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Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive cerebellar degeneration that is typically diagnosed in early childhood. A-T is associated with a predisposition to malignancies, particularly lymphoid tumors in childhood and early adulthood. An adolescent girl with minimal neurologic symptoms was diagnosed with A-T 8 years after completing therapy for T-cell acute lymphoblastic leukemia, following a diagnosis of ATM-mutated breast cancer in her mother. We highlight the importance of recognizing ATM mutations in T-cell acute lymphoblastic leukemia, appreciating the phenotypic heterogeneity of A-T, and defining optimal cancer screening in A-T patients.

Objective: Neurological complications of celiac disease (CD) include neuropathy, myeloneuropathy, and cerebellar degeneration. The cause of neuropathy in patients with CD is not known. Prior publications describe copper deficiency in CD patients with myeloneuropathy and neuropathy and posit that hypocupremia is the cause of these neurological conditions. However, based on our clinical experience, we hypothesized that CD patients with polyneuropathy are not deficient in copper. Methods: Patients who met diagnostic criteria for CD and peripheralneuropathywere included.We reviewed the patient’s records, including assessment of serum copper level and other clinical parameters. Results: Eighteen patients met inclusion criteria. Sixteen patients (89%) had normal copper levels, 2 had mild hypercupremia, and none had low copper levels. Of the 18 patients, 4 (22%) had large fiber neuropathy and 14 (78%) had a small fiber neuropathy. Conclusions: No patient in this study showed hypocupremia. We are unable to demonstrate a relationship between our CD patients with Peripheral Neuropathy and copper deficiency.

Objectives: The cerebellum is known to play a strong functional role in both motor control and motor learning. Hence, the benefit of physiotherapeutic training remains controversial for patients with cerebellar degeneration. In this study, we examined the effectiveness of a 4-week intensive coordinative training for 16 patients with progressive ataxia due to cerebellar degeneration (n = 10) or degeneration of afferent pathways (n = 6). Methods: Effects were assessed by clinical ataxia rating scales, individual goal attainment scores, and quantitative movement analysis. Four assessments were performed: 8 weeks before, immediately before, directly after, and 8 weeks after training. To control for variability in disease progression, we used an intraindividual control design, where performance changes with and without training were compared. Results: Significant improvements in motor performance and reduction of ataxia symptoms were observed in clinical scores after training and were sustained at follow-up assessment. Patients with predominant cerebellar ataxia revealed more distinct improvement than patients with afferent ataxia in several aspects of gait like velocity, lateral sway, and intralimb coordination. Consistently, in patients with cerebellar but without afferent ataxia, the regulation of balance in static and dynamic balance tasks improved significantly. Conclusion: In patients with cerebellar ataxia, coordinative training improves motor performance and reduces ataxia symptoms, enabling them to achieve personally meaningful goals in everyday life. Training effects were more distinct for patients whose afferent pathways were not affected. For both groups, continuous training seems crucial for stabilizing improvements and should become standard of care. Level of evidence: This study provides Class III evidence that coordinative training improves motor performance and reduces ataxia symptoms in patients with progressive cerebellar ataxia.

Background: CACNA1A encodes CaV2.1, the pore-forming subunit of P/Q-type voltage-gated calcium channel complexes. Mutations in CACNA1A cause a wide range of neurologic disturbances variably associated with cerebellar degeneration. Functional studies to date focus on electrophysiologic defects that do not adequately explain the phenotypic findings.Objective: To investigate whether some missense mutations might interfere with protein folding and trafficking, eventually leading to protein aggregation and neuronal injury.Methods: The authors studied the functional consequences of two pore missense mutations, C287Y and G293R, in two families with EA2, one newly discovered and the other previously reported. Both mutations caused episodic and interictal ataxia. The biophysical properties of mutant and wild type calcium channels were examined by whole-cell patch-clamp recordings in transfected COS-7 cells. The plasma membrane targeting was visualized by confocal fluorescence imaging on CaV2.1 tagged with green fluorescent protein.Results: The mutant channels exhibited a marked reduction in current expression and deficiencies in plasma membrane targeting.Conclusions: In addition to altered channel function, the deficiency in protein misfolding and trafficking associated with the C287Y and G293R mutants may contribute to the slowly progressive cerebellar ataxia.

This review discusses the varied clinical spectrum of neurologic paraneoplastic disorders, describes recent advances in our understanding of autoimmunity in these disorders, and outlines a practical clinical approach to patient management.Paraneoplastic disorders may affect any part of the central or peripheral nervous system. Although relatively uncommon, these disorders are a significant cause of severe and permanent neurologic disability. Syndromes such as limbic encephalitis or opsoclonus-myoclonus should always raise suspicion of a paraneoplastic condition, but any paraneoplastic syndrome can also occur in patients without a neoplasm. Most neurologic paraneoplastic disorders are thought to be caused by an autoimmune reaction directed against 'onconeural' antigens expressed by neurons and tumor cells. Some syndromes such as Lambert-Eaton myasthenic syndrome and neuromyotonia are clearly mediated by autoantibodies. Much less is known about the immunopathogenesis of syndromes that affect the central nervous system, although a growing body of evidence implicates cellular immune effectors in causing neuronal injury. Many patients have circulating antineuronal antibodies, which can be useful in identifying a neurologic disorder as paraneoplastic and in finding the associated neoplasm. Early diagnosis of the neurologic disorder and prompt initiation of tumor treatment probably increase the likelihood of neurologic improvement.Neurologists must be able to recognize the clinical manifestations of neurologic paraneoplastic disorders, and to distinguish them from other causes of neurologic dysfunction in cancer patients. Early diagnosis of paraneoplastic syndromes maximizes the likelihood of a favorable oncologic and neurologic outcome.

This study investigated whether the cerebellum is essential for rapid saccade adaptation. Saccade adaptation was elicited by 30% backward target steps during the primary saccade. Patients with cerebellar lesions adapted less than normal subjects, but saccade adaptation was most impaired in the group of patients with cerebellar degeneration. As the variability of the saccade gain in patients with cerebellar degeneration did not significantly differ from that in the other patients, the increased variability in motor performance due to a cerebellar lesion cannot alone explain this impaired adaptation.

Formalin-fixed sections from the brains of 36 patients (30 alcoholic and 6 nonalcoholic) with autopsy-proven cirrhosis who died while in a hepatic coma were stained with hematoxylin and eosin, and examined for the presence of diencephalic, cerebellar, pontine, and basal ganglia lesions. Significant neuropathology was identified in 23 of 36 cases consisting of mammillary body and thalamic lesions characteristic of Wernicke encephalopathy (WE) (9 cases, all alcoholic patients) and cerebellar degeneration (20 cases, 17 alcoholic and 3 nonalcoholic patients). Clinical diagnosis of WE had been entertained during life in only 2 of these patients. All cases, alcoholic and nonalcoholic, manifested mild to severe Alzheimer's type II astrocytosis. No cases of central pontine myelinolysis nor acquired (non-Wilsonian) hepatocerebral degeneration were found. These findings show that the brains of a high proportion of cirrhotic patients with end-stage liver disease manifest concomitant unsuspected diencephalic and cerebellar pathology. The high incidence of WE underscores the need for early sustained treatment of alcoholic cirrhotic patients with vitamin B1. Evaluation of the neurological sequelae of liver transplantation, particularly of alcoholic patients with end-stage liver disease, may require a careful neurological and radiological assessment both before and after surgery.

A rare case of paraneoplastic cerebellar degeneration (PCD) in a 36-year-old woman is reported. She developed hyposthenia of the inferior limbs, diplopia, and disequilibrium in July 2001. Routine blood tests, tumoral markers, brain MRI, evoked potentials, and cerebrospinal fluid (CSF) examination were substantially normal. The clinical syndrome rapidly worsened in the following 2 months; she was wheelchair-bound with marked limb ataxia. CSF showed an increase of the IgG index with oligoclonal bands; brain MRI remained negative. The patient's serum and CSF were analyzed to detect antineuronal antibodies; anti-Yo antibodies were found that is typical of PCD. No tumor was found until April 2003; repeated CT scan, ultrasound, and mammographic examinations were negative. A further worsening in clinical symptoms was observed with a complete loss of autonomy (Rankin score 5) despite the performance of immunosuppressive therapy. In April 2003, an F-18 FDG PET scan visualized an area of abnormal uptake in the upper outer quadrant of the left breast. Interestingly, brain F-18 FDG uptake was normal. Suspicious microcalcifications were found on a new mammography and malignant cells were disclosed at cytology. The patient was operated on and final histologic examination revealed an infiltrating ductal breast cancer. In the reported case, F-18 FDG PET played a crucial role in detecting the unknown primary tumor in a young patient with PCD.

Objectives: To describe response to treatment in a patient with autoantibodies against voltage-gated calcium channels (VGCCs) who presented with autoimmune cerebellar degeneration and subsequently developed Lambert-Eaton myasthenic syndrome (LEMS), and to study the effect of the patient9s autoantibodies on Purkinje cells in rat cerebellar slice cultures. Methods: Case report and study of rat cerebellar slice cultures incubated with patient VGCC autoantibodies. Results: A 53-year-old man developed progressive incoordination with ataxic speech. Laboratory evaluation revealed VGCC autoantibodies without other antineuronal autoantibodies. Whole-body PET scans 6 and 12 months after presentation detected no malignancy. The patient improved significantly with IV immunoglobulin G (IgG), prednisone, and mycophenolate mofetil, but worsened after IV IgG was halted secondary to aseptic meningitis. He subsequently developed weakness with electrodiagnostic evidence of LEMS. The patient9s IgG bound to Purkinje cells in rat cerebellar slice cultures, followed by neuronal death. Reactivity of the patient9s autoantibodies with VGCCs was confirmed by blocking studies with defined VGCC antibodies. Conclusions: Autoimmune cerebellar degeneration associated with VGCC autoantibodies may precede onset of LEMS and may improve with immunosuppressive treatment. Binding of anti-VGCC antibodies to Purkinje cells in cerebellar slice cultures may be followed by cell death. Patients with anti-VGCC autoantibodies may be at risk of irreversible neurologic injury over time, and treatment should be initiated early.

Patients with rheumatic diseases can present with movement and other neurodegenerative disorders. It may be underappreciated that movement and other neurodegenerative disorders can encompass a wide variety of disease entities. Such disorders are strikingly heterogeneous and lead to a wider spectrum of clinical injury than seen in Parkinson's disease. Therefore, we sought to stringently phenotype movement and other neurodegenerative disorders presenting in a case series of rheumatic disease patients. We integrated our findings with a review of the literature to understand mechanisms which may account for such a ubiquitous pattern of clinical injury.Seven rheumatic disease patients (5 Sjogren's syndrome patients, 2 undifferentiated connective tissue disease patients) were referred and could be misdiagnosed as having Parkinson's disease. However, all of these patients were ultimately diagnosed as having other movement or neurodegenerative disorders. Findings inconsistent with and more expansive than Parkinson's disease included cerebellar degeneration, dystonia with an alien-limb phenomenon, and nonfluent aphasias.A notable finding was that individual patients could be affected by cooccurring movement and other neurodegenerative disorders, each of which could be exceptionally rare (ie, prevalence of ∼1:1000), and therefore with the collective probability that such disorders were merely coincidental and causally unrelated being as low as ∼1-per-billion. Whereas our review of the literature revealed that ubiquitous patterns of clinical injury were frequently associated with magnetic resonance imaging (MRI) findings suggestive of a widespread vasculopathy, our patients did not have such neuroimaging findings. Instead, our patients could have syndromes which phenotypically resembled paraneoplastic and other inflammatory disorders which are known to be associated with antineuronal antibodies. We similarly identified immune-mediated and inflammatory markers of injury in a psoriatic arthritis patient who developed an amyotrophic lateral sclerosis (ALS)-plus syndrome after tumor necrosis factor (TNF)-inhibitor therapy.We have described a diverse spectrum of movement and other neurodegenerative disorders in our rheumatic disease patients. The widespread pattern of clinical injury, the propensity of our patients to present with co-occurring movement disorders, and the lack of MRI neuroimaging findings suggestive of a vasculopathy collectively suggest unique patterns of immune-mediated injury.

Gait ataxia is one of the most common and debilitating motor disorders associated with cerebellar damage.1 Although some recovery occurs following a single, focal lesion (e.g., stroke, benign tumor),2 steady declines in gait and balance function are typical among individuals with cerebellar degenerative diseases. Currently, there are no pharmacologic treatments available to reverse or even substantially reduce motor disability caused by cerebellar degeneration. Thus, physical therapy forms the sole form of intervention to improve walking ataxia in these individuals. Studies of rehabilitation interventions in this population are difficult, and reports in the literature of their effectiveness remain scarce. Any improvement caused by an intervention could be masked completely by the natural decline associated with disease progression. Perhaps more importantly, the cerebellum is thought to be a primary site of motor learning3,4 and individuals with cerebellar lesions are known to have deficits in motor learning.5,6 This has led many to question whether these individuals are even capable of benefitting from any intervention …

Head-shaking nystagmus (HSN) refers to the nystagmus induced by head oscillation, and usually beats to the healthy side in unilateral peripheral vestibulopathy.1 It may occur from velocity storage mechanism and Ewald second law.1,2 In perverted HSN (pHSN), the nystagmus develops in the plane other than that being stimulated, i.e., downbeat or upbeat after horizontal head oscillation. pHSN has been reported in diffuse cerebellar degeneration or medullary lesion,3,4 and signifies central vestibular lesion. However, isolated pHSN from focal cerebellar lesions has not been described. A 59-year-old man reported recurrent dizziness that most often occurred from exposure to heat or after taking a hot bath and lasted several minutes without other neurologic symptoms. On initial examination, he had blood pressure of 155/95 mm Hg and fasting blood glucose of 206 mg/dL. Other physical, neurotologic, and routine laboratory examinations were normal. In view of hypertension, diabetes, and duration of the dizzy spells, he was suspected to have vertigo of vascular origin and was scheduled for brain MRI. Five days later, while …

Cerebellar degeneration has been associated with gluten sensitivity and celiac disease. Patients with celiac disease may have neuropathy and antibodies to gangliosides. The authors investigated the presence of antiganglioside antibodies in 22 patients with hereditary and nonhereditary ataxia and found 64% reactive in a novel agglutination test.

Objective: To evaluate disease progression and determine validity of clinical tools for therapeutic trials in a cohort of dominant ataxias. Background Autosomal dominant cerebellar ataxias (SCAs) are genetically heterogeneous with more than 30 loci involved. Cerebellar degeneration is accompanied by changes in the brainstem, basal ganglia, cerebral cortex, spinal cord and peripheral nervous system. Design/Methods: 162 patients with SCAs, including SCAs with polyglutamine expansions (25 SCA1, 35 SCA2, 58 SCA3, 5 SCA6, 10 SCA7) and other SCAs (1 SCA5, 1 SCA14, 2 SCA21,1 SCA25, 2 SCA28, 22 unknown genotypes) were followed prospectively for 3 years in the national French Referral Network including 7 centers. The outcome measures were the quantitative composite cerebellar functional score with writing (CCFSw) and the scale for the assessment and rating of ataxia (SARA). Results: Disease worsened in patients with SCA1, 2, 3 mutations and remained stable in patients with SCA6, SCA7 or other SCA mutations with both the CCFSw and the SARA. CCFSw progression was faster in SCA3 patients with Parkinsonism and/or dystonia at baseline (p=.003) while SARA progression in SCA2 patients depend of the gender, the age at onset and at inclusion, the number of repeats of the normal SCA2 allele, and the posterior column dysfunction. A two-arm trial with SARA as the outcome measure would require 57 SCA2, 70 SCA1 and 75 SCA3 patients per group to detect a 50% reduction in disease progression (power 80%, alpha 0.05). Conclusions: Disease progressed faster in SCAs with polyglutamine expansions in SCA1, 2 and 3 than the other groups. Both outcome measures are suitable for therapeutic trials; SARA requires fewer patients to attain the same power, but CCFSw needs less stratification. We demonstrate that the choice of clinical outcome measure is critical for reliable evaluation of progression in neurodegenerative diseases. Disclosure: Dr. Tezenas Du Montcel has nothing to disclose. Dr. Charles Ignatiew has nothing to disclose. Dr. Goizet has received research support from Genzyme Corporation. Dr. Marelli has nothing to disclose. Dr. Anheim has nothing to disclose. Dr. Guyant-Marchal has nothing to disclose. Dr. Le Bayon has nothing to disclose. Dr. Vandenberghe has nothing to disclose. Dr. Tchikviladze has nothing to disclose. Dr. Devos has received personal compensation for activities with Novartis and Aguettant. Dr. Le Ber has nothing to disclose. Dr. N9Guyen has nothing to disclose. Dr. Cazeneuve has nothing to disclose. Dr. Tallaksen has nothing to disclose. Dr. Brice has nothing to disclose. Dr. Durr has nothing to disclose.

To the Editor: HIV type 1 (HIV-1) infection can produce neurologic complications such as dementia, myelopathy, and peripheral neuropathy. Tagliati et al.1 described 10 such patients with symptoms of cerebellar dysfunction that they similarly ascribed to HIV-1 infection. These patients were screened for toxic and neoplastic etiologies of cerebellar degeneration. However, no genetic testing was performed. This sample was quite heterogeneous. Although ataxia was present in all 10 patients, and dysmetria in 9, other cerebellar symptoms including tremor (4 patients), nystagmus (3 patients), and dysdiadochokinesis (6 patients) were less prevalent. Radiologic imaging showed severe cerebellar atrophy in 4 patients, and mild-moderate atrophy in 3 others. Imaging was not performed on 3 patients. Pathologic studies demonstrated cerebellar granular cell loss in only 2 out of 3 autopsied patients. Do such variegated data truly define an HIV-1 related cerebellar disorder? The following report demonstrates that HIV-1–infected individuals may have superimposed genetic disorders that need to be excluded before concluding such a syndrome exists. A 33-year-old man presented in October 1998 with a 1-year history of progressive gait ataxia, dysarthria, and clumsiness. HIV-1 infection had been diagnosed in 1985. He denied any history of alcohol or drug use or opportunistic infections. His viral load was undetectable (less than 50 copies per milliliter) and his CD4 count was 733 cells per mm3. A brain MRI in August 1998 showed …

Five women are presented with a subacute pure pancerebellar syndrome of ataxia and dysarthria to emphasize that this illness may occur without anti-Purkinje-cell or anti-Yo antibodies, or associated systemic cancer. The syndrome evolved over weeks or less and stabilized in four of the patients. Three had had a preceding infection and one, a rash, but there was no inflammatory response in the spinal fluid. Over the 5-year period during which these patients appeared in an individual general neurology practice, there was only one patient with paraneoplastic cerebellar degeneration. Despite the association of this syndrome with cancer, particularly in women, clinicians will still commonly confront the idiopathic variety.

We reviewed the clinical findings in 55 patients with cerebellar degeneration associated with the anti-Yo antibody (an anti-Purkinje cell antibody identified in this study by histochemistry and Western blot). The patients were all women, 26 to 85 years old. Fifty-two of them proved to have malignancies, almost exclusively breast or gynecologic cancers and usually confined to the involved organs and local lymph nodes. One woman had adenocarcinoma of the lung, and in three no malignancy has yet been identified. In 34 of 52 patients with cancer, the neurologic syndrome preceded the diagnosis of cancer and in many led to that diagnosis. Patients subacutely developed a pancerebellar disorder that was substantially disabling in most, with 37 of 48 assessable patients being unable to walk or sit unassisted. Laboratory evaluation revealed lymphocytic pleocytosis in 35 patients, with eventual cerebellar atrophy on imaging studies in seventeen. The disabling neurologic syndrome generally did not respond to treatment, but the cancer was often successfully treated. The presence of the anti-Yo antibody in patients with cerebellar symptoms warrants an aggressive approach to diagnosis and treatment of the underlying cancer, as many are curable at the time neurologic symptoms develop.

We used CT to make a quantitative evaluation of the pontine volumes of 55 patients with adult-onset cerebellar degeneration and compared the results with their clinical records. Patients with pontine atrophy showed significantly more autonomic dysfunction and extrapyramidal signs; their other clinical features did not differ from patients without pontine atrophy. After dividing the patients into 2 groups, those with and without autonomic dysfunction or extrapyramidal signs, we found that those with these manifestations also had pontine atrophy, a later onset and shorter duration of the disease, and impairment of higher brain functions. The group without these manifestations had relatively normal pontine volume, a greater familial tendency for cerebellar degeneration, and longer duration of the disease. Our results suggest that quantitative volume evaluation of the pons by CT is important for the clinical categorization of cerebellar degeneration.

Risk factors for epithelial ovarian cancer are summarized in Table 1. Calculation of ovulation-years appears to be a potentially useful and practical method for identification of the high-risk individual. Risk factors for nonepithelial ovarian cancer are largely unknown, and consequently clinical diagnosis is stressed in the early detection of these tumors. Patients with Peutz-Jeghers syndrome or ovarian dysgenesis are significantly at risk and require at least regular pelvic examination. Of course, individuals with sexual precocity are at high risk for sex cord/stromal or germ cell malignancies. Individuals with a family history of Sertoli-Leydig cell tumors and benign thyroid disease also deserve close observation. Early clinical detection requires a sensitivity to presenting symptomatology (e.g., diffuse abdominopelvic complaints) as well as the skill and knowledge needed to recognize and appropriately manage adnexal masses. Harbingers of ovarian malignancy in the elderly woman, including unexplained hypercalcemia, new onset dermatomyositis, and cerebellar degeneration, should motivate thorough gynecologic evaluation. While radionuclide ovarian imaging for detection of early epithelial cancers of the ovary may become more generally available in the future, ultrasound imaging of the postmenopausal ovary, and peritoneal cytology may be of immediate value in screening high-risk women.

Sera from three of four patients with paraneoplastic cerebellar degeneration (PCD) associated with gynecologic cancer had antibodies that stained the cytoplasm of Purkinje cells in a characteristic discrete and coarsely granular pattern. No such antibodies were found in PCD patients with small cell cancer of the lung, in patients with cerebellar degeneration without cancer, in nonneurologic patients with small cell carcinoma or gynecologic cancer, or in normal subjects. Immunoelectron microscopy revealed that the antibodies of PCD bound to clusters of ribosomes, granular endoplasmic reticulum, and the trans-face of the vesicles of the Golgi complex in Purkinje cells. Immunostaining was localized in orderly arrays of stacked parallel cisternae of the endoplasmic reticulum in the perikaryon and dendritic processes. This pattern suggested that at least one autoantigen of PCD may be a glycoprotein specific cerebellar tissue that is associated with the endoplasmic reticulum. Some patches of Purkinje plasma membrane also were immunostained.

Two siblings had olivopontocerebellar degeneration, failure to thrive, hepatic fatty change and cirrhosis, and a dyslipoproteinemia characterized by low cholesterol and elevated triglycerides. This condition was distinct from other cerebellar atrophies and ataxias and was not due to malabsorption or malnutrition. Cerebellar degeneration progressed rapidly during the first year of life, and both children died from intercurrent infections and surgical complications at 11 and 17 months. Stereotyped clinical and pathologic findings in the two patients suggest a previously unreported genetic metabolic disorder affecting the liver and the CNS.

Diffuse loss of cerebellar Purkinje cells and to some extent, of granule cells occurred in a 78-year-old woman who had been continually treated with phenytoin for more than 20 years and in whom progressive cerebellar deficits developed in the later years of life. In the absence of other demonstrable cause, the selective morphologic changes in the cerebellum are attributed to long-term administration of phenytoin.