Primary progressive apraxia

Similar to primary progressive aphasia, primary progressive apraxia has been considered to cause slowly progressive apraxia without dementia and to be a dependent disease. Of the 3 cases reported by De Renzi in 1986, 1 case showed slowly progressive apraxia without dementia. Since then, cases of primary progressive apraxia have been reported occasionally. Studies on primary progressive apraxia indicate that not only focal lesions caused by vascular disease or brain trauma but also lesions caused by neurodegenerative disease can cause apraxia alone, thereby supporting the hypothesis that apraxia-associated neurodegeneration may develop in cases of primary progressive apraxia. The pathogenesis of primary progressive apraxia is yet to be elucidated. Clinical features of primary progressive apraxia are not precisely distinguishable from those of corticobasal degeneration (CBD); further, previous studies have indicated that the brain pathology observed in primary progressive apraxia is consistent with that in Alzheimer disease (AD) or Pick disease. "Primary" progressive apraxia may be intrinsically different from slowly progressive apraxia that is associated with CBD, AD, or Pick disease and may show specific pathological findings. On the other hand, primary progressive apraxia may not be a dependent disease but a syndrome characterized by prolonged neurodegeneration that is observed in various degenetive dementias such as CBD, AD, or Pick disease.     

Increased circulating T cell reactivity to GM3 and GQ1b gangliosides in primary progressive multiple sclerosis.

We have previously shown that patients with primary progressive multiple sclerosis (MS) have significantly elevated plasma levels of antibody to GM3 ganglioside compared to patients with relapsing-remitting MS, healthy subjects and patients with other neurological diseases. Anti-GM3 antibody levels were elevated also in patients with secondary progressive MS but to a lesser extent than in primary progressive MS. As gangliosides are particularly enriched in the axonal membrane, these findings suggested that antiganglioside immune responses might contribute to the axonal damage in progressive forms of MS. The present study was performed to determine whether peripheral blood T cell responses to GM3 are also increased in progressive MS. Blood was collected from 98 untreated patients with MS (40 with relapsing-remitting, 27 with secondary progressive and 31 with primary progressive MS), 50 healthy subjects and 24 patients with other disorders of the CNS, and reactivity to GM1, GM3, GD1a, GD1b, GD3, GT1b, GQ1b and sulphatide was assessed by 6-day T cell proliferation assays. Increased T cell reactivity to GM3 and GQ1b occurred significantly more often in patients with primary progressive MS than in healthy subjects and patients with other CNS diseases. These findings suggest that ganglioside-specific T cells may contribute to the axonal damage in primary progressive MS.     

Progressive myoclonus ataxia: Time for a new definition?

Background: The clinical demarcation of the syndrome progressive myoclonus ataxia is unclear, leading to a lack of recognition and difficult differentiation from other neurological syndromes. Objectives: The objective of this study was to apply a refined definition of progressive myoclonus ataxia and describe the clinical characteristics in patients with progressive myoclonus ataxia and with isolated cortical myoclonus. Methods: A retro‐ and prospective analysis was performed in our tertiary referral center between 1994 and 2014. Inclusion criteria for progressive myoclonus ataxia patients were the presence of myoclonus and ataxia with or without infrequent (all types, treatment responsive) epileptic seizures. Inclusion criteria for isolated cortical myoclonus was the presence of isolated cortical myoclonus. Clinical and electrophysiological characteristics data were systematically scored. Results: A total of 14 progressive myoclonus ataxia patients (males, 7; females, 7), median age 14.5 years, and 8 isolated cortical myoclonus patients (males, 2; females, 6), median age 23.5 years, were identified. In 93% of the progressive myoclonus ataxia patients, ataxia started first (median 2 years) followed by myoclonus (4 years) and finally infrequent epilepsy (9.3 years), with a progressive course in 93%. In 64% of the progressive myoclonus ataxia patients, a genetic underlying etiology was identified, including 3 not earlier reported causative progressive myoclonus ataxia genes. In isolated cortical myoclonus patients, myoclonus started at (median) 12 years with progression over time in 63% and a single epileptic seizure in 1 patient. No genetic causes were identified. Conclusion: Using a refined definition, we could create a rather homogenous progressive myoclonus ataxia group. Patients with isolated cortical myoclonus have a different course and do not appear to evolve in progressive myoclonus ataxia. The refined progressive myoclonus ataxia definition is a successful first step toward creating a separate syndrome for both clinical practice and future genetic research. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Progressive idiopathic axonal neuropathy

Abstract. Patients with a progressive disabling idiopathic axonal neuropathy could have a potentially treatable immune mediated neuropathy. To evaluate whether progressive idiopathic axonal neuropathy could be a pathologically difficult to prove vasculitic neuropathy pathologically difficult to prove or if it could be a separate clinical entity (i. e. with the axon as the primary immunological target), we performed a comparative clinical and histopathological study in 10 patients with progressive idiopathic axonal neuropathy, 10 patients with vasculitic neuropathy, and 12 patients with chronic idiopathic axonal polyneuropathy (CIAP). The clinical features and disease course in patients with progressive idiopathic axonal neuropathy and patients with vasculitic neuropathy were similar. Six patients with progressive idiopathic axonal neuropathy had been treated with prednisone and/or intravenous immunoglobulin. Disability decreased in all these six patients, but also in two of the four non-treated patients. Upon reviewing the sural nerve biopsy specimens, vasculitis was found in one patient with progressive idiopathic axonal neuropathy. Vasculitis-associated signs of ischemic injury or inflammation (most notably: large variation in fascicular axonal degeneration, perivascular inflammation, inflammation of the blood vessel wall without lumen obstruction) were found in four patients with progressive idiopathic axonal neuropathy, in all patients with vasculitic neuropathy, but were absent in patients with CIAP. The findings show that there is a small chance of finding sural nerve vasculitis upon scrutinising biopsy examination in progressive idiopathic axonal neuropathy. The presence of vasculitisassociated signs in progressive idiopathic axonal neuropathy suggests that some of these patients could have vasculitic neuropathy, even if vasculitic lesions cannot be demonstrated. However, if inflammatory changes cannot be demonstrated this does not preclude an immune-mediated origin.     

Treatment of progressive multiple sclerosis with pulse cyclophosphamide/methylprednisolone: response to therapy is linked to the duration of progressive disease

OBJECTIVE: To determine if there are variables linked to responsiveness to pulse cyclophosphamide/methylprednisolone therapy in progressive Multiple Sclerosis (MS). BACKGROUND: MS is a presumed autoimmune disease of the CNS in which immunosuppressive and immunomodulatory treatments are being used. We have treated patients with the progressive form of MS using a regimen consisting of pulse cyclophosphamide/methylprednisolone that is given as an outpatient at 4 - 8 week intervals similar to lupus nephritis protocols. DESIGN/METHODS: We investigated a series of 95 consecutive progressive MS patients treated in an open label fashion in an effort to identify factors linked to response to treatment. Clinical outcome measures included status at 12 months and time to failure determined by EDSS change and global physician impression. For each endpoint, associations were examined between outcome and patient characteristics including gender, age at onset of disease and treatment, EDSS 1 year previously and at start of treatment, duration of MS, previous treatment, age at onset and duration of progression, and primary vs secondary progressive MS. RESULTS: Of the variables studied, age, gender, age at onset, and age at treatment did not correlate with response to therapy. The most significant variable that correlated with response was length of time the patient was in the progressive phase (P=0.048, 12 month change in EDSS; P=0.017, risk for time to failure). Patients that improved on therapy at 12 months had progressive disease for an average of 2.1 years prior to treatment, whereas those stable or worse had progressive disease for 5.0 and 4.1 years respectively. There was a trend (P=0.08) favoring positive clinical responses in secondary progressive as opposed to primary progressive patients. CONCLUSIONS: Our data suggest that progressive MS may become refractory to immunosuppressive therapy with time and early intervention when patients enter the progressive stage should be considered. Furthermore, in trials of immunosuppressive agents for progressive MS, duration of progression should be considered as a randomization and analysis variable.     

Neuropsychiatric symptoms in behavioral variant frontotemporal dementia and primary progressive aphasia

Neuropsychiatric symptoms are well defined in behavioral variant frontotemporal dementia but are not as well studied in primary progressive aphasia. This study compared caregiver reported neuropsychiatric symptoms in these 2 forms of dementia at short and long disease duration. Patients with behavioral variant frontotemporal dementia had more symptoms than patients with primary progressive aphasia. However, when divided by duration of disease, patients with primary progressive aphasia with long duration had a similar number of symptoms to patients with behavioral variant frontotemporal dementia at either duration. Furthermore, this group of patients with primary progressive aphasia had more symptoms typical of behavioral variant frontotemporal dementia and less mood-related symptoms which were more common in patients with primary progressive aphasia with shorter duration. This study illustrates the emergence of neuropsychiatric symptoms as primary progressive aphasia progresses and highlights the increasing overlap with behavioral variant frontotemporal dementia because the disease affects areas outside of the language network.     

A procedural distinction between elective and progressive mutism

This paper introduces a procedural distinction between elective and progressive mutism. In elective mutism, a child elects to talk freely with intimates (e.g. family members); in progressive mutism a child does not communicate verbally with anyone (including intimates). This analysis argues that clinicians' therapeutic goals and parents' expectations of treatment outcomes for elective mutism would differ from those applied to a case of progressive mutism and that the selection of the appropriate concept (elective vs progressive) to name the type of mutism prior to intervention would enhance treatment outcomes.     

Recovery of uremic neuropathy after renal transplantation

Two patients are presented with progressive invalidating uremic peripheral neuropathy. The peripheral neuropathy developed despite frequent hemodialysis with a polyacrylonitrile membrane and afterwards in combination with CAPD. The first patient with a long history of progressive peripheral neuropathy before renal transplantation recovered incompletely after renal transplantation, whereas the second patient with a short history of a severe progressive UPN recovered completely after renal transplantation.     

Brain stem auditory evoked potentials in patients with multiple system atrophy with progressive autonomic failure (Shy-Drager syndrome).

Brain stem potentials from three groups of patients, namely those with pure progressive autonomic failure, Parkinson's disease and multisystem atrophy with progressive autonomic failure (Shy-Drager syndrome) were compared with each other and a group of normal subjects. In virtually all the patients with multisystem atrophy with progressive autonomic failure the brain stem potentials were abnormal in contrast to normal findings with Parkinson's disease. The closely associated group of patients with progressive autonomic failure alone also revealed no abnormalities of the BAEP. This separation of the two groups, Parkinson's disease and progressive autonomic failure from multisystem atrophy with progressive autonomic failure is important clinically as multiple system atrophy of the Shy-Drager type has extra-pyramidal features closely resembling Parkinsonism or a late onset cerebellar degeneration. From the abnormalities of the brain stem response in multisystem atrophy with progressive autonomic failure, it is clear that some disruption of the auditory pathway occurs in the ponto-medullary region as in nearly all patients there is a significant delay or reduction in the amplitude of components of the response generated beyond this region. The most likely area involved is the superior olivary complex.     

Serial Computed Tomography in Professional Boxers

Forty-five licensed professional boxers underwent serial computed tomography (CT). The average duration between the initial and last follow-up scan was 31.3 months (range, 1 5–48 mo). Six (13%) had evidence of progressive brain injury between the first and last scan. Three boxers exhibited progressive atrophy and three developed a cavum septum pellucidum. Boxers with progressive CT changes tended to have had more fights (mean, 24.2) and more losses (mean, 7.3) than those without progressive changes (16.0 fights and 3. 7 losses) at the time of the last scan. Compared to boxers without progressive changes on CT, boxers with progressive changes had twice the frequency of losses and losses secondary to technical knockout or knockout during the time period between scans. Progressive changes on serial CT were associated with having more than ten losses (p < 0.05). These findings suggest that boxers with more than ten losses undergo a detailed evaluation.     

Progressive myoclonic ataxia (the Ramsay Hunt syndrome)

It has been suggested from studies of patients with progressive myoclonus epilepsy that the term Ramsay Hunt syndrome should be abandoned, as its use has led to nosologic confusion, and because, in the light of modern diagnostic techniques, the majority of cases can be allocated to specific disease categories, chiefly, Unverricht-Lundborg disease (Baltic myoclonus) and mitochondrial encephalomyopathy. Review of 30 cases of this syndrome, defined as progressive ataxia and myoclonus and infrequent seizures in the absence of dementia, showed that a clinical or biochemically supported diagnosis could not be made in 43%. This low diagnostic yield probably reflects differences in ascertainment of patients; those described here were referred with a syndrome of progressive myoclonic ataxia (the Ramsay Hunt syndrome) rather than progressive myoclonus epilepsy. These two syndromes share common causes, but a smaller proportion of patients with progressive myoclonic ataxia can currently be diagnosed precisely during life.     

PRKCG mutation (SCA-14) causing a Ramsay Hunt phenotype.

Progressive myoclonic ataxia, also referred to as Ramsay Hunt syndrome, is characterized by a combination of myoclonus and cerebellar ataxia, infrequently accompanied by tonic-clonic seizures. Its differential diagnosis overlaps with progressive myoclonic epilepsy, a syndrome with myoclonus, tonic-clonic seizures, progressive ataxia and dementia. In patients with progressive myoclonic epilepsy, specific diseases can frequently be recognized, but the diagnostic yield in progressive myoclonic ataxia is much lower. We describe a patient who presented with multifocal myoclonus in his thirties and who later developed cerebellar ataxia and focal dystonia. His father was similarly affected. Genetic studies revealed a mutation in the protein kinase C gamma (PRKCG) gene, known to cause spinocerebellar ataxia type 14 (SCA-14). This case illustrates that both myoclonus and dystonia are part of the clinical spectrum in SCA-14 and that myoclonus can even be the presenting symptom. We suggest that SCA-14 should be considered in the differential diagnosis of progressive myoclonic ataxia.     

Progressive focal cortical atrophies

Progressive focal cortical atrophies are degenerative conditions characterised by the insidious onset and gradual exacerbation of an impairment in a single cognitive domain related to circumscribed cerebral atrophy. Several focal cortical syndromes with deficits in the realm of cognition are reviewed: progressive impairment of language (primary progressive aphasia), speech (progressive anarthria), semantic memory (semantic dementia), episodic memory (pure progressive amnesia), vision (progressive perceptual or visuo-spatial deficits) and gesture (progressive apraxia). These conditions are histologically heterogeneous and can be associated with focal non-specific neuronal loss and gliosis with some spongiform changes (non-specific lesions), pathological features of Pick's disease (inclusion bodies and swollen neurones) or Alzheimer's disease (AD) (senile plaques and neurofibrillary tangles). A relationship between neuropsychological profiles and lesional types emerges from this review of the literature. Non-fluent primary progressive aphasia, semantic dementia and progressive anarthria are usually associated with non-specific lesions and Pick-type pathology. Progressive disorders of episodic memory and progressive visuo-spatial deficits are more often related to AD. If adequate clinical characterisation can determine the underlying disorder, it appears even more important to establish the neuropsychological profile in patients with cortical degenerative disease. Progressive deficits of only one domain of cognition may well be due to preferential involvement of anatomically and functionally defined neural systems and could therefore be considered as "system atrophies". There remains no doubt that these syndromes are particularly well suited models for studies on the relationship between cerebral functions and their neural substrate.     

Prognostic factors for progression of disability in the secondary progressive phase of multiple sclerosis

Predicting clinical outcome is one of the major and most interesting issues in MS patients. If the global evolution of disability (usually chosen levels on the Kurtzke's Disability Status Scale) has been widely studied, much less is known about the progression of disability during the secondary progressive phase of the disease. It is usually said that there is a poorer prognosis once patients enter a progressive phase, whether from onset (like in primary progressive MS) or after an initial relapsing-remitting phase. The secondary progressive phase of multiple sclerosis (MS) is the one most often associated with the development of severe and irreversible disability. Despite this fact, there is a lot of information about the initial relapsing-remitting phase in the literature, but much less about the secondary progressive one. We review here information available from the literature and from the Lyon MS database about this secondary progressive phase.     

Hypointense lesions on T1-weighted spin-echo magnetic resonance imaging: relation to clinical characteristics in subgroups of patients with multiple sclerosis

CONTEXT: Hypointense lesions on T1-weighted spin-echo magnetic resonance images (T1 lesions) represent destructive multiple sclerosis (MS) lesions, consisting of axonal loss and matrix destruction. These lesions are being used as a secondary outcome measure in phase III clinical trials. Clinical determinants of T1 lesions may differ between subgroups of patients with MS and subsequently may have implications for the selection of patients for clinical trials. OBJECTIVE: To determine if clinical characteristics of patients with MS are related to T1 lesion volume. DESIGN: A survey of 138 patients with MS (52 with relapsing-remitting MS, 44 with secondary progressive MS, and 42 with primary progressive MS). SETTING: The Magnetic Resonance Center for Multiple Sclerosis Research, University Hospital "Vrije Universiteit," Amsterdam, the Netherlands. MAIN OUTCOME MEASURES: Type of MS, Expanded Disability Status Scale (EDSS) score, sex, age at first symptoms, and T1 lesion volume. RESULTS: Patients with secondary progressive MS have the highest T1 lesion volume. Patients with relapsing-remitting MS have a lower T1/T2 ratio than patients with secondary progressive MS and patients with primary progressive MS. In patients with relapsing-remitting MS and secondary progressive MS, T1 lesion volume relates to disease duration and EDSS score, while in patients with primary progressive MS sex is important. A trend toward higher T1 lesion volume was shown for male patients with primary progressive MS when compared with female patients with primary progressive MS (1.0 cm(3) vs 0.3 cm(3), P=.03); a trend toward higher T1 lesion volume was found with age at onset in patients with relapsing-remitting MS and in patients with primary progressive MS. CONCLUSIONS: In patients with MS different clinical characteristics associate with T1 lesion volume, suggesting a more destructive type of lesions in certain subgroups. A possible sex difference in (destructive) lesion development on magnetic resonance imaging should be evaluated in more detail, preferably in a cohort.     

Syntactic impairments can emerge later: Progressive agrammatic agraphia and syntactic comprehension impairment

Background & Aims: Recent studies suggest that agrammatism is not a major feature of progressive nonfluent aphasia, at least not in the earlier years post-onset. We investigated the emergence of syntactic impairments over a 3-year period in CS, a 63-year-old man 8 years post-onset of progressive speech difficulties. CS has a range of progressive cognitive impairments, including progressive nonfluent aphasia, and limb and other apraxias (with a progressive non-aphasic and mostly non-dysarthric speech deterioration), but relatively intact intelligence, perception, orientation, long-term memory, semantics, and phonology. Writing impairments did not emerge until some 8 years after naming and speech impairments were first noticed, and after CS became mute. Methods & Procedures: We undertook detailed longitudinal examination of word and sentence writing and syntactic comprehension across a range of tasks and examined the impact of short-term memory. We were concerned to examine the data for evidence of agrammatic features, particularly in noun and verb use, and use of formulaic and simplified syntactic structures as the condition progressed. Outcomes & Results: Analysis showed a progressive emergence of deficits on tests of written syntax, syntactic comprehension, and auditory-verbal short-term memory. There was a progressive reduction in verb and noun use, but this was related to the kind of stimulus used. Features of agrammatism were evident in writing with a progressive dependence on formulaic and simplified syntax. Conclusions: It may be that agrammatism in PNFA is a feature that develops late in the progression, showing up only in writing because it is masked in speech by motor speech impairment. Increasing reliance on formulaic and simplified structures with progression suggests compensatory adaptation of CS's system. Impairments appeared to emerge in parallel with deterioration of syntactic comprehension and phonological short-term memory.     

Treatment of progressive multiple sclerosis with monthly pulsed cyclophosphamide-methylprednisolone: predictive factors of treatment response

INTRODUCTION: Cyclophospamide is used in the treatment of progressive multiple sclerosis. We were looking for predictive indicators of treatment response. MATERIAL AND METHODS: Forty-seven patients with secondary progressive multiple sclerosis and seven others with primary progressive received monthly infusions of cyclophosphamide (750mg/m2) and methylprednisolone (500mg). During the year before cyclophosphamide the EDSS had worsened one point in all patients with or without surimposed relapses. Evaluation was based on EDSS change at 6, 12, 24 months and 5 years. RESULTS: Among secondary progressive patients, 91 per 100 (43/47) were stable or improved at 12 months, 65 per 100 (26/40) at 24 months and 22 per 100 (5/23) at 5 years. Annual relapse rate decreased from 0.81 before treatment to 0.48 during treatment and 0.12 after treatment (p<0.001). At 24 months, efficacy was correlated to a progressive phase lasting less than 5 years (p<0.01) and to a rapid increase of EDSS of at least 2 points the year before treatment (p<0.05). There were no influences of age, EDSS and surimposed relapses at the beginning of treatment, and other immunoactive drugs administrated before cyclophosphamide. There was no significant difference in quality of response to treatment between patients with primary progressive and secondary progressive multiple sclerosis. CONCLUSION: Cyclophosphamide appears to be more efficient in early stage of progressive multiple sclerosis independently of age, relapses or neurological disability scale.     

进行性肌阵挛癫一家系临床与遗传学特征分析

目的 研究一个进行性肌阵挛癫(癎)家系的临床特点、遗传性特征并复习文献.方法 搜集并整理一个进行性肌阵挛癫(癎)家系患者临床表现、辅助检查及影像学资料,分析其临床特点和遗传性特征.结果 该家系呈母系遗传,先证者表现为进行性肌阵挛癫(癎)发作,同时伴有近端肌无力、肌肉萎缩、腱反射减弱.肌电图提示肌源性改变,头颅磁共振提示皮层萎缩,该家系中除先证者外其他患者均在发病后6～8 a死亡,预后差.结论 该进行性肌阵挛癫(癎)家系很可能为线粒体脑肌病的肌阵挛癫(癎)伴破碎红细胞纤维(MERRF)型,确诊有待进一步的肌肉活检和基因诊断.     

The pathology of primary progressive multiple sclerosis

The present review will focus on the current knowledge of the pathology of primary progressive multiple sclerosis lesions. Multiple sclerosis (MS) is an inflammatory demyelinating disease with a broad clinical variability. The main disease courses are relapsing-remitting, secondary progressive and primary progressive MS. Pathological studies examining the specific underlying pathology of a defined clinical subtype are rare. Here, we focus on the pathological characteristics of the MS lesions and summarize the current findings of the pathology of primary progressive MS with respect to inflammation, oligodendrocyte myelin pathology, axon destruction and immunopathology of the lesions.