Idiopathic blepharospasm does not lead to a parkinsonian syndrome: results of a questionnaire-based follow-up study

It has been suggested that a lesion in the dopaminergic neurons of the substantia nigra pars compacta combined with eye irritation is involved in the pathophysiology of idiopathic blepharospasm. If so, these patients might be prone to develop Parkinson’s disease or a parkinsonian syndrome. We therefore conducted a validated questionnaire-based follow-up study to estimate (a) the frequency of local eye disorders at onset and (b) frequency of development of parkinsonian symptoms in blepharospasm patients. Ninety-nine patients previously diagnosed with idiopathic blepharospasm were sent a two-part questionnaire to assess parkinsonian and other symptoms associated with their condition. The average period of follow-up was 12.7 years, ranging from 3 to 26 years, with an average age at onset of 53.5 years. Sixty-two patients reported other ocular symptoms prior to or at the onset of blepharospasm, and therefore ocular disease may act as a trigger to produce blepharospasm in those already predisposed. Only two patients had developed a score on the parkinsonism rating scale indicating possible Parkinson’s disease, but clinical examination confirmed this not to be the case. If a lesion in the dopaminergic neurons is involved in blepharospasm, it would appear to be relatively minor (and non-progressive), since patients with idiopathic blepharospasm do not seem prone to develop parkinsonian symptoms. Received: 14 April 1998 Received in revised form: 15 July 1998 Accepted: 4 August 1998     

Epidemiology of primary blepharospasm.

We review epidemiological data on primary blepharospasm (BSP). There is a large variation in the stated prevalence of BSP, with crude estimates ranging from 16 to 133 per million in different studies. A large proportion of this variability may be the result of differences in physician education on BSP. Age and female gender may increase the risk of developing BSP. The few case-control studies focusing on adult dystonias including BSP showed an increased risk in association with family history of dystonia and/or postural tremor, prior head and face trauma, and prior eye disease (e.g., blepharitis and keratoconjunctivitis), and a decreased risk associated with cigarette smoking. No association was found with age-related medical conditions such as hypertension and diabetes, family history of parkinsonism, and a history of anxiety or depression. Broocks et al. [Am J Psychiatry, 1998;155:555-557] found a significantly higher frequency of obsessive-compulsive symptoms in BSP than hemifacial spasm despite the clinical similarity. Among putative risk factors for BSP, age at onset, female gender, and prior head or face trauma may affect spread of dystonia to adjacent body regions. While limited, the body of epidemiological data support the idea that environmental and familial, possibly genetic, factors may both be important in the etiology of BSP.     

Influence of coffee drinking and cigarette smoking on the risk of primary late onset blepharospasm: evidence from a multicentre case control study

Prior coffee and smoking habits were investigated in a multicentre case control study involving 166 patients presenting with primary late onset blepharospasm (BSP), 228 hospital control patients with primary hemifacial spasm and 187 population control subjects from five Italian centres. Information on age at disease onset, smoking and coffee drinking status at the reference age and average number of cups of coffee drunk/cigarettes smoked per day reached high and similar test-retest reproducibility in case and control patients. Unadjusted logistic regression analysis yielded a significant inverse association of prior coffee drinking and cigarette smoking with case status for the control groups. After adjustment for age, sex, referral centre, disease duration, years of schooling and ever coffee drinking/cigarette smoking, as appropriate, the smoking estimate lacked significance whereas the association of coffee intake and BSP did not (cases vs hospital control patients: OR 0.37 (95% CI 0.20 to 0.67); cases vs population control subjects: OR 0.44 (95% CI 0.23 to 0.85)). The strength of the inverse association between BSP and coffee intake tended to increase with the average number of cups drunk per day. There was a significant correlation between age of BSP onset and number of cups per day (adjusted regression coefficient 1.73; p = 0.001) whereas no correlation was found with number of packs of cigarettes per day. Coffee drinking may be inversely associated with the development of primary BSP and this association may partly depend on the amount consumed.     

Menopause and menarche in patients with primary blepharospasm: an exploratory case-control study

We studied the relationships between blepharospasm (BSP) and menopause/menarche in female patients with primary BSP (n = 83) and age-matched healthy (n = 83) and disease controls (n = 83). BSP patients and matched controls had comparable age at menopause, and there was no correlation between age at menopause and age at BSP onset. Thus, menopause probably exerts no significant influence on the age-dependent development of BSP. BSP cases tended to have a later menarche than either group of controls. The association was independent of age, disease duration and education level. Because the higher the age at menarche, the higher the age at BSP onset, later menarche was unlikely to be a risk factor for BSP. Rather, the two conditions may share pathophysiologic mechanisms, for example minor abnormality of neurotransmitter systems controlling both the motor system and the maturation of the hypothalamic-pituitary-gonadal axis responsible for the onset of puberty.     

Risk factors for spread of primary adult onset blepharospasm: a multicentre investigation of the Italian movement disorders study group

OBJECTIVES: Little is known about factors influencing the spread of blepharospasm to other body parts. An investigation was carried out to deterrmine whether demographic features (sex, age at blepharospasm onset), putative risk, or protective factors for blepharospasm (family history of dystonia or tremor, previous head or face trauma with loss of consciousness, ocular diseases, and cigarette smoking), age related diseases (diabetes, hypertension), edentulousness, and neck or trunk trauma preceding the onset of blepharospasm could distinguish patients with blepharospasm who had spread of dystonia from those who did not. METHODS: 159 outpatients presenting initially with blepharospasm were selected in 16 Italian Institutions. There were 104 patients with focal blepharospasm (mean duration of disease 5.3 (SD 1.9) years) and 55 patients in whom segmental or multifocal dystonia developed (mainly in the cranial cervical area) 1.5 (1.2) years after the onset of blepharospasm. Information was obtained from a standardised questionnaire administered by medical interviewers. A Cox regression model was used to examine the relation between the investigated variables and spread. RESULTS: Previous head or face trauma with loss of consciousness, age at the onset of blepharospasm, and female sex were independently associated with an increased risk of spread. A significant association was not found between spread of dystonia and previous ocular diseases, hypertension, diabetes, neck or trunk trauma, edentulousness, cigarette smoking, and family history of dystonia or tremor. An unsatisfactory study power negatively influenced the validity and accuracy of the negative findings relative to diabetes, neck or trunk trauma, and cigarette smoking. CONCLUSIONS: The results of this exploratory study confirm that patients presenting initially with blepharospasm are most likely to experience some spread of dystonia within a few years of the onset of blepharospasm and suggest that head or face trauma with loss of consciousness preceding the onset, age at onset, and female sex may be relevant to spread. The suggested association between edentulousness and cranial cervical dystonia may be apparent because of the confounding effect of both age at onset and head or face trauma with loss of consciousness. The lack of influence of family history of dystonia on spread is consistent with previous findings indicating that the inheritance pattern is the same for focal and segmental blepharospasm.     

The association between narcolepsy and REM behavior disorder (RBD)

BACKGROUND AND PURPOSE: Rapid eye movement (REM) sleep Behavior Disorder (RBD) is a movement disorder associated with loss of REM-related muscle atonia and is characterized by complex, vigorous and frequently violent dream-enacting behavior during REM sleep. RBD is usually idiopathic or secondary to neurological problems such as Parkinson's disease. This study looked at the association of RBD with another sleep disorder, narcolepsy. PATIENTS AND METHODS: Seventy-eight questionnaires were sent to known narcoleptics chosen at random from those with contact details available at the center. The questionnaire addressed current narcolepsy symptoms, medication use and symptoms of RBD. Positive questionnaire results were followed up with a telephone interview. Limited polysomnography (PSG) data was also analyzed. RESULTS: Fifty-five patients responded (response rate 71%). Of these, 20 (36%) had symptoms suggestive of RBD. The typical RBD patient is an older male (mean age of onset 60.9 years, 87% male); however, in this study, females were as likely to have RBD as males, and the mean age was 41 years. Sixty-eight percent of patients who regularly experienced cataplexy and the associated symptoms of narcolepsy (sleep paralysis, hypnogogic hallucinations and automatic behavior) had RBD, compared to 14% of those who never or rarely experienced these symptoms. CONCLUSION: This study implies a stronger relationship between these disorders than a previously published figure of 7-12% This is clinically significant as RBD is a potentially distressing but readily treatable disorder. It follows that narcoleptics, especially those with cataplexy and other associated symptoms, should be questioned about symptoms of RBD and treated accordingly. Similarly, anyone presenting with RBD should be assessed for symptoms of narcolepsy, particularly if female or of a younger age group than would otherwise be expected.     

Altered regional spontaneous neuronal activity in blepharospasm: a resting state fMRI study

The resting state amplitude of low-frequency fluctuations (ALFF) in functional magnetic resonance imaging (fMRI) is believed to reflect spontaneous cerebral neural activity. The pathophysiology of blepharospasm (BSP), which is characterized by motor symptoms and also sensory symptoms, remains unclear. The present study aims to localize possible cerebral functional abnormalities in BSP patients using resting state fMRI, and explore their possible associations with clinical variables. Voxel-based analysis was used to characterize the difference of ALFF between eighteen BSP patients and eighteen matched healthy controls. Separate correlation analyses were conducted to explore the possible association between ALFF values of significantly different areas and clinical measures including onset age, disease duration, symptom severity evaluated by Jankovic rating scale (JRS), and presence of geste antagoniste. The whole-brain analysis indicated that the BSP group had significantly decreased ALFF in the left thalamus while increased ALFF in the left orbitofrontal areas extending from middle frontal gyrus to inferior frontal gyrus. The mean ALFF in the left thalamus was negatively correlated with the subscore of JRS-frequency (r = ?0.484, p = 0.042) and JRS total score (r = ?0.477, p = 0.045). A borderline positive correlation was detected between the mean ALFF in the left orbitofrontal area and disease duration(r = 0.485, p = 0.049). Our findings suggest sensorimotor integration is abnormal in BSP, and dysfunctional activity of thalamus may be used to measuring symptom severity in BSP patients.     

Clinical Course of Two Italian Siblings with Ataxia-Telangiectasia-Like Disorder

Ataxia-telangiectasia-like disorder (ATLD) due to mutations in the MRE11 gene is a very rare autosomal recessive disease, described so far in only 20 patients. Little is known about the onset of the first symptoms or the clinical course of the disease. The present report contributes to the diagnosis of ATLD and its prognosis at onset. We report 30 years of clinical and ophthalmic observations and the results of quantitative magnetic resonance (MR), MR spectroscopy (proton magnetic resonance spectroscopic imaging) and neuropsychological assessment in the first Italian siblings identified with ATLD. Although the disease had early onset and the clinical picture was initially severe, suggesting ataxia-telangiectasia, neurological impairment, ocular motor apraxia and neuropsychological tests showed very slow deterioration in adult age. The patients developed eye and head motor strategies to compensate ocular motor apraxia. MR measurements and MR spectroscopy disclosed widespread neuronal and axonal involvement. ATLD should be considered in patients with ocular apraxia and ataxia in infancy. The long follow-up provided insights into clinical outcome, with functional neuroimaging studies shedding light on the pathogenetic mechanisms of this rare disease.     

UPDRS activity of daily living score as a marker of Parkinson's disease progression

The activities of daily living (ADL) subscore of the Unified Parkinson's Disease Rating Scale (UPDRS) captures the impact of Parkinson's disease (PD) on daily function and may be less affected than other subsections by variability associated with drug cycle and motor fluctuations. We examined UPDRS mentation, ADL and motor subscores in 888 patients with idiopathic PD. Multiple linear regression analyses determined the association between disease duration and UPDRS subscores as a function of medication status at examination and in a subset of patients with multiple examinations. Independent of medication status and across cross‐sectional and longitudinal analyses, ADL subscores showed a stronger and more stable association with disease duration than other UPDRS subscores after adjusting for age of disease onset. The association between disease duration and the motor subscore depended on medication status. The strong association between ADL subscore and disease duration in PD suggests that this measure may serve as a better marker of disease progression than signs and symptoms assessed in other UPDRS sections. © 2008 Movement Disorder Society     

Prevalence and risk factors of post-polio syndrome in a cohort of polio survivors

OBJECTIVE: To investigate frequency and associated factors of post polio syndrome (PPS) in an Italian cohort of people with prior poliomyelitis. METHODS: We screened subjects admitted for poliomyelitis at the paediatric hospital of the University of Palermo during the time frame 1945-1960. Patients who developed PPS were identified through a structured questionnaire and a neurologic examination. PPS diagnosis was made according to specified diagnostic criteria. Frequency of PPS was calculated in the selected cohort of polio survivors. The association with the investigated risk factors (sex, age at onset of polio, extension and severity of polio, education, associated diseases, cigarette smoking, trauma, polio vaccination) was analysed by the calculation of the odds ratio. RESULTS: Forty-eight participants met the adopted diagnostic criteria for PPS, giving a prevalence of 31.0%. The prevalence rate was significantly higher in women than in men (p=0.02). Logistic regression analyses revealed a significant inverse association with onset of poliomyelitis at over 12 months of age (OR 0.33; CI 0.14-0.79) a higher degree of education (OR 0.20; CI 0.07-0.79), and a significant association with the presence of other diseases (OR 9.86; CI 3.69-26.34). CONCLUSIONS: In our survey one-third of patients with prior poliomyelitis had PPS. Higher age at onset of poliomyelitis is inversely associated with PPS. The association with other diseases may indicate that a chronic physical stress, particularly in already weak motor units, can contribute to the development of signs and symptoms of PPS. Our results also suggest the impact of socio-economic conditions on the risk of PPS.     

The phenomenology of the geste antagoniste in primary blepharospasm and cervical dystonia

The geste antagoniste (GA), a relatively common feature of adult‐onset primary dystonia, has been systematically evaluated only in cervical dystonia, but it is still unclear whether its frequency and phenomenology differ among the various forms of focal dystonia. We analysed the frequency, phenomenology, effectiveness, and relationship of the GA with demographic/clinical features of dystonia in a representative clinical series of patients with the two most common forms of adult‐onset primary dystonia, blepharospasm (BSP) and cervical dystonia (CD). Clinical data were gathered using a standardized questionnaire, which showed substantial test‐retest reliability (κ = 0.79, P < 0.00001). The frequency of GA was similar among patients with BSP (42/59, 71.2%) and patients with CD (27/32, 84.4%), and in both groups GA showed similar effectiveness in reducing dystonia. The repertoire of GA was heterogenous in both BSP and CD patients, in whom seven BSP‐related and five CD‐related types of GA were recorded, and a “forcible” type of GA was present in 69% of BSP patients and in 48.1% of CD patients. In our whole patient population, age at dystonia onset was significantly lower among patients reporting a GA compared to those without GA (P = 0.01). GA features shared by BSP and CD predominate over differences, suggesting common mechanisms underlying this phenomenon in the two forms of primary adult‐onset dystonia. © 2010 Movement Disorder Society     

Antibody profile may predict outcome in ocular myasthenia gravis

An unsolved issue remains whether there are clinical and immunological features to predict in a single patient the risk of conversion from ocular Myasthenia Gravis (OMG) to generalized disease (GMG) as 50–60% of patients may progress within 1–2 years since onset. Anti-acetylcholine receptor antibodies (AChR Abs) are found in up to 50% of OMG patients; muscle-specific tyrosine kinase antibodies (MuSK-Abs) are present in about 70% of the whole seronegative (SN), who usually develop a severe disease with bulbar involvement. We surveyed a cohort of 175 OMG patients with purely ocular symptoms and we compare the outcome of patients with antibodies to AChR or to MuSK with those seronegative for both Abs (DSN). All patients had purely ocular signs for at least 24 months. Gender, age at onset, time to generalization or to worsening in quantitative ocular QMG scores, electrophysiological results were analyzed. Males were 58.9%, females 41.1%. Patients with late onset of symptoms after 50 years (LOMG) were 78.3%. We assayed anti-MuSK-Abs in 4.7%, anti-AChR Abs in 38.5%; 57.3% were defined DSN. Thirty-seven patients (21.1%) progressed to GMG during the observational time: 23 were females, 62% of the whole group of the generalized subjects, 75% of MuSK-positive OMG converted to GMG versus the 26.2% of AChR positive and 13.7% of DSN. Statistical analysis showed that gender and presence of antibodies either to AChR or to MuSK were independent predictors of worse outcome; the DSN subjects had lower risk of conversion to GMG.     

Juvenile myasthenia gravis with prepubertal onset

Juvenile myasthenia gravis (JMG) with prepubertal onset is an uncommon disease. We studied 19 patients with age at onset ranging from 1.5 to 9.2 years and compared their clinical characteristics and response to therapy with 114 cases with MG onset after the prepubertal age, up to 20 years. Neither sex prevalence nor autoimmune diseases other than MG were found in younger patients. Although ocular myasthenia was more frequent than in later-onset JMG, children with generalized symptoms were often severely affected and respiratory involvement was present in 8/19 patients. Anti-acetylcholine receptor antibodies were detected at a lower rate and, in contrast with results in older patients, seronegativity was more frequent among children with generalized disease. Three out of six patients with onset before the age of five showed spontaneous remission. Nine prepubertal patients underwent thymectomy and, as most of them also received immunosuppressive therapy, the influence of surgery on disease outcome remains unclear; in no case was thymoma found. This is in contrast to the good results after thymectomy and the presence of thymoma in the later-onset group. Eleven patients in the prepubertal series were treated with immunosuppressive therapy. At the end of follow-up, most patients were in good condition. The frequency of immunosuppressive therapy and the rate of good therapeutic results did not differ from those observed in older patients.     

Prognosis of ocular myasthenia

A retrospective study of 108 patients with myasthenia gravis who had solely ocular symptoms and signs at onset was carried out to identify factors influencing prognosis. Increasing duration of pure ocular myasthenia was associated with a decreasing risk of late generalized symptoms; only 9 (15%) of the observed generalizations occurred after more than 2 years of solely ocular symptoms. Increasing age at onset was associated with greater risk of respiratory crisis or death caused by myasthenia, whereas patients younger at onset had a greater chance of a benign outcome. Neither systemic curare tests nor responses to repetitive nerve stimulation had prognostic value.     

Family history in patients with transient ischemic attacks

To determine the influence of family history on vascular disease, we surveyed hospital patients discharged with a diagnosis of transient ischemic attack. Of 117 respondents, 81 knew their family history for myocardial infarction and 81 knew their family history for stroke. Of 83 responding 43 reported a personal history of myocardial infarction, and of 85 responding 66 reported a personal history of stroke. As expected, there was an association between positive family and personal histories of myocardial infarction in younger (aged less than 70 years) patients (Fisher's two-tailed exact test, p = 0.014). This association was reversed for stroke (Fisher's two-tailed exact test, p = 0.017). Older (aged greater than or equal to 70 years) patients had a stronger association between positive family and personal histories of stroke; 14 (74%) of 19 older patients with a positive personal history of stroke had a positive family history of stroke. The reason for this reversal in the relation between family and personal histories of stroke compared with myocardial infarction may relate to the older age at onset of most strokes, differing stroke subtypes in older age groups, or lower rates of fatal myocardial infarction. This study suggests that familial factors may be important in some subtypes of cerebrovascular disease. Familial effects may be different in vascular diseases of the heart and brain.     

Myasthenia gravis in children: a longitudinal study

BACKGROUND: Juvenile myasthenia gravis (JMG) is an uncommon disease. Unlike adults, clinical characteristics and outcomes of myasthenia gravis (MG) are not well studied in children. PATIENTS AND METHODS: Case records of 77 patients with MG who were 15 years of age or less at disease onset, evaluated over a period of 34 years at the National Institute of Mental Health and Neurosciences, Bangalore, India, were reviewed. Their clinical characteristics and response to therapy was compared with 290 patients with MG onset after 15 years of age. RESULTS: Median age at onset was 8 years and mean period of follow-up was 6.2 years (range 6 months to 25 years). At presentation, 30% of patients had ocular myasthenia and the rest had generalized disease. Twenty-one patients (27%) had disease confined to ocular muscles throughout the course and three had limb girdle myasthenia. Familial myasthenia was more common than adult onset disease, 10 patients had positive family history. Unlike adults, none of the patients had associated autoimmune disease. Fifty-two patients (67%) received corticosteroids, and azathioprine was added in five patients. Thymectomy was performed in 11 patients, six below the age of 15 years. Thymic histology was normal in one and showed hyperplasia in eight and thymoma in one. Four patients had crisis. At the end of follow-up, 25 patients were asymptomatic, 28 had partial improvement, and nine remained unchanged or worsened and two died. Ten patients achieved complete stable remission. CONCLUSIONS: This study shows some distinctive characteristics of JMG, such as higher frequency of ocular myasthenia, benign course, better long-term outcome and lack of association of thymoma and other autoimmune disorders.     

High frequency of psoriasis in relatives is associated with early onset in an Italian multiple sclerosis cohort

OBJECTIVES: An exploratory study has been carried out to assess the association of autoimmune diseases in multiple sclerosis (MS) families with clinical features and disability of MS patients. MATERIAL AND METHODS: Age at onset, symptoms and signs at onset, and disability were assessed in 177 patients with definite MS and 178 age- and sex-matched control patients with autoimmune diseases (78 with endocrine and 100 with rheumatological diseases) and correlated with the most frequent autoimmune diseases recorded in the families. RESULTS: Psoriasis was found in 30 relatives of 177 (16.9%) MS patients, thyroid disorders in 17 (9.6%) and allergies in 17 (9.6%). In the control group, psoriasis was found in 22 relatives of 178 (12%) patients, thyroid diseases in 19 (10.7%) and allergies in seven (3.9%). Of the 30 relatives with psoriasis in the MS group, 16 (53.3%) were fathers (P < 0.0001). There was a significant association of high frequency of family psoriasis with early age of MS onset (P = 0.025) but not with onset of symptoms or severe disability. CONCLUSION: In this Italian MS cohort, a subgroup of patients with a first- or second-degree relative with psoriasis had early onset of MS.     

The eye and sleep apnea

Several eye disorders have been found in association with obstructive sleep apnea (OSA). This paper reviews the current state of knowledge of eye disorders associated with OSA. OSA is associated with a number of eye disorders including floppy eyelid syndrome (FES), optic neuropathy, glaucoma, non-arteritic anterior ischemic optic neuropathy and papilledema secondary to raised intracranial pressure. FES patients have a very high incidence of OSA and a causal relationship may exist, but amongst patients with OSA, FES is uncommon but commoner than in the general population. Treatment of OSA may help floppy eyelid syndrome, halt progression of associated glaucoma or optic neuropathy, and reduce intracranial pressure in patients with associated papilledema. Sleep apnea patients should be asked about ocular symptoms and appropriately examined or referred for assessment as some of the associated eye disorders may permanently impair vision. Ophthalmologists should be aware of the association of sleep apnea with these eye disorders and consider referral to a sleep physician for investigation and possible treatment.     

Conformational diseases: Looking into the eyes

Conformational diseases, a general term comprising more than 40 disorders are caused by the accumulation of unfolded or misfolded proteins. Improper protein folding (misfolding) as well as accrual of unfolded proteins can lead to the formation of disordered (amorphous) or ordered (amyloid fibril) aggregates. The gradual accumulation of protein aggregates and the acceleration of their formation by stress explain the characteristic late or episodic onset of the diseases. The best studied in this group are neurodegenerative diseases and amyloidosis accompanied by the deposition of a specific aggregation-prone proteins or protein fragments and formation of insoluble fibrils. Amyloidogenic protein accumulation often occurs in the brain tissues, e.g. in Alzheimer's disease with the deposition of amyloid-β and Tau, in scrapie and bovine spongiform encephalopathy with the accumulation of prion protein, in Parkinson's disease with the deposition of α-synuclein. Other examples of amyloid proteins are transthyretin, immunoglobulin light chain, gelsolin, etc. In addition to the brain, the accumulation of unfolded or misfolded proteins leading to pathology takes place in a wide variety of organs and tissues, including different parts of the eye. The best studied ocular conformational diseases are cataract in the lens and retinitis pigmentosa in the retina, but accumulation of misfolded proteins also occurs in other parts of the eye causing various disorders. Furthermore, ocular manifestation of systemic amyloidosis often causes the deposition of amyloidogenic proteins in different ocular tissues. Here we present the data regarding naturally unfolded and misfolded proteins in eye tissues, their structure-function relationships, and molecular mechanisms underlying their involvement in diseases. We also summarize the etiology of ocular conformational diseases and discuss approaches to their treatment.