M.W.I.M. Horstink

Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations

A Dutch family with autosomal recessive early-onset parkinsonism showed a heterozygous missense mutation in combination with a heterozygous exon deletion in the parkin gene. Although the main clinical syndrome consisted of parkinsonism, the proband clinically had additional mild gait ataxia and pathologically showed neuronal loss in parts of the spinocerebellar system, in addition to selective loss of dopaminergic neurons in the substantia nigra pars compacta. Lewy bodies and neurofibrillary tangles were absent, but tau pathology was found.

The clinical benefit of imaging striatal dopamine transporters with [123I]FP-CIT SPET in differentiating patients with presynaptic parkinsonism from those with other forms of parkinsonism

Abstract[123I]FP-CIT (N-ω-fluoropropyl-2β-carbomethoxy-3β-{4-iodophenyl}nortropane) has been developed successfully as a radioligand for single-photon emission tomography (SPET) imaging of dopamine transporters, which are situated in the membrane of dopaminergic neurons. Imaging of these transporters has shown promise as a clinical tool to detect degeneration of the dopaminergic nigrostriatal pathway. Several presynaptic parkinsonian syndromes, such as Parkinsons disease or multiple system atrophy, are characterised by degeneration of the nigrostriatal pathway. [123I]FP-CIT SPET imaging studies have shown the ability to detect loss of striatal dopamine transporters in such syndromes. However, in clinical practice it is sometimes difficult, but important, to discriminate patients with presynaptic parkinsonism from those with other forms of parkinsonism not characterised by loss of presynaptic dopaminergic cells (e.g. psychogenic parkinsonism or drug-induced postsynaptic parkinsonism). In these inconclusive cases, it may be of value to confirm or exclude the existence of degeneration of nigrostriatal dopaminergic cells by using imaging techniques such as [123I]FP-CIT SPET. Using [123I]FP-CIT SPET, we have imaged the striatal dopamine transporters in a group of patients with inconclusive forms of parkinsonism, and, moreover, have been able to perform clinical follow-up of these patients 2–4 years after imaging. In 33 inconclusive cases, ratios of specific to non-specific binding were calculated for the caudate nucleus and putamen following [123I]FP-CIT SPET imaging and compared with ratios obtained in healthy controls. In nine of the patients, degeneration of the nigrostriatal pathway was found scintigraphically and in all these cases, presynaptic parkinsonism was confirmed by clinical follow-up. In the other 24 subjects no degeneration was found scintigraphically. Forms of parkinsonism other than the presynaptic were confirmed at follow-up in 19 cases, and in three cases no conclusive diagnosis was established, but presynaptic parkinsonism was excluded clinically. A clinical diagnosis of presynaptic parkinsonism was established in two cases: one case of multiple system atrophy (in this patient loss of dopamine D2 receptors was found with [123I]iodobenzamide SPET performed 2 weeks after [123I]FP-CIT imaging) and one case of Parkinsons disease. Our data suggest that the positive predictive value of [123I]FP-CIT imaging is very high, and although the negative predictive value is lower, dopamine transporter imaging offers the prospect of a quick, objective method to confirm or exclude presynaptic parkinsonism in inconclusive cases.

Genetic and environmental risk factors in Parkinson's disease

Parkinsons disease (PD) is a multifactorial disorder, caused by a combination of age, genetics and environmental factors. Nigral cells are susceptible to multiple causes of derangement of normal cell function, all of which may contribute to the same Parkinson phenotype. Autosomal dominant alpha-synuclein-gene PD represents one of the pure genetic forms, whereas cases of sporadic PD probably depend more on age and environmental factors, MPTP-Parkinsonism being the purest example of an environmentally caused Parkinson phenotype. This review suggests that pesticides-herbicides, smoking and head trauma probably represent the most eligible candidates for environmental factors involved in provoking PD or influencing its natural course.

Improvement of voicing in patients with Parkinson's disease by speech therapy.

Speech therapy in PD patients, focusing on an increase of phonatory–respiratory effort, has adverse effects because it raises vocal pitch and laryngeal muscle tension. The authors’ approach, the Pitch Limiting Voice Treatment (PLVT), increases loudness but at the same time sets vocal pitch at a better level. In this study, the Lee Silverman Voice Treatment (“think loud, think shout”) and PLVT (“speak loud and low”) are compared. Both treatments produce the same increase in loudness, but PLVT limits an increase in vocal pitch and prevents a strained or pressed voicing.

Comparison of a timed motor test battery to the Unified Parkinson's Disease Rating Scale‐III in Parkinson's disease

The most widely used scale currently available for the clinical evaluation of motor dysfunction in Parkinsons disease (PD)—the Unified Parkinsons Disease Rating Scale‐III (UPDRS‐III) —is time‐consuming, subjective, and has suboptimal sensitivity. A brief timed motor test (TMT) battery could possibly overcome these drawbacks. Two hundred eighty‐eight PD patients (disease duration 3.1 years; preceding dopaminergic treatment initiation) were assessed with the UPDRS‐III and nine TMTs based on aspects of (a) walking, (b) writing, (c) single and double‐handed pegboard performance, (d) finger tapping, and (e) rapid alternating forearm movements. We investigated validity, reliability, responsiveness, and feasibility. Completing the TMT battery took less than 5 minutes. The TMT correlated well with UPDRS‐III and disease duration. Two factors explained 61% of the TMT variance, the first represented mainly upper extremity function, the second mainly axial/lower extremity function. Cronbachs α was equal for the TMT and the UPDRS‐III (0.8). Test–retest reliability of the TMT sumscore was 0.93 to 0.89 for measurements separated by 3 up to 24 months, whereas UPDRS‐III correlations were 0.88 to 0.84. At group level, a trial using “change from baseline” as endpoint requires only 75% of the patients needed with the UPDRS‐III when applying the TMT battery, and 57% using the pegboard dexterity test. At patient level, TMT and UPDRS‐III were equally responsive. The TMT battery described here is valid, reliable, and feasible. Compared to the UPDRS‐III, it is more objective and more sensitive to change. Therefore, it could be a useful tool for both practical and scientific purposes.

Timed motor tests can detect subtle motor dysfunction in early Parkinson's disease.

Early diagnosis of Parkinsons disease (PD) is important for putative neuroprotective therapies to be initiated in the earliest stage of the disease. We investigated whether a previously validated timed motor test (TMT) battery could detect subtle motor dysfunction in early PD patients and even in clinically unaffected limbs of strictly hemiparkinsonian patients. We assessed 107 PD patients (symptom duration ≤2 years; dopa‐naive) and 100 healthy, age‐matched controls with eight simple TMTs based on aspects of (a) walking, (b) writing, (c) single and double‐handed pegboard performance, (d) finger tapping, and (e) diadochokinesis. We evaluated the ability of individual and combined TMTs to discriminate patients from controls using ROC curves. Second, we investigated whether these TMTs could identify motor dysfunction of the clinically unaffected limb in 42 strictly hemiparkinsonian patients. The pegboard dexterity test had the best ROC curve (AUC 0.97; 95% sensitivity, 89% specificity) for patients versus controls. It retained reasonable accuracy when testing the clinically unaffected limb of hemiparkinsonian patients versus the mean of right and left‐hand scores in controls (AUC 0.73). The pegboard dexterity test is a sensitive and inexpensive instrument to detect motor dysfunction in early PD. Therefore, it may be worth evaluating as a diagnostic tool in everyday clinical practice to assess patients with early symptomatic PD, or as part of a more elaborate screening battery in a defined population at risk.

Side of symptom onset affects motor dysfunction in Parkinson's disease

The healthy brain appears to have an asymmetric dopamine distribution, with higher levels of dopamine in the left than in the right striatum. Here, we test the hypothesis that this neurochemical asymmetry renders the right striatum relatively more vulnerable to the effects of dopaminergic denervation in Parkinsons disease (PD). Using the pegboard dexterity test, we compared motor performance of both hands between healthy subjects (n=48), PD patients with predominantly right-hemispheric dopamine depletion (PD-RIGHT; n=83) and PD patients with more severe left-hemispheric dopamine depletion (PD-LEFT; n=103). All subjects were right-handed. After adjusting for hand-dominance effects, we found that PD-RIGHT patients exhibited a 55% larger difference between right and left dexterity scores than PD-LEFT patients. This effect could be attributed to greater motor dysfunction of the more-affected hand in PD-RIGHT patients, while the less-affected hand performed similarly in both groups. We conclude that the side of symptom onset affects motor dysfunction in PD, and suggest that the non-dominant right hemisphere may be more susceptible to dopaminergic denervation than the dominant left hemisphere.

Pallidopyramidal disease: a misnomer?

The combination of recessive early‐onset parkinsonism and pyramidal tract signs caused by pallidopyramidal degeneration is known as pallidopyramidal disease or syndrome (PPD/S). We investigated whether patients diagnosed as Davisons PPD/S showed any definite proof of pyramidal and pallidal involvement, without findings suggestive of other nosological entities. Since Davisons original description, 15 other PPD/S cases have been reported, yet all lack proof of pyramidal or pallidal degeneration. Because of the dopa‐responsiveness in all patients subsequent to Davisons report, we argue that these patients probably suffered from early‐onset nigral parkinsonism or dopa‐responsive dsystonia, rather than pallidal parkinsonism; in such cases, the presumed pyramidal Babinski could be a pseudobabinski (“striatal toe”). Secondary pallidopyramidal syndromes do occur, for example, in multiple system atrophy or Wilsons disease, but in these patients additional findings indicate diseases other than Davisons PPD/S. We conclude that the existence of PPD/S as a distinct clinico‐pathological nosological entity, as proposed by Davison, is doubtful. In cases reported as Davisons PPD/S, the description “pallidopyramidal” seems to be a misnomer.

Parkin gene related neuronal multisystem disorder

We read with much interest the article on Japanese patients with parkin gene related autosomal recessive juvenile parkinsonism (ARJP) complicated by cerebellar and pyramidal tract dysfunction.1 Recently, we described a Dutch family with parkin gene related ARJP showing typical levodopa responsive parkinsonism. The proband clinically had additional mild gait ataxia and pathologically showed—besides classic parkin gene related ARJP findings—neuronal loss in parts of the spinocerebellar system—namely, Purkinje cell layer, dentate nucleus, and gracile fascicles.2 Just as our Japanese colleagues, we suspected some kind of hereditary multiple system degeneration with predominant parkinsonism until genetic analysis indicated parkin gene related ARJP. Although the non-extrapyramidal abnormalities in the Japanese and in our patients could have been coincidental, the recent Japanese findings seem to confirm that the spinocerebellar and probably also other systems can be affected in parkin gene related ARJP. The fact that the Japanese patients did not respond to levodopa …

Movement disorder of the lower lip

Four years ago, at age 27 years, having experienced a severe headache during the night, on awakening this woman noticed slight dysfunction of the right oral musculature combined with a degree of numbness in the right cheek and right half of the tongue, whereas taste remained normal. Examination performed on the same day revealed no objective abnormalities besides some diminished function of the right corner of the mouth. We suspected the onset of Bell’s palsy. Within a few weeks, a continuous lateral and outward protrusion of the right lower lip appeared, followed soon afterward by deviation of the jaw to the same side. The full picture consisted of lateral and outward protrusion of the right lower lip and deviation of the jaw to the right (see Video, Segment 1). While talking and making voluntary movements of the mouth and jaw, the abnormal postures might diminish momentarily. According to the patient’s mother, the abnormal jaw and lip position did not disappear during sleep. On request, the patient could voluntarily keep the jaw and lip in a normal position for several seconds. If the jaw was pushed into its normal position and held there by the examiner, the lower lip automatically adopted its normal shape as long as the jaw was kept in this normal position. However, a geste antagonistique by the patient herself was not helpful. No abnormalities of the eyelid were found. There was slight hypoesthesia in the areas of nerve V and V. Two months after the first symptom, electromyography (EMG) showed normal blink and masseter reflexes. However, the right masseter and zygomaticus muscles showed reduced interference patterns and prolonged duration of motor unit potentials. The left internal pterygoid muscle showed spontaneous continuous motor activity, which diminished when the patient tried to move the jaw to the left by voluntary effort. The patient was treated with botuline toxin injections in the right lower lip and in the left internal pterygoid muscle. The effect on deviation of the jaw was minimal but the lower lip clearly improved with botuline toxin.