Correlation of diabetic retinopathy and corneal neuropathy using confocal microscopy.

PURPOSE/AIM: To employ corneal confocal microscopy to assess differences in the extent of corneal nerve fiber alterations between diabetic patients classed according to retinopathy status and nondiabetic patients. MATERIALS AND METHODS: Two hundred seventy-eight corneas of 139 patients with type 2 diabetes mellitus and 94 corneas of 47 age-matched control participants were scanned using corneal confocal microscopy. Images of the subbasal nerve plexus were collected and analyzed for nerve fiber density (NFD), nerve branch density (NBD), nerve fiber length (NFL), and nerve fiber tortuosity (NFT). Diabetic patients were categorized into three groups according to the classification of diabetic retinopathy (DR) proposed in the Early Treatment of Diabetic Retinopathy Study, based on indirect fundoscopy, fundus photography, and fluorescein angiography findings. A separate classification into four groups according to the severity of peripheral diabetic neuropathy (DN) was also used, based on the results of clinical and electrodiagnostic examinations. RESULTS: Average NFD, NBD, and NFL differed significantly according to DR status and were found to be lower, whereas NFT was found to be higher in diabetic patients than control participants. A positive correlation between diabetic corneal neuropathy and peripheral DN was also found. CONCLUSIONS: Nerve fiber alterations of the subbasal nerve plexus of diabetic corneas appear to progress in parallel with DR and peripheral DN. Corneal confocal microscopy could possibly represent a promising adjuvant technique for the early diagnosis and assessment of human DN.

Patients with horizontal gaze palsy and progressive scoliosis due to ROBO3 E319K mutation have both uncrossed and crossed central nervous system pathways and perform normally on neuropsychological testing.

BACKGROUND: Horizontal gaze palsy and progressive scoliosis (HGPPS) is caused by mutations of the ROBO3 gene, which encodes a receptor associated with axonal guidance during development. Although there is evidence for uncrossed cuneatal and corticospinal tracts in HGPPS, it is unclear whether other central nervous system pathways are involved. OBJECTIVE: To study two patients with HGPPS homozygotic for the ROBO3 E319K mutation using a variety of neurophysiological and neuropsychological tests. METHODS: A battery of neuropsychological tests was applied to assess various cognitive and perceptual functions. The corticospinal, somatosensory and auditory pathways were evaluated using appropriate neurophysiological tests. To access motor pathways to the neck muscles, electromyographic recordings were obtained from the sternocleidomastoideus and splenius capitis muscle during active head rotation. RESULTS: Both patients performed normally on manual dexterity, complex sensory and visuospatial functions, reading and general intelligence tests. Motor evoked potentials in both patients showed uncrossed corticospinal tracts for the extremities, although in one patient, electromyography indicated pyramidal tract crossing for the neck muscles. Although somatosensory evoked potentials showed uncrossed somatosensory fibres subserving proprioception and light touch, right median nerve somatosensory evoked potential in one patient indicated a partial lemniscal crossing. Sympathetic skin response and blink reflex showed a midline crossing of the spinothalamic and quintothalamic tracts. Brain stem auditory evoked potentials indicated a lack of crossing in the level of the trapezoid body. CONCLUSIONS: Our patients with the ROBO3 E319Kappa mutation show normal perceptual and cognitive functions and have both crossed and uncrossed motor, sensory and auditory pathways.

Unilateral reduction of the cervical response in median SEP due to a vertebral fracture, unrecognized in plain films.

We report on a patient presenting with hypaesthesia in first, second and third finger of the right hand following a motorcycle accident. Conventional X-ray showed only a mild dislocation in C6/C7 segment. Cervical MRI in order to prove a root avulsion, was reported to be normal. Somatosensory evoked potentials (SEP) revealed a reduced amplitude of the cervical response on right median nerve stimulation. Needle-EMG showed a mild reduced recruitment pattern in triceps brachii muscle compatible with an anterior root lesion. Reviewing MRI, a signal loss in the course of C7 root was suspicious for an articular process fracture. This was proved in a CT scan. This case report emphasizes the topodiagnostic value of the reduced amplitude of the cervical potential of median nerve SEP and the importance of the CT in evaluating cervical spine fractures, as plain films frequent fail to do so.

Age related axonal neuropathy in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD).

To identify determinants of peripheral involvement in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) the influence of CAG repeat length, age of onset, disease duration and age on the results of nerve conduction studies was analysed in 58 patients with SCA3/MJD. Patients with SCA3/MJD showed marked reduction of compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes indicating axonal neuropathy of both motor and sensory fibres. In addition, there was moderate slowing of nerve conduction suggestive of mild peripheral demyelination. Multivariate regression showed that CMAP and SNAP amplitudes decreased with age, but were not affected by CAG repeat length, age of onset, or disease duration. The age related decline of CMAP and SNAP amplitudes in SCA3/MJD was greater than in normal subjects. The data suggest that the degree of peripheral damage in SCA3/MJD does not depend on CAG repeat length, age of onset, or disease duration, but is mainly related to the time period over which the SCA3/MJD mutation exerts its effect.

Sleep disturbance in spinocerebellar ataxias: is the SCA3 mutation a cause of restless legs syndrome?

OBJECTIVE: To identify and to characterize sleep disturbances in patients with hereditary ataxias. BACKGROUND: We observed restless legs syndrome (RLS) and impaired sleep as a frequent yet unrecognized symptom in spinocerebellar ataxia type 3 (SCA3). METHODS: A total of 89 patients with genetically defined subtypes of autosomal dominant cerebellar ataxias were investigated for sleep history and neurologic findings according to a standardized protocol. Nerve conduction studies were performed. Sleep was studied by overnight polysomnography in seven patients. RESULTS: RLS was present in 45% of SCA3 patients but is rare in other types of autosomal dominant cerebellar ataxias. RLS was a frequent but not the only cause of sleep impairment in SCA3. Impaired sleep in SCA3 is associated with older age, long-standing disease, and brainstem involvement. RLS tended to be more frequent in patients with clinical signs of polyneuropathy, but RLS was not restricted to patients with peripheral neuropathy. RLS was not observed in healthy members of SCA3 families. CONCLUSIONS: RLS is a frequent and treatable cause of disabling sleep disturbance in SCA3. This study provides evidence for the expanded CAG repeat in the SCA3 gene as a molecular factor causing RLS.

Spinocerebellar ataxia type 6: genotype and phenotype in German kindreds.

OBJECTIVE: Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant cerebellar ataxia (ADCA) of which the mutation causing the disease has recently been characterised as an expanded CAG trinucleotide repeat in the gene coding for the alpha1A-subunit of the voltage dependent calcium channel. The aim was to further characterise the SCA6 phenotype METHODS: The SCA6 mutation was investigated in 69 German families with ADCA and 61 patients with idiopathic sporadic cerebellar ataxia and the CAG repeat length of the expanded allele was correlated with the disease phenotype. RESULTS: Expanded alleles were found in nine of 69 families as well as in four patients with sporadic disease. Disease onset ranged from 30 to 71 years of age and was significantly later than in other forms of ADCA. Age at onset correlated inversely with repeat length. The SCA6 phenotype comprises predominantly cerebellar signs in concordance with isolated cerebellar atrophy on MRI. Non-cerebellar systems were only mildly affected with external ophthalmoplegia, spasticity, peripheral neuropathy, and parkinsonism. Neither these clinical signs nor progression rate correlated with CAG repeat length. CONCLUSIONS: This study provides the first detailed characterisation of the SCA6 phenotype. Clinical features apart from cerebellar signs were highly variable in patients with SCA6. By comparison with SCA1, SCA2, and SCA3 no clinical or electrophysiological finding was specific for SCA6. Therefore, the molecular defect cannot be predicted from clinical investigations. In Germany, SCA6 accounts for about 13% of families with ADCA. However, up to 30% of SCA6 kindreds may be misdiagnosed clinically as sporadic disease due to late manifestation in apparently healthy parents. Genetic testing is therefore recommended for the SCA6 mutation also in patients with putative sporadic ataxia.

Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes?

Seventy-seven families with autosomal dominant cerebellar ataxia were analyzed for the CAG repeat expansions causing spinocerebellar ataxia (SCA) types 1, 2, 3, and 6. The SCA1 mutation accounted for 9%, SCA2 for 10%, SCA3 for 42%, and SCA6 for 22% of German ataxia families. Seven of 27 SCA6 patients had no family history of ataxia. Age at onset correlated inversely with repeat length in all subtypes. Yet the average effect of one CAG unit on onset age was different for each SCA subtype. We compared clinical, electrophysiological, and magnetic resonance imaging (MRI) findings to identify phenotypic characteristics of genetically defined SCA subtypes. Slow saccades, hyporeflexia, myoclonus, and action tremor proposed SCA2. SCA3 patients frequently developed diplopia, severe spasticity or pronounced peripheral neuropathy, and impaired temperature discrimination, apart from ataxia. SCA6 presented with a predominantly cerebellar syndrome and patients often had onset after 55 years of age. SCA1 was characterized by markedly prolonged peripheral and central motor conduction times in motor evoked potentials. MRI scans showed pontine and cerebellar atrophy in SCA1 and SCA2. In SCA3, enlargement of the fourth ventricle was the main sequel of atrophy. SCA6 presented with pure cerebellar atrophy on MRI. However, overlap between the four SCA subtypes was broad.

Motor fibers in the sural nerve of humans.

Although motor fibers in the sural nerve were already described in three individuals, this nerve is considered purely sensory. We investigated the occurrence of motor fibers in 331 sural nerves of 207 individuals. We found motor fibers in 15 nerves (4.5%) or in 13 individuals (6.2%). The identification of motor fibers in the sural nerve before nerve biopsy has important implications for the interpretation of pathologic findings.

Spinocerebellar ataxia type 2. Genotype and phenotype in German kindreds.

BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant cerebellar ataxia (ADCA) for which the disease-causing mutation has recently been characterized as an expanded CAG trinucleotide repeat. We investigated 64 families of German ancestry with ADCA and 55 patients with sporadic ataxia for the SCA2 mutation. RESULTS: Expanded alleles were found in 6 of the 64 families and in 1 patient with sporadic ataxia. This patient had a de novo mutation from an intermediate paternal allele. Length of repeats in 21 patients with SCA2 ranged from 36 to 52 CAG motifs and was inversely correlated with age at onset and progression of the disease. Expanded alleles were unstable during meiosis; paternal transmission especially caused significant anticipation of onset up to 26 years earlier. The SCA2 phenotype differed from those of SCA1 and SCA3 with higher frequencies of slowed ocular movements, postural and action tremor, myoclonus, and hyporeflexia. However, no single feature was sufficient to permit a specific clinical diagnosis. CONCLUSIONS: Spinocerebellar ataxia type 2 accounts for about 10% of German families with ADCA but may also be present in sporadic ataxia due to de novo mutations. Clinical features are highly variable among and even within families. However, the size of the expanded repeat influences the phenotype and is relevant for course and prognosis of the disease.

Lumbosacral perineural cysts as a cause for neurogenic muscular hypertrophy.

We report the case of a 40 year-old man with a severe lesion of the anterior rami of the left spinal nerves L5 and S1 who showed hypertrophy of the leg and atrophy of the intrinsic foot and gluteal muscles. In the biopsy of the hypertrophied gastrocnemius muscle, perivascular inflammatory infiltrates were observed, apart from atrophied and hypertrophied muscle fibres. Electromyography revealed no pathologic spontaneous activity but chronic neurogenic changes. The precise site of the lesion was predicted by electrophysiologic investigations. The lesion was caused by two perineural cysts in the region of the upper sacral plexus, as demonstrated by MRI and CT of the small pelvis and confirmed at operation. Three years earlier, when almost only L5 muscles were affected, an intervertebral disc prolapse L5/S1 had been suspected on myelography and CT but could not have been confirmed at operation.

[Genetic diagnosis, classification and clinical hereditary ataxia disease entities]. / Genetische Diagnostik, Klassifikation und klinische Krankheitsentitäten hereditärer Ataxien.

Hereditary ataxias are a heterogeneous group of neurodegenerative diseases. Neither the clinical features nor the findings at autopsy provide a satisfactory basis for the isolation of distinct categories and classification. Recently, several gene loci responsible for inherited ataxias have been identified. For several hereditary ataxias even the disease causing mutations have been described. These findings lead to a new classification of the inherited ataxias based on genotypes rather than pathology or phenotypes. Such a classification will potentially gain wide acceptance since it derives from the molecular genetic cause of the diseases. Furthermore, recent advances in molecular biology improved the understanding of the clinical variability of hereditary ataxias that occurs even within the same family. All forms of progressive dominant ataxias are most likely caused by the same type of mutation: an unstable and expanded trinucleotide repeat. The repeat expansion is moderate in patients with later onset and mild progression but is extensive in juvenile cases with a more rapid course of the disease. Furthermore, the extent of the expansion seems to be at least partially responsible for the development of different phenotypes. The identification of gene loci and mutations allows reliable diagnosis even at a presymptomatic or prenatal stage for an increasing number of inherited ataxias. Although molecular genetics has improved the diagnosis and understanding considerably for most forms of hereditary ataxias a causal therapy is still missing. Therefore, it is essential that presymptomatic analysis is always performed according to the international guidelines. They include genetic counselling by a team of experienced neurologists, geneticists, psychologists and social workers.

Transmission distortion of the mutant alleles in spinocerebellar ataxia.

Spinocerebellar ataxia type 1 and type 3 (SCA1, SCA3) are autosomal dominant neurodegenerative disorders caused by expanded CAG trinucleotide repeats in novel genes. In our collective of SCA1 and SCA3 families, we observed distortion of the Mendelian 1:1 segregation of the disease. The mutated alleles were preferentially transmitted by female carriers in SCA3, whereas a gender effect on clinical features such as age of onset was not obvious. The mechanism underlying segregation distortion remains to be established.

Friedreich's ataxia. Revision of the phenotype according to molecular genetics.

Friedreich's ataxia is an autosomal recessively inherited neurodegenerative disorder caused by expansions of an unstable GAA trinucleotide repeat in the STM7/X25 gene on chromosome 9q. We studied the (GAA)n polymorphism in 178 healthy controls and 102 patients with idiopathic ataxia. The repeat size ranged from 7 to 29 (GAA)n motifs on normal chromosomes and from 66 to 1360 trinucleotide repetitions in Friedreich's ataxia patients. Meiotic instability of expanded alleles was observed without significant differences in maternal and paternal transmissions. Thirty-six of 102 patients were typed homozygous for expanded (GAA)n alleles. Twenty-seven of these presented with the typical Friedreich's ataxia symptoms and nine patients with an atypical Friedreich's ataxia phenotype. Before molecular genetic diagnosis had been performed seven of these patients had been classified as early onset cerebellar ataxia and two as idiopathic sporadic cerebellar ataxia of late onset. In contrast, in one family with typical Friedreich's ataxia phenotype we did not find an expanded allele; this suggests that there can be either point mutations in the X25 gene on both chromosomes or locus heterogeneity in Friedreich's ataxia. The phenotypic spectrum of Friedreich's ataxia is much broader than considered before. Early onset, areflexia, extensor plantar responses and reduced vibration sense should no longer be considered essential diagnostic criteria of Friedreich's ataxia. In comparison with the non-Friedreich's ataxia group hypertrophic cardiomyopathy seems to be the only symptom specific for Friedreich's ataxia. However, it is not obligatory. The phenotype is significantly influenced by the number of GAA repeats with close genotype-phenotype relationships when the smaller of the two alleles is considered. Repeat length correlated inversely with age at onset, onset of dysarthria and progression rate. In conclusion, molecular genetic analysis appears mandatory for the diagnosis and genetic counselling of Friedreich's ataxia. The molecular genetic test should be applied not only to patients with typical Friedreich's ataxia phenotype but also in all cases of idiopathic autosomal recessive or sporadic ataxia.

[Drug-induced rhabdomyolysis and lesions of peripheral nerves. Sequelae of local ischemia within the scope of circulatory collapse?]. / Drogeninduzierte Rhabdomyolyse und Läsionen peripherer Nervenstränge. Folge einer territorialen Ischämie im Rahmen eines Kreislaufkollapses?

We report on two patients with severe rhabdomyolysis and peripheral nerve involvement after drug intoxication. Nerve conduction studies of the paretic extremities of both patients could be performed within 12 h of the onset. Several nerves revealed evidence of conduction blocks in the paretic extremities. One of the patients who had taken heroin died and postmortem examination was performed. A drug-induced immune vasculitis could not be demonstrated. Besides striated muscle necrosis, extensive myocardial fragmentation was shown. Territorial ischemia, resulting from systemic hypotension and mechanical compression of arteries, seems to have been the cause of the myonecroses and peripheral nerve damage in the unconscious patients.