levodopa | ||
| 25 | Kang54 | 6 | ^ | F | Parkinsonism | Propranolol | Clonazepam | ||||
| 26 | Thomas18/Invernizzi58 | 6.2 | 53 | M | 3 | None | Rest hand | Parkinsonism, PEO, myopathy (POLG1 compound heterozygous mutations) | Pramipexole, Levodopa | Gabapentin | MRI brain normal; SPECT bilateral reduced dopamine uptake striatum, R>L |
| 27 | Kobylecki31 | 6.25 | 62 | M | 12 | # | Rest + postural arms, 6.5 Hz | None | Levodopa | Trihexyphenidyl, Topiramate | SPECT normal |
| 28 | Thomas18 | 6.3 | 52 | M | 5 | PD | NA | Parkin homozygous, PD | Pergolide, Levodopa | Gabapentin | SPECT reduced uptake posterior left striatum |
| 29 | Cleeves45 | 6.4 | 53 | F | 15 | Hand tremor | Postural hand 7 Hz | ET | Primidone, Clonazepam | Diazepam, Propranolol | |
| 30 | Thomas18 | 6.7 | 47 | F | 13 | None (PINK1) | Postural leg | PINK1 PD | Clonazepam, levodopa, ropinirole | Gabapentin | SPECT bilateral reduced striatal uptake, L>R |
| 31 | Thomas18 | 6.9 | 26 | F | 8 | NA | Rest foot R | Parkinsonism | Cannabis, Levodopa | Alcohol, Gabapentin, Propranolol Lorazepam, Carbamazepine, Topiramate, Acetazolamide | SPECT bilateral reduced striatal reuptake, maximal left putamen |
| 32 | Wee7 | 6–7 | 53 | F | 9 | ET | Lips | None | Clonazepam | Metoprolol, Lorazepam, Amirtriptyline, Anticholinergics, Alcohol, caffeine | CT head, isotope brain scan normal |
| 33 | Wee7 | 6–7 | 70 | F | 15 | ET | Clonazepam | Propranolol, diazepam, perphenazine, lorazepam, clorazapate, amitripyline | |||
| 34 | Gabellini10 | 6–7 | 75 | F | 3 | NA | Postural arm, tongue | ||||
| 35 | Gabellini10 | 6–7 | 64 | M | 3 | NA | |||||
| 36 | Gabellini10 | 6–7 | 66 | M | 4 | NA | |||||
| 37 | Gabellini10 | 6–7 | 59 | M | 3 | NA | Postural arm | Hydrocephalus aqueduct stenosis, parkinsonism | Phenobarbitone, VP shunt | CT head hydrocephalus due to non-tumral aqueduct stenosis | |
| 38 | Gabellini10 | 6–7 | 47 | F | 7 | NA | Postural arm | Chronic relapsing polyradiculoneuropathy | Prednisone | CT head normal | |
| 39 | Alonso-Navarro35 | 6–7 | 60 | M | 0.5 | Sulpiride and thyethlperazine induced | Stop DA blocker | ||||
| 40 | Kang54 | 6–7 | ^ | F | Parkinsonism | Propranolol, Levodopa, Clonazepam, Benztropine | |||||
| 41 | Kobylecki31 | 7–7.5 | 46 | F | 2 | # | Postural arm, head | Dystonia | Trihexyphenidyl | ||
| 42 | Kobylecki31 | 7.5 | 33 | M | 16 | # | Rest + postural arms, head | Dystonia | Propranolol | Topiramate | |
| 43 | Benito Leon34 | 7–8 | 49 | F | NA | NA | None | Right pontine cavernoma, resection with right CN 6, 7 palsies, ataxic gait | Clonazepam | MRI brain postsurgical changes of resected right pontine cavernoma | |
| 44 | Leu-Semenescu17 | 7.5–9 | 76 | F | 8 | NA | Rest arm bilateral 6.8 Hz | PD | Clonazepam | NA | NA |
| 45 | Thompson6 | 8 (coexistent 16 Hz) | 55 | M | NA | None | Postural arm 10 Hz | None | - | Alcohol | CT head normal |
| 46 | Deuschl40 | 8 (coexistent 16 Hz) | 48 | F | 6 | ET | Hand | _ | Primidone | Benzodiazepine, Trazodone, Amitriptyline | _ |
| 47 | Cano15 | 8 (coexistent 16 Hz) | 54 | M | Gabapentin | ||||||
| 48 | Kobylecki31 | 8 | 77 | F | 15 | # | Postural arm | Dystonia | |||
| 49 | Mazzucchi59 | 8 | 70 | F | 1 | NA | None | Graves’ disease | Methimazole | MRI brain and spinal cord normal | |
| 50 | Lin47 | 8–9 | 26 | M | 0.3 | NA | None | Graves’ disease | Methimazole | Clonazepam | MRI brain, T, LS spine normal |
| 51 | Uncini28 | 8–10 | 73 | M | 0.5 | None | Postural hand | Primidone | Propranolol | CT head normal | |
| 52 | Williams27 | 9 | 70 | F | 1.5 | NA | Postural arm | Ataxia, mild cognitive impairment | NA | NA | SPECT normal; MRI Brain cerebellar atrophy |
| 53–60 | Rigby20 | <10 | 75* | 7F; 1M | 2* | Tremor 3/8 | Postural arm 6/8 | None | Clonazepam, Gabapentin, Primidone | ||
| 61 | Coffeng29 | 10–11 | 86 | M | 0.5 | NA | Postural arm | None | NA | NA | MRI brain age-related atrophy |
| 62 | Pazzaglia3 | 10–12 | 56 | M | Parkinsonism, tabes dorsalis | ||||||
| 63 | Pazzaglia3 | 10–12 | 66 | M | Flaccid paralysis, parkinsonism | ||||||
| 64–69 | Rigby20 | 10–13 | 69.5* | 2F; 4M | 8.0* | 0 | Postural arm 2/6 | Spinal dural AVF, Cerebellar degeneration, autoimmune PQ antibodies, PN, myelopathy | Clonazepam, Gabapentin | ||
| 70 | Fitzgerald8 | 12 | 70 | M | 5 | ET | Postural hand 8–9 Hz | ET | Clonazepam, Phenobarbital | Primidone, Valproate | NA |
[i] *Mean; ^Duration was calculated as age at diagnosis minus age at onset for some cases; +Invernizzi et al. reported case 3 in Thomas 2007 paper in more details; #Kobylecki et al. reported 2/8 with ET family history and 3/8 had co-contraction or irregular relationship between ipsilateral agonists/antagonists; ^Kang et al. reported mean age 59 years in case series. Abbreviations: AVF, Arteriovenous Fistula; ET, Essential Tremor; L, Left; LS, Lumbosacral; MS, Multiple Sclerosis; PD, Parkinson Disease; PEO, Progressive External Ophthalmolpegia; R, Right; T, Thoracic.
Table 2
Electrophysiology Characteristics of Slow OT (Listed in Order of EMG Frequency) (N = 70 cases)
| Burst Duration, Other Comments | ||||||||
|---|---|---|---|---|---|---|---|---|
| 1 | Kang54 | 3–4 | NA | F | R distal synchronous, L proximal alternating bursts | |||
| 2 | Hegde33 | 3–4 | 69 | M | Alternating bursts in corresponding TAs | |||
| 3 | Bonnet49 | 3.2–3.5 | 45 | M | OT and postural leg tremor had same frequency 3.2–3.5 Hz | |||
| 4 | Oda14 | 4 | 79 | F | Not evoked by muscle contraction against resistance | Alternating bursts in antagonist muscles. Synchronous in corresponding leg muscles. | Reset bilaterally by unilateral voluntary or passive leg movement | |
| 5 | Yoo30 | 4 | 48 | M | Asynchronous antagonistic muscle activation | |||
| 6 | Baker36 | 4 | 38 | F | 100 ms bursts. Dominant peak 4 Hz and subharmonic 8 Hz, and 8–15 Hz subpeaks in left MG/TA | Significant unilateral and bilateral coherence at 4 Hz, 8–12 Hz, and 13–18 Hz range. | Patella tendon stimulation could not reset tremor | |
| 7 | Stitt46 | 4–4.5 | 79 | F | Longer duration EMG bursts. Did not transmit by leaning. | Synchronous bursts bilat TAs. | ||
| 8 | Yokota32 | 4.4–4.8 | 67 | F | Synchronous in corresponding leg muscles, alternating bursts in antagonist muscles | |||
| 9 | Kim55 | 4–5 | 68 | F | ||||
| 10 | Kim16 | 4–5 | 45 | F | Alternating bursts in antagonistic muscle groups | |||
| 11 | Setta48 | 4–5 (coexistent 14 Hz) | 63 | F | 14 Hz tremor leg + paraspinals which intermittently slowed to 4–5 Hz | Synchronous bursts in bilateral quadriceps at 4–5 Hz | ||
| 12 | Kang54 | 4–5 | ^ | F | R>L, R synchronous and L alternating bursts | |||
| 13 | Kobylecki31 | 4–5 | 53 | F | 150 msec bursts | |||
| 14 | Leu-Semenescu17 | 4.3–5.0 | 54 | F | 90–120 ms bursts | Coherence 0.6 at 4.8 Hz | Symmetric, R/L alternating | |
| 15 | Setta48 | 4–6 (coexistent 15 Hz) | 61 | F | 15 Hz tremor leg/paraspinals, occasionally slowed to 4–6 Hz | |||
| 16 | Lee56 | 4–6 | 81 | F | 50–120 ms bursts | Alternating bursts in analogous muscles (bilateral TAs), and right TA/MG, but synchronous is left TA/MG | ||
| 17 | Bonnet49 | 4.2–6.5 | 45 | F | OT slowed from 6.5 to 4.2 Hz over 8 yr follow-up. Rest tremor and OT had similar declining frequencies, 5.4 and 4.2 Hz | |||
| 18 | Leu-Semenescu17 | 5 | 85 | F | 110–120 ms bursts, symmetric; Rest arm L, 6 Hz, 80 ms bursts | Bilateral burst synchrony | ||
| 19 | Infante57 | 5 | 62 | M | Agonist-antagonist leg muscles | |||
| 20 | Kobylecki31 | 5.3 | 43 | M | 80 msec bursts | |||
| 21 | Kobylecki31 | 5.8 | 70 | F | 80–100 msec bursts | |||
| 22 | Alonso-Navarro35 | 5–6 | 80 | F | Synchronous agonists and antagonists | |||
| 23 | Leu-Semenescu17 | 5–6 | 57 | F | 80–100 ms bursts R leg only | |||
| 24 | Kobylecki31 | 5–6 | 50 | F | 100–120 msec bursts, Dominant frequency 6 Hz, and subpeaks 12–13 Hz, 18–19 Hz | Significant bilateral coherence at 12–14 Hz and 17–18 Hz | Variation in burst duration and asymmetry with more distinct bursts on the R. | |
| 25 | Kang54 | 6 | ^ | F | R>L, alternating bursts | |||
| 26 | Thomas18/Invernizzi58 | 6.2 | 53 | M | Subharmonic 8.1 Hz | Coherence 0.6–0.9 for 6.2 Hz vs. 0.32 for arm tremor | ||
| 27 | Kobylecki31 | 6.25 | 62 | M | 60–80 msec bursts | |||
| 28 | Thomas18 | 6.3 | 52 | M | Subharmonic 10.4 Hz | Coherence 0.6–0.9 | ||
| 29 | Cleeves45 | 6.4 | 53 | F | Synchronous antagonist muscles | Peripheral stimulation could not reset | ||
| 30 | Thomas18 | 6.7 | 47 | F | Subharmonic 14.3 Hz | Coherence 0.6–0.9 at 6.7 Hz vs. 0.13 for arm tremor | ||
| 31 | Thomas18 | 6.9 | 26 | F | Subharmonic 18.2 Hz | Coherence 0.6–0.9 | ||
| 32 | Wee7 | 6–7 | 53 | F | 6–7 Hz tremor also with legs contracted while seated | Synchronous EMG activity in antagonistic leg muscle pairs | Normal H reflex | |
| 33 | Wee7 | 6–7 | 70 | F | 6–7 Hz tremor also with legs contracted while seated | Synchronous EMG activity in antagonistic leg muscle pairs | Normal H reflex | |
| 34 | Gabellini10 | 6–7 | 75 | F | Alternating and synchronous bursts antagonistic muscles | |||
| 35 | Gabellini10 | 6–7 | 64 | M | Tremor dissipates with walking | Alternating and synchronous bursts antagonistic muscles. Marked reduction of tremor during walking | ||
| 36 | Gabellini10 | 6–7 | 66 | M | Alternating and synchronous bursts antagonistic muscles | |||
| 37 | Gabellini10 | 6–7 | 59 | M | Alternating and synchronous bursts antagonistic muscles | |||
| 38 | Gabellini10 | 6–7 | 47 | F | Alternating and synchronous bursts antagonistic muscles. Tremor appeared more irregular | |||
| 39 | Alonso-Navarro35 | 6–7 | 60 | M | Synchronous agonists and antagonists | |||
| 40 | Kang54 | 6–7 | ^ | F | L>R, alternating bursts | |||
| 41 | Kobylecki31 | 7–7.5 | 46 | F | Dominant 7 Hz frequency. | Significant bilateral coherence at 15–17 Hz + and 20 Hz | ||
| 42 | Kobylecki31 | 7.5 | 33 | M | ||||
| 43 | Benito Leon34 | 7–8 | 49 | F | Synchronous agonists and antagonists | |||
| 44 | Leu-Semenescu17 | 7.5–9 | 76 | F | 80–100 ms bursts, symmetric | |||
| 45 | Thompson6 | 8 (coexistent 16 Hz) | 55 | M | Predominantly 16 Hz tremor with intermittent halving of tremor to 8 Hz in quads coinciding with increased unsteadiness. | Alternating between antagonist muscles and synchronous in corresponding muscles for 16 Hz, but 8 Hz isolated to quads | Peripheral stimulation could not reset. Normal H reflex and sensory EPs | |
| 46 | Deuschl40 | 8 (coexistent 16 Hz) | 48 | F | Highly synchronous in leg muscles and arm muscles | |||
| 47 | Cano15 | 8 (coexistent 16 Hz) | 54 | M | 8 Hz + 16 Hz tremor | |||
| 48 | Kobylecki31 | 8 | 77 | F | 50–60 msec bursts | |||
| 49 | Mazzucchi59 | 8 | 70 | F | 80 msec bursts uniform | Alternating in agonist and antagonist muscles | Motor EP normal | |
| 50 | Lin47 | 8–9 | 26 | M | ||||
| 51 | Uncini28 | 8–10 | 73 | M | Tremor with isometric contraction also. | Synchronous EMG bursts in antagonistic muscles; out of phase between antagonist muscle pairs and synchronous in corresponding muscles | Peripheral stimulation could not reset. Normal sensory NCS, H reflex latency, and peroneal EPs. | |
| 52 | Williams27 | 9 | 70 | F | 50–100 ms. 15,22,35 Hz harmonics. Unilateral and bilateral coherence peaks at 9,15,22,35 Hz. Persisted walking backward. | Synchronous EMG bursts in bilateral gastrocnemius | ||
| 53–60 | Rigby20 | <10 | 75* | 7F; 1M | Longer duration bursts | Coherence 0.53* | ||
| 61 | Coffeng29 | 10–11 | 86 | M | Synchronous bursts in R TA and quads, and L MG | |||
| 62 | Pazzaglia3 | 10–12 | 56 | M | Less regular contractions | |||
| 63 | Pazzaglia3 | 10–12 | 66 | M | Less regular contractions | |||
| 64–69 | Rigby20 | 10–13 | 69.5* | 2F; 4M | Shorter duration EMG bursts | Coherence 0.74* | ||
| 70 | Fitzgerald8 | 12 | 70 | M | Asynchronous bursts in both legs |
[i] *Mean; ^Kang et al. reported mean age 59 years in case series. Abbreviations: EP, Evoked Potentials; L, Left; MG, Medial Gastrocnemius; NCS, Nerve Conduction Studies; TA, Tibialis Anterior; R, Right.
Table 3
Neurological and Medical Disorders Associated with Slow OT
| Parkinsonism18
Idiopathic Parkinson disease16,17,30 Genetic Parkinson disease [parkin,18,57 PINK1,18], POLG1 mutation58] Cerebellar disease27,48 Multiple sclerosis36 Dystonia *Anti-Hu antibody60 PQ calcium channel antibodies20 Graves’ disease47,59 Vocal tremor32 Essential tremor7,8 Alexander disease46 Myelopathy20 Dural arteriovenous fistula20 Dopamine blocking medication35 Chronic relapsing polyneuropathy10 Peripheral neuropathy Hydrocephalus10 |
[i] *Clinical diagnosis only.
Table 4
Differential Diagnosis of Mimics of Slow Orthostatic Tremor
| Classical orthostatic tremor (>13 Hz) Orthostatic myoclonus Re-emergent leg tremor in parkinsonism Negative myoclonus (asterixis) Isolated generalized polymyoclonus61 Titubation Clonus Postural orthostatic intolerance (hypotension, dehydration, hyperadrenergic state, deconditioning) Epileptic cortical myoclonic tremor Limb-shaking transient ischemic attack Functional tremor Enhanced physiological tremor |