Ataxia telangiectasia with long survival

A few patients with ataxia telangiectasia survive into the 3rd decade. In the central nervous system, dilated meningeal veins have been noted in a few cases but as a rule the vasculature in both brain and spinal cord appears normal. We present the case of the longest reported surviving patient with ataxia telangiectasia who died at the age of 34 years and showed numerous vascular malformations with gliosis and haemosiderin in the cerebral white matter and spinal cord. These are similar to the features described in three previously reported long surviving cases of ataxia telangiectasia. In addition, however, numerous corpora amylacea were present, a finding not previously described. Also presented is the magnetic resonance imaging (MRI) scan which was of diagnostic-value; there have been very few MRI scans recorded in ataxia telangiectasia. It showed lesions consistent with vascular malformations in cerebral white matter with surrounding abnormal tissue consistent with gliosis. Gross cerebellar atrophy was also demonstrated. It is significant that MRI scans 6 months apart at the age of 32 years showed progression of the lesions.     

Progressive multifocal leukoencephalopathy in a lymphoma patient with complete remission after treatment with cytostatics and rituximab: case report and review of the literature

A 44-year-old woman presented with dysarthria, visual disturbances, ataxia and cognitive impairment. There was a rapid progression of her neurological disease, and she died 8 months later. She was previously treated for a low-grade follicular B-cell lymphoma; complete remission was achieved by conventional radiotherapy and chemotherapy, including rituximab. Two years later, the neurological symptoms and signs started. MRI revealed a cerebral demyelinating process. Serology was negative. Autopsy disclosed areas in cerebral white matter with grey discoloration. Microscopy revealed demyelination, oligodendroglial viral inclusions and gliosis with bizarre astrocytes. Polymerase chain reaction (PCR) was positive for JC virus. These findings were consistent with progressive multifocal leukoencephalopathy (PML). This is one of recent reports on PML occurring in a patient treated with the anti-20 monoclonal antibody rituximab.     

Frataxin point mutations in two patients with Friedreich's ataxia and unusual clinical features

Two patients with a progressive ataxia are presented with clinical features consistent with classic Friedreich's ataxia (FRDA), but also with features unusual for FRDA. Analysis of DNA showed that each patient is heterozygous for the expanded GAA repeat of FRDA, but carries a base change on his other frataxin allele. For one patient a non-conservative arginine to cysteine amino acid change is predicted at amino acid 165 whereas the other mutation is found at the junction of exon one and intron one. Muscle biopsy showed an absence of frataxin immunoreactivity in the patient harbouring the intronic mutation, confirming the pathological nature of the base change. These mutations extend the range of point mutations seen in FRDA, and agree with recent reports suggesting phenotypic variation in patients with FRDA harbouring point mutations in conjunction with an expanded GAA repeat.     

Gliomatosis cerebri may present as an atypical parkinsonian syndrome.

An 85-year-old man presented with 3 years of a progressive akinetic rigid syndrome with ataxia, falls, levodopa unresponsiveness, and autonomic dysfunction. Early in the course of illness, cranial magnetic resonance imaging (MRI) was thought to show pontine enlargement but later was reinterpreted by experts as normal. Two subsequent cranial MRIs were believed to show only mild atrophy. An initial clinical diagnosis of multiple system atrophy was made. The patient died 4 years after the onset of symptoms. Pathological examination revealed diffuse infiltration of multiple brain regions with cells of astrocytic and microglial origin consistent with a diagnosis of gliomatosis cerebri.     

Brain stem and cerebellar dysfunction with Legionnaires' disease.

A 37-year-old man under treatment for manic-depressive illness developed pneumonia identified as Legionnaires' disease accompanied by a severe neurological disorder with profound dysarthria, ataxia, gaze paralysis, and downbeat nystagmus. At review six months later, he has made only a partial recovery with persisting limb and gait ataxia. Difficulties in diagnosing neurological complications of Legionnaires' disease in a patient with a psychiatric disorder requiring psychotropic medication are discussed.     

Tacrolimus (FK506)-induced mutism after liver transplant

Tacrolimus (FK506), an immunosuppressant, has been associated with mutism in adults after liver transplant. Speech arrest, agitation, tremor, ataxia, and downward gaze deviation in a 5-year-old female 13 days after orthotopic liver transplant are reported. FK506, which began to be administered 12 days earlier, rose to a level of 44 ng/mL (normal range, 10-20 ng/mL) 1 day before neurologic abnormalities began. FK506 dose level was maintained and then reduced. Three days later the patient could say a few single words and extra-ocular movement returned to normal. Four months later, she continued to exhibit decreased fluency and dysarthria with ataxia. One year later, decreased fluency and mild ataxia persists. Rapid identification of speech loss linked to FK506 may be important because reduction or cessation of the drug may be associated with reverse of speech loss.     

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.     

Optic ataxia as a deficit specific to the on-line control of actions

Optic ataxia is characterized by inaccuracies in body movements under visual control, and is a common consequence of damage to the posterior parietal lobes in humans. It is argued here that optic ataxia can be characterized as a deficit in the visual on-line guidance of actions, with action planning remaining relatively intact. This contrasts with the common view of optic ataxia as representing a deficit in the transformations that take place between visual inputs and motor outputs. Evidence in support of the planning-control view comes from the pattern of spared and disrupted behaviors in patients with optic ataxia. It is shown that spared behaviors are those that emphasize planning, whereas disrupted behaviors are those that emphasize control. In particular, recent studies have highlighted the inability of a patient with optic ataxia to make on-line adjustments to targets that change position during the movement. Taken in sum, the data from patients with optic ataxia is more consistent with the planning-control interpretation of optic ataxia than with the visuomotor transformation interpretation.     

Diffuse central hypomyelination presenting as 4H syndrome caused by compound heterozygous mutations in POLR3A encoding the catalytic subunit of polymerase III

We describe a 33-year-old male patient with mental retardation and cerebellar ataxia whose brain magnetic resonance imaging (MRI) showed diffuse central hypomyelination. The associated hypogonadotropic hypogonadism and hypodontia were consistent with the clinical diagnosis of 4H syndrome. Two compound heterozygous mutations in POLR3A were found: p.Met852Val and p.Asn1249His. MRI of the brain showed cerebellar atrophy, atrophy of the corpus callosum, and diffuse hypomyelination extending as far as the U-fibers, with preservation of the basal ganglia. T2 hyperintensity was observed in the bilateral middle cerebellar peduncles. The patient showed almost normal development until 4-5years of age. After 25years of age, the patient showed a gradual but consistent motor and cognitive deterioration. We demonstrated the involvement of the corticospinal tract electrophysiologically, but peripheral nerve conduction was normal. Although this disease may start very early in life, the clinical course in the present case suggests that brains that initially appear to have developed normally may show dysfunction later in life, although the pathophysiological bases for this dysfunction may not be evident on MRIs.     

Intracranial hypotension with parkinsonism, ataxia, and bulbar weakness.

OBJECTIVE: To describe a case of spontaneous intracranial hypotension with a previously unreported constellation of presenting features. DESIGN: Case report. SETTING: Tertiary care center. MAIN OUTCOME AND RESULTS: We describe a patient with intracranial hypotension who presented with a parkinsonian syndrome and later development of ataxia and prominent bulbar symptomatology. Headache was not a feature of her initial presentation and was only reported after repeated questioning during later evaluations. Magnetic resonance imaging of the patient's head revealed findings characteristic of intracranial hypotension. An [18F]fluoro-m-tyrosine positron emission tomographic scan showed normal striatal activity, suggesting intact presynaptic nigrostriatal function. Opening pressure on lumbar puncture was reduced at 40 mm H2O. A source of cerebrospinal fluid leakage was not identified on nuclear cisternography and the patient underwent lumbar epidural blood patching, which resulted in complete resolution of her signs and symptoms as well as in a marked improvement in her imaging findings. CONCLUSIONS: The clinical spectrum of intracranial hypotension can be broadened to include parkinsonism, cerebellar ataxia, and prominent bulbar dysfunction. As with more common manifestations of the disorder, these features may resolve after appropriate treatment.     

Two in one: report of a patient with spinocerebellar ataxia types 2 and 10

OBJECTIVE To report a rare case of the coexistence of 2 spinocerebellar ataxia (SCA) mutations in a single patient. DESIGN Case report. SETTING University hospital, Movement Disorders Center. PATIENT A 54-year-old man of Mexican, American Indian, and French descent with an 11-year history of gait and limb ataxia. MAIN OUTCOME MEASURES Findings of clinical examination, magnetic resonance imaging, and video electroencephalographic monitoring. RESULTS Neurologic history revealed a gradually progressive gait and limb ataxia along with muscle cramps and sensory symptoms in his distal extremities; examination revealed executive dysfunction, dysarthria, ataxia, and sensory neuronopathy. Episodes of loss of awareness were reported, but electroencephalograms were negative. Brain imaging demonstrated severe cerebellar and brainstem atrophy. Genetic evaluation of the case revealed mutations in both the SCA2 and SCA10 genes. CONCLUSION Our patient has a unique combination of genetic mutations for 2 different SCAs, types 2 and 10, which to our knowledge, has not been previously reported. His clinical phenotype is largely consistent with SCA2, but his possible seizures and Mexican heritage suggest influences of SCA10.     

Anti-GAD antibodies in paraneoplastic cerebellar ataxia associated with limbic encephalitis and autonomic dysfunction

IntroductionCerebellar ataxia and stiff person-syndrome are the main neurological syndromes associated with antibodies to glutamic acid decarboxylase (GAD).Case reportA 59-year-old patient, with history of polymyalgia rheumatica and active smoking, was admitted for subacute cerebellar ataxia and memory dysfunction explained by limbic encephalitis on brain MRI. He also presented with orthostatic hypotension and erectile dysfunction revealing autonomic dysfunction. CSF was inflammatory and antibodies to GAD were positive. Onconeuronal antibodies including GABA_B receptor antibodies were negative. Patient's condition quickly improved after intravenous immunoglobulins. A few months later, a small cell lung carcinoma was diagnosed and precociously treated.ConclusionThis case report underlines the importance of appropriate studies to confirm a primitive neoplasia, when confronted with limbic encephalitis and cerebellar ataxia, even if anti-GAD antibodies rarely define paraneoplastic syndromes.     

Cognition in Late-Onset Friedreich Ataxia

Friedreich ataxia (FRDA) is the most common hereditary ataxia. Since the discovery of the genetic cause of this disease, the phenotypic spectrum seems to be wider, including late-onset forms such as late-onset Friedreich ataxia—LOFA (25–39 years at onset). The neuropathological and clinical patterns in patients with LOFA are similar to those in patients with typical FRDA, but LOFA patients tend to have an overall milder, slowly evolving disease. Given the lack of data about cognitive performance of LOFA, we aimed to investigate whether differences in age at disease onset may be related also to differences at a cognitive level. Twenty-nine typical FRDA and seven LOFA patients were administered a comprehensive neuropsychological battery measuring multiple domains: processing speed, attention, working memory, executive functions, verbal and visual memory, visuoperceptive and visuospatial skills, visuoconstructive functions, and language. There were no significant differences in disease duration between the two groups of patients. Every patient group was matched in gender, age, years of education, and estimated IQ with a healthy-participant control group. Results indicate that both patient groups shared slowed motor processing speed and impaired conceptual thinking and verbal fluency. However, only typical FRDA patients showed a diminished cognitive processing speed and impaired visuoperceptive and visuoconstructive abilities. This pattern indicates that a later disease onset is associated to a milder cognitive impairment. Thus, our findings are in concordance with those related to clinical differences between typical FRDA and LOFA.     

Post-traumatic intradiploic leptomeningeal fistula and cyst.

A 59 year old female patient presented with ataxia and difficulty in walking. The neurological examination revealed right homonymous hemianopia and ataxia. Radiographic evaluation revealed a large occipital intradiploic cyst mainly in the left suboccipital area. There was also moderate hydrocephalus and encephalomalacia of the left occipital pole. Bone window studies also demonstrated a growing fracture extending from the upper pole of the cyst to the vertex. Both pathologies were attributed to child abuse the patient suffered when she was a child. At first surgery, decompression of the cerebellum was followed by duroplasty and acrylic cranioplasty to the posterior cranial fossa. A month later, a shunt had to be inserted for hydrocephalus. At 7 months postoperatively, the patient is well and free of any symptoms or recurrence.     

Syndrome of palatal myoclonus and progressive ataxia: two cases with magnetic resonance imaging

Two patients are reported with palatal myoclonus, progressive ataxia, and dysarthria, unresponsive to treatment with trihexyphenidyl or L-5-hydroxytryptophan. MRI showed enlargement of the inferior olives in one patient, consistent with the pathology usually associated with palatal myoclonus. The syndrome of progressive ataxia and palatal myoclonus should be distinguished from other ataxias and degenerations that affect the brainstem and cerebellum. Pathology and specificity of site of the lesions are distinctive.     

Friedreich ataxia: effects of genetic understanding on clinical evaluation and therapy

The discovery of the genetic cause of Friedreich ataxia has significantly affected our understanding of the disorder at both the clinical and basic science levels. Friedreich ataxia results from a deficiency of functional frataxin, a protein that appears to be involved in mitochondrial iron homeostasis. This leads to iron accumulation and mitochondrial abnormalities with consequent oxidant damage. The clinical spectrum of Friedreich ataxia has also expanded with the recognition of broader phenotypic features, including the absence of classical Friedreich ataxia features, later age at onset, and spasticity instead of ataxia. Although no proven therapy is yet available, antioxidants are a potential method for therapeutic intervention.     

FMR1 gene premutation is a frequent genetic cause of late-onset sporadic cerebellar ataxia

In an Italian population of 275 unrelated men affected by adult-onset sporadic progressive cerebellar ataxia, the authors found six patients carrying an FMR1 gene premutation. Age at onset (range, 53 to 69 years) and clinical-neuropathologic findings were consistent with the fragile-X tremor ataxia syndrome (FXTAS), although tremor was not as common as previously described. FXTAS accounted for 4.2% of the cases diagnosed at >50 years, suggesting that it is a frequent genetic cause of late-onset sporadic ataxia.     

Machado-Joseph disease with retinal degeneration and dementia

OBJECTIVES: To clarify the phenotypic varieties in Machado-Joseph disease (MJD). MATERIALS AND METHODS: We studied a 64-year-old man with ataxia, retinal degeneration and dementia neurologically, ophthalmologically and genetically. RESULTS: The patient noted dysesthesia of his hands at age 57 and later had memory disturbance. He had gait disturbance and needed a wheelchair at age 64. His total IQ was 61 on the WAIS-R. He had loss of central vision, ophthalmoplegia, hearing impairment, dysarthria, truncal and limb ataxia, sensory disturbance, and mild weakness of the extremities. Electrophysiologically he was suspected to have polyneuropathy. Brain MRI showed marked atrophy of the cerebellum and pons with mild cerebral atrophy. Ophthalmologic evaluation revealed multiple chorioretinal atrophy. Expanded CAG repeat numbers in MJD1 were 64. CONCLUSION: These findings indicate that the clinical features of MJD might cover a wider spectrum than previously expected, though it is possible that these complications, namely retinal degeneration and dementia, were incidental findings in this patient.     

Ataxia with oculomotor apraxia type 1 in Southern Italy: late onset and variable phenotype

Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive disorder characterized by early-onset cerebellar ataxia, oculomotor apraxia, and peripheral neuropathy. The causative gene (APTX) has been recently identified in Portuguese and Japanese kindreds. Three patients with AOA1 were identified in an APTX mutation screening on 28 Southern Italian patients with progressive ataxia and peripheral neuropathy. A novel homozygous missense mutation (H201Q) was found in one patient and a Japanese missense mutation (P206L) in two. AOA1 clinical heterogeneity and onset later than previously described are shown.     

An unusual complication of immunosuppression in myasthenia gravis: Progressive multifocal leukoencephalopathy

We present a 44-year-old female patient with generalised myasthenia gravis who developed progressive multifocal leukoencephalopathy. She was receiving high dose corticosteroids, azathioprine 200 mg daily and high dose intravenous immunoglobulin during relapses. Two months after thymectomy she presented with progressive cognitive decline, asymmetric quadriparesis and ataxia. Two months later she was bedridden. Cranial MRI showed large asymmetric T2 and FLAIR hyperintense lesions in cortical and subcortical structures. Positive CSF PCR of JC virus confirmed the diagnosis. The patient survives with severe sequela which confirms slow progression as typical in nonAIDS cases. This is the second case of progressive multifocal leukoencephalopathy in a myasthenic patient.