Lewy body dementias. Dement Geriatr Cogn Disord 2009; 28 : 493 \200\223506 . 16. McKeith I, O \200\231Brien J, Walker Z, Tatsch K, Booij J, et al . Sensitivity and spec ifi city of dopamine transporter imaging with 123I-FP-CIT SPECT in dementia with Lewy bodie s: a phase III, multicentre study. Lancet Neurol 2007; 6(4) : 305 \200\22313 . FTD is a clinically, genetically, and pathologically heterogeneous disorder. Th e recent ad vances in unraveling the genetic and patho- logical mechanisms in FTD have greatly improved insight into these devastating diseases and will guide future research towards better trea tment of patients with FTD. 17. Walker Z, Costa DC, Walker RW, Shaw K, Gacinovic S, et al . http://www. ncbi.nlm.nih.go v/pubmed/12122169 Diff erentiation of dementia with Lewy bodies from Alzheimer \200\231s di sease using a dopaminergic presynaptic ligand. J Neurol Neurosurg Psychiatry 2002; 73(2) : 134 \200\22340 . Top clinical tips 18. Lim SM, Katsifi s A, Villemagne VL, et al. Th e 18 F-FDG PET cingulate island sign and comparison to 123 I-beta-CIT SPECT for diagnosis of dementia with Lewy bodies. J Nucl Med 2 009; 50 : 1638 \200\22345 . Frontotemporal dementia (FTD) is hereditary in 20 \200\22330% of patients in whom MAPT or P GRN gene mutations or hexanucle- otide repeat expansions in C9orf72 can be found. \227\206 19. Brooks DJ . Imaging amyloid in Parkinson \200\231s disease dementia and demen- tia with Lewy bodies with positron emission tomography. Mov Disord 2009; 24 (Suppl 2): S 742 \200 \2237 . To determine the family history, ask about the presence of FTD or dementia, Parkinson \200 \231s disease or parkinsonism, and motor neuron disease in all fi rst- and second-degree re latives. \227\206 20. Villemagne VL, Okamura N, Pejoska S, et al . Diff erential diagnosis in Alzheimer \200 \231s disease and dementia with Lewy bodies via VMAT2 and amyloid imaging. Neurodegener Dis 2012; 10 : 161 \200\2235 . Functional imaging using PET or SPECT may reveal hypome- tabolism or hypoperfusion before s tructural changes on MRI are detectable. \227\206 21. Johansen KK, White LR, Sando SB, Aasly JO . Biomarkers: Parkinson dis- ease with dement ia and dementia with Lewy bodies. Parkinsonism Relat Disord 2010; 16 : 307 \200\22315 . 22. Mollenhauer B, Locascio JJ, Schulz-Schaeff er W, Sixel-Doring F, Trenkwalder C, Schloss macher MG . Alpha-synuclein and tau concen- trations in cerebrospinal fl uid of patients pr esenting with parkinsonism: a cohort study. Lancet Neurol 2011; 10 : 230 \200\22340 . Genetic counseling is possible in patients with hereditary FTD. \227\206 Th e underlying pathology in FTD can be tau, TDP-43, or FUS. \227\206 CHAPTER 15 Primary Dementia Syndromes and Parkinsonism 161 41. Renton AE, Majounie E, Waite A, et al . A hexanucleotide repeat expan- sion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011; 72 : 257 \200\22368 . 23. Aarsland D, Laake K, Larsen JP, Janvin C . Donepezil for cognitive impair- ment in Park inson \200\231s disease: a randomized controlled study. J Neurol Neurosurg Psychiatry 2002; 72 : 708 \200\22312 . 42. Brettschneider J, van Deerlin, VM, Robinson JL, et al . Pattern of ubiqui- tin patholog y in ALS and FTLD indicates presence of C9ORF72 hexanu- cleotide expansion. Acta Neuropatho l 2012; 123 : 825 \200\22339 . 24. Emre M, Aarsland D, Albanese A, et al . Rivastigmine for dementia asso- ciated with Par kinson \200\231s disease. N Engl J Med 2004; 351 : 2509 \200\22318 . 25. McKeith I, Del ST, Spano P, et al . Effi cacy of rivastigmine in dementia with Lewy bod ies: a randomized, double-blind, placebo-controlled inter- national study. Lancet 2000; 356 : 2031 \200\2236 . 43. Cooper-Knock J, Hewitt C, Highley JR, et al . Clinico-pathological fea- tures in amyotr ophic lateral sclerosis with expansions in C9ORF72. Brain 2012; 135 : 751 \200\22364 . 26. Emre M, Tsolaki M, Bonuccelli U, et al . Memantine for patients with Parkinson \200\231 s disease dementia or dementia with Lewy bodies: a randomized, double-blind, placebo-contro lled trial. Lancet Neurol 2010; 9 : 969 \200\22377 . 27. Seelaar H, Rohrer JD, Pijnenburg Y A, Fox NC, van Swieten JC . Clinical, genetic and pathological heterogeneity of frontotempo ral dementia: a review. J Neurol Neurosurg Psychiatry 2011; 82 : 476 \200\22386 . 44. Snowden JS, Rollinson S, Th ompson JC, et al . Distinct clinical and pathological chara cteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 2012; 135 : 693 \200\223708 . 45. Dobson-Stone C, Hallupp M, Bartley L, Shepherd CE, Halliday GM, Schofi eld PR . C9orf72 repeat expansion in clinical and neuropathologi- cal dementia cohorts. Neurology 2012; 79 : 995 \200\2231001 . 28. Rascovsky K, Hodges JR, Knopman D, et al . Sensitivity of revised diag- nostic criteria for the behavioral variant of frontotemporal dementia. Brain 2011; 134 : 2456 \200\22377 . 46. Sha SJ, Takada LT, Rankin KP, Yokoyama JS, Rutherford NJ, Fong JC . Frontotemporal deme ntia due to C9orf72 mutations: clinical and imag- ing features. Neurology 2012; 1002 \200 \22311 . 29. van Swieten J, Spillantini MG . Hereditary frontotemporal dementia caused by Tau gene mutations. Brain Pathol 2007; 17 : 63 \200\22373 . 47. Mahoney CJ, Beck J, Rohrer JD, Lashley T, Mok K, Shakespeare T, et al . Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and ne uropathological features. Brain 2012; 135 (Pt 3) : 736 \200\22350 . 30. Spillantini MG, Goedert M . Tau protein pathology in neurodegenerative diseases. Trends Neurosci 1998; 21 : 428 \200\22333 . 31. Boeve BF, Hutton M. Refi ning frontotemporal dementia with parkin- sonism linked to chr omosome 17: introducing FTDP-17 (MAPT) and FTDP-17 (PGRN). Arch Neurol 2008; 65 : 460 \200 \2234 . 48. Whitwell JL, Weigand SD, Boeve BF, et al . Neuroimaging signatures of frontotemporal de mentia genetics: C9ORF72, tau, progranulin and spo- radics. Brain 2012; 135 : 794 \200\2238 06 . 32. Cruts M, Gijselinck I, van der Zee J, et al . Null mutations in progranulin cause ubiqu itin-positive frontotemporal dementia linked to chromo- some 17q21. Nature 2006; 442 : 920 \200\2234 . 49. Boeve BF, Boylan KB, Graff -Radford NR, et al . Characterization of fron- totemporal de mentia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 2012; 135 : 765 \200\22383 . 33. Baker M, Mackenzie IR, Pickering-Brown SM, et al . Mutations in pro- granulin cause tau -negative frontotemporal dementia linked to chromo- some 17. Nature 2006; 442 : 916 \200 \22319 . 50. Simon-Sanchez J, Dopper EG, Cohn-Hokke PE, et al . Th e clinical and pathological pheno type of C9ORF72 hexanucleotide repeat expansions. Brain 2012; 135 : 723 \200\22335 . 34. van Swieten JC, Heutink P . Mutations in progranulin (GRN) within the spectrum of clini cal and pathological phenotypes of frontotemporal dementia. Lancet Neurol 2008; 7 : 965 \200\22374 . 51. Mahoney CJ, Beck J, Rohrer JD, et al . Frontotemporal dementia with the C9ORF72 hexanuc leotide repeat expansion: clinical, neuroanatomical and neuropathological features. Brain 2 012; 135 : 736 \200\22350 . 35. Cairns NJ, Neumann M, Bigio EH, et al . TDP-43 in familial and spo- radic frontotempora l lobar degeneration with ubiquitin inclusions. Am J Pathol 2007; 171 : 227 \200\22340 . 52. McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ . Clinical and p athological diagnosis of frontotemporal dementia: report of the Work Group on Frontotempora l Dementia and Pick \200\231s Disease. Arch Neurol 2001; 58 : 1803 \200\2239 . 36. Neumann M, Sampathu DM, Kwong LK, et al . Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006; 314 : 130 \200\2233 . 53. Pijnenburg YA, Schoonenboom NS, Rosso SM, et al . CSF tau and Abeta42 are not useful in the diagnosis of frontotemporal lobar degen- eration. Neurology 2004; 62 : 1649 . 37. Le Ber I, Camuzat A, Hannequin D, et al . Phenotype variability in pro- granulin mutati on carriers: a clinical, neuropsychological, imaging and genetic study. Brain 2008; 131 : 7 32 \200\22346 . 54. Lebert F, Stekke W, Hasenbroekx C, Pasquier F . Frontotemporal demen- tia: a randomized , controlled trial with trazodone. Dement Geriatr Cogn Disord 2004; 17 : 355 \200\2239 . 38. Rademakers R, Baker M, Gass J, et al . Phenotypic variability associ- ated with progran ulin haploinsuffi ciency in patients with the common 1477C \206\222 T (Arg493X) mutation: an international initiative. Lancet Neurol 2007; 6 : 857 \200\22368 . 55. Deakin JB, Rahman S, Nestor PJ, Hodges JR, Sahakian BJ . Paroxetine does not improve sy mptoms and impairs cognition in frontotemporal demen- tia: a double-blind randomized contro lled trial. Psychopharmacology 2004; 172 : 400 \200\2238 . 39. Rohrer JD, Warren JD, Omar R, et al . Parietal lobe defi cits in frontotem- poral lobar degeneration caused by a mutation in the progranulin gene. Arch Neurol 2008; 65 : 506 \200 \22313 . 56. Miller RG, Mitchell JD, Moore DH . Riluzole for amyotrophic lateral scle- rosis (ALS)/m otor neuron disease (MND). Cochrane Database Syst Rev 2012; 3 : CD001447 . 40. Jesus-Hernandez M, Mackenzie IR, Boeve BF, et al . Expanded GGGGCC hexanucleotide repea t in noncoding region of C9ORF72 causes chromo- some 9p-linked FTD and ALS. Neuron 2011; 72 : 245 \200\22356 . This page intentionally left blank CHAPTER 16 Essential Tremor and Other Tremors Ste \200 en Paschen and G nther Deuschl Essential tremor Epidemiology Essential tremor (ET) is the second most common move- ment di sorder and the most frequent tremor type (1). A recent meta-analysis of 28 studies found th e overall prevalence to be 0.4 \200\2230.9% and the prevalence in people aged 60 and above to be 4.6% (1). However, prevalence estimates vary between 0.008 and 22%, and increase with age. A third of published studies show a gender diff erence, with males generally being af f ected more oft en (1). Most people with ET have only a mild tremor and have not consulted a physician about their problem (2, 3). In a recent population-based study of subjects age d over 50, the prevalence of any kind of tremor was 14.5%, with 3.05% suff ering from ET, 9 .52% from exaggerated physiological tremor, 2.75% from par- kinsonian tremor, and fewer tha n 0.2% from other tremors (4). Most patients with ET do not receive a diagnosis and therefo re are never treated (3). the overwhelming epidemiological, genetic, pathological, and clin- ical information does no t support it (19). Th us the relationship is unclear and needs further study, but in practi ce we do not explain this possible risk to our patients. Pathology of ET Routine post-mortem studies have not shown a consistent pathol- ogy (20, 21 ). However, two pathological variants have recently been proposed in a group of 33 patients (22 \200\22331): a cerebellar variant in 75% of the patients with Purkinje cell loss, axon al torpedoes, and basket cell changes, and a Lewy body variant in about 25% with increased numbers of brainstem Lewy bodies. So far these fi nd- ings have not been reproduced. One gr oup found no increase in Lewy bodies, but observed some cases with cerebellar pathology (32 ), and another group did not fi nd a higher Purkinje cell loss in ET patients compared with controls (33). Incidental neuropathol- ogy and the clinical diagnosis of the patient may c ompromise the results and therefore more studies are needed. Etiology and genetics Twin studies have shown a high heritability of ET of up to 99% (5), a nd therefore genetic factors play a major role in pathogenesis of the condition. Moreover, 80% of young patients with early-on- set ET have a positive family history (6). Genetic ana lysis has so far revealed three chromosomal loci: 3q13 (ETM1) (7), 2p22 \200\22325 (ETM2) ( 8), and 6p23 (ETM3) (9), but attempts to fi nd the respon- sible genes in these loci (e.g. dopamine D3 receptor or heat shock 1 protein) have been unsuccessful (10). A genome-wide as sociation study demonstrated an association of ET with the protein LINGO1 (7), and this was subsequently confi rmed in independent cohorts (10 \200\22315). LINGO1 has diff erent func tions and is involved in myeli- nation of the central nervous system (CNS). Regarding envir on- mental factors, harmaline, a beta-carboline which produces tremor in animals and intoxi cation in humans, has also been shown to pro- duce an action tremor in humans (16). Beta-ca rbolines have been found to be elevated in the blood of ET patients compared with controls (17). Pathophysiology and pathogenesis Physiological mechanisms generating tremor Almost all path ological tremors, particularly ET, emerge from net- works within the central nervous system . ET and parkinsonian tremor are the most common examples. Damped mechanical oscil- lations and refl ex contributions may also contribute to the expres- sion of tremor (34), but they play a minor role. Coherence analysis of tremor signals and simultanous electro- encephalography (EEG) or magn etoencephalography (MEG) have revealed involvement of the ipsilateral cerebellum and contra lateral thalamus and sensorimotor cortex in ET (35, 36). Th erefore, it is believed that th ese structures are involved in the genesis of essen- tial tremor. For many reasons it is as sumed that the olivocerebel- lothalamic nuclei play a pacemaker role in ET, but this has no t yet been proved. Coherence analysis has also been used to study the relation between rhyt hms in the muscles of diff erent extremities. Th ere is oft en strong coherence between the muscles of one extrem- ity, little or no coherence between the muscles of the ipsilateral arm and leg, and no coherence between extremities on diff erent sides of the body (37, 38). It is believed that rhythmically fi ring thalamic Th ere is an ongoing discussion about ET as a risk factor for developing Parkinson \200\231 s disease. Th is notion is supported by epide- miological studies which have recently been summarized (18), but Oxford Textbook of Movement Disorders 164 neurons have variable coherence with ET recorded from various muscles. Th us, the \200\230 central oscillator \200\231 in these disorders may be a network of many variably coupled os cillators. Th e sensitivity and specifi city of the supportive criteria are unknown. It is assumed tha t any other cause of tremor should become obvious aft er a period of 3 years. A family hist ory of tremor is usually assumed if patients report more than two rela- tives with an obvio us postural tremor. Alcohol sensitivity is not pathognomonic for ET as it can also be found in other conditions (43), such as myoclonic dystonia, although it is probably more fre- qu ently found in ET even though many patients are not aware of this eff ect. General concepts on the genesis of ET Overall, two pathophysiological hypotheses for the de velopment of ET are currently accepted (39). In the fi rst, ET is thought to be a disorder which is primarily limited to the release of tremor- genic neuronal oscillations in the cen tral nervous system which is caused by both genetic abnormalities and non-genetic factors ( 39, 40). Such neuronal oscillations could be generated by, for exam- ple, altered ion chann els or altered receptors for neurotransmitters. Th is would fi t with the overall benign co urse apart from tremor, the lack of consistent pathology, and the potential reversibility. Th e other hypothesis assumes that genetic factors together with puta- tive non-genetic fac tors might lead to neurodegeneration, which consequently causes the tremor syndrome and oth er disturbances of neurological function (27). In this sense, it is proposed that ET is a n eurodegenerative disease. Th e evidence for this hypothesis is relatively weak, given the b enign course of the disease and the inconsistent pathological data. Clinical features of ET Th e topographical distribution of ET diff ers from other tremors. A meta-analysis of 1569 patients illustrated that the tremor in ET has a typical topographi cal distribution, with the hands aff ected in 94% (80 \200\223100%), the head in 33% (20 \200\22341%), the voice in 16% (9 \200\22320%), the chin in 8% (0 \200\2239%), the face in 3%, and the trunk in 2.5% (0 \200\2233%) (44, 45). Alcohol leads to a reduction of the trem or in two out of every three patients. Moreover, there are no signifi cant diff erences in clinical features between patients with a positive fam- ily history and sporadic cases. Th e main characteristic of ET is the bilateral visible postural and kinetic tremor of the forearms. In advanced ET, which is more common at older ages, a subgroup of 50 \200\22360% of patients develop a severe intention tremor of the hands which is found in cerebellar dis ease. Intention tremor is a characteristic hallmark of a cerebellar syndrome and may be see n in advanced essen- tial tremor syndrome (46), but clinically visible cerebellar symp- tom s are generally unusual in ET, except for impaired tandem gait. Tremor at rest occurs in 10 \200\22315% (47, 48). Sometimes slight postural abnormalities may be observed, such as fl exion of the hands during postural tasks in the context of upper limb tremor or slight devi ations of the head in cases of head tremor. Th ese signs have been interpreted as evidence of dystonic tremor (49) but they could also be a postural adaptation to minimize tremor amp litude. Diagnosis Since no specifi c biomarker or diagnostic test is available, the diagnosis of ET is mainly based on clinical examination and the patient \200\231s history. Th e published clinical criteria for the diagnosis in ET diff er slightly. An ad hoc group of the Movement Disorder Society (MDS) agreed on the following defi nition of classic ET in a consensus st atement (41) (Table 16.1). Th e criteria of the Tremor Investigation Group (TRIG) are simi- lar, but they exclude isol ated head tremor in the absence of dys- tonic posturing as a variant of ET and suggest a 5- year history of hand tremor without any signs of other disease for the diagnosis of defi ni te ET (41). However, the presenting symptom of ET is always tremor. Finally, particularly f or epidemiological studies, research criteria have been defi ned which request that, in add ition, the tremor has an amplitude of at least 2 cm (42). Th e condition may begin in childhood, but the incidence increases above age 40 years, with a mean onset at 35 \200\22345 years (50, 51). At older ages the incidence increases, but m ost cases seem to be sporadic and there is almost complete penetrance for familial cases by the age of 65 (5, 52). Currently, few data on progression of the condition are available, but they have shown a decrease in tremor frequency and a tendency to develop larger amplitu des (53). Intention tremor develops between 3 and 30 years aft er the onset of postural tre mor (46). Table 16.1 Diagnostic criteria for essential tremor (41) Inclusion criteria 1. Bilateral, largely symmetric postural or kinetic tremor involving han ds and forearms that is visible and persistent 2. Additional or isolated tremor of the head may occur but in the absence of abnormal posturing Disease-related disability varies signifi cantly and depends on the severity of intention t remor (2). Disability and handicap vary among patients. Notably, studies with community-bas ed cohorts show less severe tremor compared with outpatient cohorts. Fine motor control of the hands is most aff ected, leading to impair- ments in activities of daily living (ADL) s uch as eating, drinking, and writing. In severe cases the patients are unable to drink and eat independently. Head and voice tremor may cause separate disabili- ties, including handi caps in communication. Tremor severity has been classifi ed on the basis of the ability to drink from a glass (54). Most patients suff er from a signifi cant disability (55). Up to 2 5% of patients seeking medical attention have to change jobs or retire from work (56, 57). A third to two-thirds of outpatient cohorts have reduced working abilities or retire premat urely (3, 58). On a generic quality of life (QoL) questionnaire ET patients had reduced sco res Exclusion criteria 1. Other abnormal neurological signs, especially dystonia, in addition t o the cogwheel sign and a mild gait impairment 2. Th e presence of known causes of enhanced physiological tremor, including current or rec ent exposure to tremorgenic drugs or the presence of a drug withdrawal state 3. Further exclusion criteria: evidence for psychogenic tremor, primary orthostatic tremor, isolated voice tremor, isolated position-speci \201 c or task-speci \201 c tremors (primary writing tremor), other isolated tremors (tongue, chin, leg) Supportive criteria 1. Tremor duration of >3 years 2. Positive family history 3. Reduction of tremor by alcohol (in 50 \200\22390% of patients with ET) CHAPTER 16 Essential tremor and other tremors 165 in all eight domains of the SF-36. Tremor severity correlated with some of the physical dom ains, as well as with social function in the mental domains (48). tremor. Th ere are proposals to defi ne essential tremor on the basis of such measurements (70). Th ese criteria are as follows (70, 71): rhythmic bursts of postural tremor on EMG; \227\206 Tremor severity is measured clinically using the Fahn \200\223Tolosa \200\223 Marin scale ( 59), which has been validated. An ET-specifi c QoL questionnaire has recently been validate d (60). tremor frequency greater than or equal to 4 Hz; \227\206 absence of latency of tremor recurrence when the hands are mov- ing from rest into postural position; \227\206 Additional symptoms Patients with ET may also suff er from a mild ataxic gait disorder whic h can be detected on tandem gait testing (61), particularly in those with a visible intenti on tremor of the hands. Furthermore, patients with ET have minor changes in oculomotor func tion which can be detected using formal oculographic measurements, again pointing to subtle but defi nite cerebellar dysfunction (62). Th e cerebellar disturbance of ET does not wors en with small amounts of alcohol, as would be expected in most cerebellar disease (63). Fur thermore, a frontal dysexecutive syndrome and mild personal- ity changes have been describe d in ET (64, 65). More recently, an increased frequency of dementia (66, 67), hearing defi cits (68), and defi cits of olfaction (69) have been described, although these fi nd- ings need independent confi rmation. changes of the dominant frequency peak less than or equal to 1 Hz aft er the weight load te st (Fig. 16.1); \227\206 no changes in tremor amplitude aft er mental concentration. \227\206 Th e major signifi cance of these criteria may be to assist in the dif- ferentiation of ET from other tremors, although further validation is necessary (70, 72). Th e most frequent diff erential diagnostic considerations are enhanced physiological, park insonian, dystonic, and psychogenic tremors. Enhanced or exaggerated physiological tremor is probably the most important diff erential d iagnosis as it is even more common than essential tremor. Enhanced physiological tremor is a revers- ible tremor with mainly postural and action tremor of the hands (41). It may occu r as a side eff ect of medication, or as a symptom of other disease. Electrophysiological t ests may help to separate ET from enhanced physiological tremor (Fig. 16.1). A detailed med ical history with a particular focus on medication (see Table 16.3) and laboratory diagnost ics (see Table 16.4) should be conducted. Di \200 erential diagnosis and ancillary tests Neurophysiological tests can be used in cli nical practice. Tremor can be measured with accelerometry and electromyography, which give the power, frequency, and additional characteristics of the Physiological tremor (mechanical component) Enhanced physiological tremor (re \202ex component) Physiological tremor (central component) Central essential tremor r e t e m o r e l e c c A ) d e d a o n u ( e r u t s o P l G M E r e t e m o r e l e c c A ) g 0 0 0 1 : d a o l ( e r u t s o P G M E 0 5 10 15 20 0 5 10 15 20 0 5 10 15 20 0 5 10 15 20 Hz Fig. 16.1 Frequency analysis of hand accelerometry and wrist extensor electromyogram. Th e \201 rst column shows a mechanical tremor in the upper row and the EMG signal which is \202 at. Loading of the hand with 1000 g shows a decrease of the mechanical frequency witho ut synchronization of the EMG. Th e second column shows a reduction of both accelerometry a nd EMG signal during loading which indicates a re \202 ex origin of tremor. Th e third col umn shows a central component in physiological tremor which is typically invariant to loadi ng of the hand and is only rarely found in normal subjects. Th e last column shows the \201 ndings in essential tremor. (Modi \201 ed from Deuschl G, Raethjen J, Lindemann M, Kr ack P. Th e pathophysiology of tremor. Muscle Nerve 2001; 24: 716 \200\22335) Oxford Textbook of Movement Disorders 166 Essential tremor Early Parkinson s disease Fig. 16.2 Dopamine transporter imaging with SPECT in a patient with essential tremor and a patient with very early Parkinson \200\231s disease. Unilateral reduction of dopamine trans porter binding can be seen in the PD patient, but the pattern is symmetric in the ET patien t. Detailed quantitative assessment demonstrates bilateral reduction in the PD patient. (Co urtesy of Dr L rcken, Dr Luetzen, and Professor Henze, Department of Nuclear Medicine, K iel University) Parkinsonian and essential tremor can oft en be separated on clinical grounds as most PD pa tients suff er from tremor at rest, have a cessation of tremor when voluntary movements are initi- ated, and display additional symptoms such as akinesia, rigidity, and postural dist urbances. However, early PD can easily be misin- terpreted as ET, and vise versa. Electroph ysiological criteria may be useful, and advanced methods of accelerometry and EMG anal- ysi s seem to separate the two conditions with high accuracy (72). Dopamine transporter SPECT o r PET imaging of the dopaminer- gic system is currently the most sensitive test for the dif f erential diagnosis of parkinsonian tremor, as the depletion of dopamine within the striat um is considered a hallmark of Parkinson \200\231s disease (Fig. 16.2). Th e sensitivity an d specifi city of these imaging tests are high, but the costs are considerable and their av ailability is limited. depends on the severity of tremor, the objective needs for improv- ing tremor severity, the psychosocial handicap, and the individual coping strategies. Th e same objective severity of tremor may or may not lead to initiation of treatment in diff erent patients. Pharmacotherapy All interventions for the treatment of ET have been discovered by chance. T h e exact mechanisms of action of drugs, deep brain stim- ulation (DBS), and lesioning are unclear. Presumably, drugs used in ET interfere with the widespread pathological oscillatio ns which occur throughout the motor system in the disorder (73). Surgical lesioning and DBS are thought to disrupt these oscillations, lead- ing to reduced tremor amplitude. All drug s recommended in this chapter have other approved clinical indications. Using them for trea tment of ET might be off -label in some countries. In order to improve compliance, the pati ent should be informed that pharma- cotherapy cannot entirely suppress tremor. Dystonic tremor usually starts with a focal distribution and may have additional clear-cut dystonic features. Th e separation of ET from psychogenic tremor is generally possible on c linical grounds. Th e co-contraction sign and the entrainment eff ect of psychogenic tremor are the most useful clinical tests. Treatment eff ects can be quantifi ed with rating scales or accel- erometry, and the relati on between these measures is well known (74). Th is was used in a recent review (73) to cal culate the percent- age improvement found for the diff erent interventions and these values are reported here (Table 16.2). Th e management of patients with ET Th erapeutic principles Since the cause of essential tr emor is still unknown, no cura- tive therapies are available. In the long-term management o f ET patients the fi rst step is always to make a proper diagnosis and to counsel the patie nt that the condition is usually slowly progressive and not a sign of a life-threatening di sease. Most patients worry that this tremor is the fi rst sign of PD. Treatment needs to be as indi- vidualized as possible. Th e indication for starting treatment for a particular p atient is mainly determined by the impairment, which Treatment attempts will be reported for hands, head, and voice separately. First-line pharm acotherapy for hand tremor has remained unchanged during the last three decades; several co ntrolled trials have shown that non-selective beta-blockers, especially propranolol, and th e anti-epileptic drug primidone are able to reduce tremor amplitude by approximately 50 \200\22360% (75, 76). Primidone is usually preferred in older patients with a possible risk of a concomitant cardiac and/or pulmonary dis- ease. Side eff ects of primidone (e.g. drow siness, dizziness, and CHAPTER 16 Essential tremor and other tremors 167 Table 16.2 Recommended drugs for the treatment of essential hand tremor (73) Recommendatio n Drug and dosage Improvemen t Treatment recommendation First-line Propranolol Dosage: 3 \227 20 to 3 \227 40 mg/day, maximum dosage 320 mg/day Primidone Do sage: 62.5 \200\223250 mg in evening, maximum dosage 750 mg/day 55% A 60% A Second-line Topiramate Increase dosage weekly by 25 \200\22350 mg, standard dosage 2 \227 50 to 2 \227 250 mg, maximum dose 400 mg/day 40% B Gabapentin Increase dosage every 3 \200\2235 days by 300 mg, standard dosage 3 \227 300 to 3 \227 600 mg, maximum dose 2400 mg/day 40% B Th ird-line Clonazepam Start with 3 \227 0.5 mg, increase dosage by 0.5 mg every 2 days, standard dosa ge 3 \227 0.5 to 3 \227 2 mg Alprazolam Start with 3 \227 0.25 \200\2230.5 mg, increase dosage every 3 days by 0.25 \200\2230.5 mg, standard dose 3 \227 0.5 to 3 \227 1 mg Botul inum toxin Symmetric injections in cervical muscles; recommended dosages: see cervical dyst onia \200\223 C (intention tremor) 50% C (risk of addiction) \200\223 C (hand tremor) \200\223 B (head tremor) Deep brain stimulation Destructive therapies like thermocoagulation have been largely aband oned since the discovery of DBS. DBS of the nucleus ventrointermedius of the thalamus (Vim) (90) is an efficient treatment in patients who are unresponsive to medical therapy, althou gh controlled studies are not yet available. Improvements are of the order of 90%, superior to any pharmacological inter- vention reported so far (73). Long-term follow-up suggests a loss of tremor control for various reasons (83). Stimulation-induced side effects (e.g. dy sarthria, paraesthesias, dystonia, balance dis- turbances, ataxia, and limb weakness) can u sually be reduced by adjusting stimulation parameters. Hardware complications may occur in up to 25% of patients (e.g. lead fracture, infec- tions, connection cable malfunction). The risk of a perioperative complication, including intracerebral hemorrhage, ischaemic stroke , or infection is less than 2% (91). The optimum stere- otactic target of Vim stimulation i s considered below the Vim in the radiation pre-lemniscalis and the caudal zona incerta (92 ) (Fig. 16.3). Other targets like the zona incerta and the subtha- lamic nucleus have been proposed, but have not yet been ade- quately studied (73). disequilibrium) are common when treatment is started. Th erefore a starting dose of 62.5 mg or less in the evening is recommended. Fatigue is a common and sometimes dose-limiting sid e eff ect of primidone. Propranolol is usually favored over primidone in young patients without any evidence of hea rt disease or bronchial asthma. Side eff ects such as bradycardia, syncope, fatigue, and er ectile dysfunc- tion may be dose-limiting. Treatment should start with 20 \200\22360 mg/ da y, and the dose should be increased gradually. Total daily doses of 60 \200\223240 mg are a dequate in most responders (73). If one of the fi rst-line drugs does not suffi ciently imp rove tremor it should be increased to the maximally tolerated dosage. Th e two drugs can be combined if required. Second-line drugs (Table 16.2) include topiramate and gabapentin (73). Alprazolam showed co mparable eff ects to fi rst-line medication in less rigorous trials, but as it is a benzodi azepine it is not recom- mended for long-term treatment because of its addictive potential. Studies with selective beta-blockers (e.g. atenolol, sotalol) have shown less benefi cial eff ects than the non-selective beta-blocker pro- pranolol (73). Injection of botulinum tox in in hand muscles has been successfully used for hand tremor, but symptomatic hand weaknes s in 30 \200\22370% of patients limits its use (77). In patients with advanced ET, intentio n tremor can cause serious disability. Th ompson and co-workers (78) showed that clonazepam can specifi cally improve action tremor compared with propranolol. Other tremors Enhanced physiological tremor Th e term enhanced physiological tremor (EPT) r efers to a tremor with the frequency and activation characteristics of normal physi- ologic al tremor but with a larger amplitude when all other causes of tremor are excluded. It is a visible postural and action tremor which can be troublesome, particularly on action. Th er e are many causes for the enhancement of tremor (Table 16.3), among which drugs are the mos t common (Table 16.4). Th e exclusion of other neurological symptoms or diseases that could cause tremor is mandatory for the diagnosis (41). For tremors of unknown origin, the labor atory tests summarized in Table 16.5 may be considered. Moreover, in the case Head and voice tremor are usually less suppressed than hand tremor with drug therapy (73). Improvements of 30 \200\22350% in head tremor with propranolol and primidone have been repo rted in sev- eral studies (79, 80). For severe head tremors, particularly when an intention tremor is present, patients may require bilateral DBS which can reduce head tremor by up t o 75% (81 \200\22386). Treatment of voice tremor with propranolol and methazolamide did not show a positive eff ec t (87). Results for laryngeal botulinum toxin injections for voice tremor are confl icting. Typical side eff ects are a weak voice, coughing, and dysphagia (88, 89). Oxford Textbook of Movement Disorders 168 Table 16.4 Drugs with tremor as a possible side e \200 ect Group Beta-adrenergic drugs Example Fenoterol, salbutamol Phosphodiesterase inhibitors Th eophylline, ca \200 eine i . V.op m V v.o.d Anti-arrhythmic drugs Amiodarone, mexiletine, procainamide i i . c . V Calcium-channel inhibitors Nifedipine, amlodipine Ce.pc Immunotherapy Ciclosporin, tacrolimus, interferon Antidepressants Tricyclic antidepressants, SSRIs Cp.i.p Lithium Zi H2 Neuroleptics, antidopaminergics Haloperidol, metoclopramide Ra.prl Antiepileptics Valproate, lamotrigine Zi L.m Anti-infective agents Co-trimoxazole, amphotericin B, vidarabine Sth Str.pd.i G L Hormone therapy Th yroxine, calcitonin, progesterone, corticosteroids Tm Ni II Table 16.5 Recommended laboratory tests for postural and action tremors of unknown origin L aboratory value Th yroid (T 3 , T 4 , TSH) Electrolytes (Na + , K + , Ca 2+ , Cl \200\223 ) Question Hyperthyroidism Fig. 16.3 Targets for the standard treatment of tremor (73). Th e standard target is the nu cleus ventrointermedius of the thalamus (Vim, gray dot) and the region below the Vim, the r adiation pre-lemniscalis (Ra.prl, black dot). Less established targets are the caudal zona incerta (Zi, dark green dot) and the subthalamic nucleus (Sth, light green dot). Sth is the standard target for Parkinson \200\231s disease. Sth, corpus subthalamicum; Ra.prl, radiat io pre-lemniscalis; H 2 , ampus forelii, pars H 2 ; V.o.d, nucleus ventro-oralis dorsalis; V.op, nucleus ventro-oralis posterior; Vim.i, nucleus ventrointermedius internus; V.c.i, nu cleus ventrocaudalis internus; Ce.pc, nucleus centralis parvocellularis; Cp.i.p, capsula in terna crus posterior; Str.pd.i, striae pedunculi interni; Tm, nucleus tuberomammillaris; L, lemniscus; L.m, lemniscus medialis; Ni, nucleus niger; Zi, zona incerta; G, fasciculus gra cilis; II, opticus. Hypocalcaemia, hypokalaemia, metabolic alteration Liver enzymes (GGT, GOT, GPT, CE) Alcoholic disease, Wilson disease (hepatocerebral degeneration) Glucose Hypoglycaemia Immuno-electrophoresis Neuropathy in paraproteinaemia, neuropathic tremor If clinically suspected Serum ceruloplasmin, copper in 24 hour urine Wilson disease Table 16.3 Causes of enhanced physiological tremor Drugs Toxicological diagnostics Arsenic, bismuth, mercury, lead poisoning, alcohol-related, medication withdrawal Neuroleptics, metoclopramide, antidepressants (tricyclics), lithium, cocaine, alcohol, symp athomimetics, steroids, valproate, anti-arrhythmics (amiodarone), thyroid hormones, cytosta tics, immunodepressants anxiety is common and may be problematic for performing artists or people who need a high a ccuracy of dexterity, such as surgeons. It is thought to be mediated via increased sympathe tic tone which results in a beta-adrenergically driven sensitization of the muscle spindles , increasing the gain in the refl ex loops (94). A similar ori- gin via the sympathetic ner vous system has been proposed for the tremor in refl ex sympathetic dystrophy. Metabolic ab normalities, drugs and toxins, or withdrawal from such substances are common causes of EPT. Th e pathophysiology may be peripheral or central, depending on the cause. Toxins Mercury, lead, manganese, alcohol, DDT, lindan Metabolic disturbances Hyperthyroidism, hyperparathyroidism, hypoglycaemia, hepatic encephalopathy, magnesium de \201 ciency, hypocalcaemia, hyponatraemia Others Anxiety, fatigue, sympathetic re \202 ex dystrophy, withdrawal of alcohol or drugs of an undiagnosed, new onset tremor syndrome without discern- ible cause, a brain MRI scan is recommended if the symptoms are unilateral, since focal lesions can produce tremor. As both EPT and early ET are unaccompanied by other obvi- ous neurological symptoms, they a re diffi cult to distinguish. Th e positive family history in ET, its chronic course, and t he lack of an overt cause for the tremor are important clues. Sometimes the diagnosis can o nly be made aft er having observed the patient for an extended time period. EPT is usually bilateral and thus any tremor presenting unilaterally, even with a high frequency and a pur e pos- tural component, must be suspected to be a symptomatic tremor. Spectral analysis of accelerometry and EMG signal data can be helpful in demonstrating a centrally driven compon ent in ET (95). A frequency below 8 Hz, which can be seen in the very early stage of ET, fa vors ET rather than EPT (96). A recent study found the prevalence of EPT to be 9.5% in sub- jects over 50 years of age. E PT was much more common than ET (3.06%), parkinsonian tremor (2.05%) or Parkinson \200\231s disease (4.49%) (4). Th ere are no studies available on the natural history of the conditi on. Th e pathophysiological mechanism may be either activation of the refl ex loops (e.g. h yperthyroidism) or activation of a central oscillator which is related to physiological tre mor (93) caused, for example, by drugs.