Vitamin D and spinal cord injury: should we care?

STUDY DESIGN: Narrative review. OBJECTIVES: This review provides an overview of the etiological factors and consequences of vitamin D insufficiency in relation to spinal cord injury (SCI) as well as important considerations for vitamin D supplementation. SETTING: Montreal, Canada. METHODS: Literature search. RESULTS: Vitamin D insufficiency is common in SCI individuals owing to the presence of many contributing factors including limited sun exposure and intake, use of medication and endocrine perturbations. Although there are several biological plausible mechanisms by which vitamin D may act upon musculoskeletal and cardiometabolic health, the impact of vitamin D insufficiency on such systems remains ill defined in SCI. In the absence of guidelines for the management of vitamin D insufficiency in this high-risk population and in an attempt to provide clinical guidance, considerations for vitamin D supplementation such as the type of vitamin D, dosing regimens and toxicity are discussed and tentative recommendations suggested with particular reference to issues faced by SCI patients. CONCLUSION: Although high rates of vitamin D insufficiency are encountered in SCI individuals, its consequences and the amount of vitamin D required to prevent insufficiency are still unknown, indicating a need for more intervention studies with well-defined outcome measures. Routine screening and monitoring of vitamin D as well as treatment of suboptimal status should be instituted in both acute and chronic setting. The close interactions between vitamin D and related bone minerals should be kept in mind when supplementing SCI individuals, and practices should be individualized with clinical conditions.

Diversity of ARSACS mutations in French-Canadians.

BACKGROUND: The growing number of spastic ataxia of Charlevoix-Saguenay (SACS) gene mutations reported worldwide has broadened the clinical phenotype of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The identification of Quebec ARSACS cases without two known SACS mutation led to the development of a multi-modal genomic strategy to uncover mutations in this large gene and explore phenotype variability. METHODS: Search for SACS mutations by combining various methods on 20 cases with a classical French-Canadian ARSACS phenotype without two mutations and a group of 104 sporadic or recessive spastic ataxia cases of unknown cause. Western blot on lymphoblast protein from cases with different genotypes was probed to establish if they still expressed sacsin. RESULTS: A total of 12 mutations, including 7 novels, were uncovered in Quebec ARSACS cases. The screening of 104 spastic ataxia cases of unknown cause for 98 SACS mutations did not uncover carriers of two mutations. Compounds heterozygotes for one missense SACS mutation were found to minimally express sacsin. CONCLUSIONS: The large number of SACS mutations present even in Quebec suggests that the size of the gene alone may explain the great genotypic diversity. This study does not support an expanding ARSACS phenotype in the French-Canadian population. Most mutations lead to loss of function, though phenotypic variability in other populations may reflect partial loss of function with preservation of some sacsin expression. Our results also highlight the challenge of SACS mutation screening and the necessity to develop new generation sequencing methods to ensure low cost complete gene sequencing.

Synapses in the hereditary ataxias.

The goal of this investigation was the systematic assessment of synapses in the hereditary ataxias by the immunocytochemical and immunofluorescent visualization of SNAP-25, a protein of the presynaptic membrane. Sections were prepared from the cerebellar cortex, dentate nucleus, basis pontis, inferior olivary nuclei, and the spinal cord in 57 cases of autosomal dominant and recessive ataxia. The neuropathological phenotype included 18 cases of olivopontocerebellar atrophy (OPCA), 14 cases of familial cortical cerebellar atrophy (FCCA), 4 cases of Machado-Joseph disease (MJD), and 21 cases of Friedreich's ataxia (FA). Among the autosomal dominant ataxias, spinocerebellar ataxia type 1 (SCA-1), SCA-2, MJD/SCA-3, and SCA-6 were represented. Expanded guanine-adenine-adenine trinucleotide repeats were confirmed in 7 patients with FA. The abundance of SNAP-25 was estimated by comparing the fluorescence of the regions of interest to that of the frontal cortex, which was considered unaffected by the disease process. Despite severe Purkinje cell loss, abundant SNAP-25 reaction product remained in the molecular layer of FCCA and OPCA. Among the cases of OPCA, those identified as SCA-2 showed the most severe overall synaptic destruction in cerebellum and brain stem. In SCA-1, which caused either OPCA or FCCA, significant synaptic loss was restricted to the inferior olivary nuclei. Sparing of cerebellar cortex and inferior olivary nuclei was the rule for MJD/SCA-3 and FA, though the dentate nucleus showed reduced SNAP-25 immunoreactivity in both ataxias. In FA, preservation of SNAP-25 in the dentate nucleus was characteristic of long survival. Severe cases with short survival revealed synaptic depletion of the dentate nucleus. At the level of the spinal cord, synaptic loss in the dorsal nuclei of Clarke characterized FA and MJD/SCA-3. The inexorable clinical progression of the hereditary ataxias could not be attributed to synaptic loss in a single anatomic structure of cerebellum, brain stem, or spinal cord. Nevertheless, synaptic loss in dentate and inferior olivary nuclei correlated more precisely with the severity of the ataxia than the changes in the cerebellar cortex.

Power spectral analysis and cortical coupling of EEG for young and old normal adults.

Power spectral analysis and cortical coupling were computed on eyes closed EEG recorded from 80 normal volunteers: 20 females and 20 males aged 25-35 years and 20 females and 20 males aged 55-70 years. Recordings were from Fz, Cz, C3, Pz and Oz areas. The results indicate that with increased age there was a greater uniformity of EEG activity across the brain. Magnitude of EEG power was significantly less variable across recording sites for the old than for the young. In addition, cortical coupling values were reliably higher for the older subjects indicating a greater congruity among EEG patterns. The EEG power and cortical coupling measures were significantly correlated and thus may indicate an underlying mechanism common to both. The results support a theory of decreased central inhibitory function in old age and may reflect an age-related breakdown of functional autonomy of cortical areas. Gender had no significant effect on either EEG power or cortical coupling.

Somatic mosaicism for Friedreich's ataxia GAA triplet repeat expansions in the central nervous system.

Most patients with Friedreich's ataxia (FRDA) carry expanded GAA repeats in both homologues of the frataxin gene on chromosome 9. We determined the size of the GAA repeats in autopsied samples from the CNS of six FRDA patients. We observed heterogeneity of repeat sizes in different CNS regions, indicative of extensive mitotic instability. Samples from the same CNS subdivision (e.g., cortex, thalamus) contained a similar mixture of alleles, suggesting that the pattern of repeat size mosaicism reflects the developmental history of each sample. Regional differences in repeat size could not account for the characteristic distribution of pathology in FRDA, which appears instead to be related to the pattern of frataxin expression.

Postnatal maturation of respiration in intact and carotid body-chemodenervated lambs.

The contribution of the carotid body chemoreceptor to postnatal maturation of breathing was evaluated in lambs from 7 to 70 days of age. The study was conducted by comparing the eupneic ventilation and resting pneumograms in intact conscious lambs with those of lambs that were carotid body chemodenervated (CBD) at birth. In comparison to the 1-wk-old intact lambs, the CBD lambs had significant decreases in minute ventilation (VE, 313 vs. 517 ml/kg), tidal volume (VT, 7.2 vs. 10.5 ml/kg), respiratory rate (f, 44 vs. 51 breaths/min), and occlusion pressure (P0.1, 2.8 vs. 7.2 cmH2O). Arterial PO2's were 59 vs. 75 Torr (P less than 0.05) and arterial PCO2's 47 vs. 36 Torr (P less than 0.05), respectively, in CBD and intact lambs. In intact lambs from 7 to 70 days, resting VE decreased progressively from 517 to 274 ml/kg (P less than 0.01) due to a fall in VT, mean inspiratory flow (VT/TI), and f, whereas the ratio of inspiratory time to total breath duration remained constant. P0.1 decreased from 7.2 to 3.9 cmH2O from 7 to 42 days. In contrast the CBD lambs experienced only minimal changes in VE, VT, VT/TI, and f during the same period. VE only decreased from 313 to 218 and P0.1 from 2.8 to 2.4 cmH2O. In contrast to that of intact lambs the resting pneumogram of CBD lambs remained relatively fixed from 7 to 70 days. Three CBD lambs died unexpectedly, without apparent cause, in the 4th and 5th wk of life.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-standing goiter and hypothyroidism: an unusual presentation of a TSH-secreting adenoma.

A 63-year-old female patient was referred to our hospital in February 1994 for a pituitary tumor. On a previous examination, in 1973, she had a goiter, nonspecific symptoms and only an elevated serum T3. In 1984 she had become hypothyroid, her goiter had increased, serum T4 was 69 nmol/L, TSH 34.4 mU/L, and TPO antibodies were positive. Hypothyroidism due to autoimmune thyroiditis was diagnosed and she received L-T4 100 micrograms/day. In 1985 and 1986, serum TSH had decreased but remained slightly elevated, while T4 was at the upper limits of normal. From 1987 to 1989 her serum TSH rose from 9 to 20 mU/L and remained at that level for the ensuing 4 years in spite of increasing L-T4 up to 150 micrograms/day. In October 1993, after discontinuing L-T4 for 6 weeks, TSH was 23.7 mU/L, T4 170 nmol/L, 131I thyroid uptake 52%, and the CT scan showed a large pituitary tumor with suprasellar extension. On preoperative investigation TSH was 40-51 mU/L with no response to TRH or GnRH. The alpha-subunit was increased at 6.33 micrograms/L with the alpha-TSH/TSH molar ratio of 1.23. Prolactin was elevated, but plasma cortisol, FSH, and LH were low. At surgery, we found a large chromophobe adenoma with few PAS-positive granules and with immunostaining positive for TSH and prolactin. From the clinical and biological data, we can conclude that the patient had probably a TSH-secreting adenoma since the goiter was first detected. The development, however, of autoimmune thyroiditis with hypothyroidism considerably modified the presentation of the disease and may have accelerated the growth of the tumor.

Ultrastructural observations on spinal ganglion biopsy in Friedreich's ataxia: a preliminary report.

We report the preliminary study of a dorsal root ganglion obtained at biopsy during a surgical intervention in a patient with Friedreich's ataxia. There was an apparent decrease in the number of large myelinated fibers without necrosis, but with numerous axonal swellings consisting mainly of dense accumulated neurofilaments. Large amounts of lipofuscin were also found as well as some onion bulb formations suggesting a process of axonal atrophy.

The cardiomyopathy of Friedreich's ataxia morphological observations in 3 cases.

In the light of the recent finding of deposits of calcium salts and iron in myocardial cells in one case of Friedreich's ataxia, we have made a detailed morphological study of 3 new cases of this cardiomyopathy. Calcium deposits were not found in the muscle fibers but lipofuscin granules and deposits of iron were observed in our 3 cases. In addition to the usual findings of interstitial fibrosis, hypertrophy and degeneration of myocardial fibers, foci of segmental active muscle necrosis were constantly present. There is a possibility that Friedreich's ataxia could be a neurocardiac degenerative disease with a membrane defect which could be related to defective metabolism of vitamin E or other micronutrients.

Paraneoplastic encephalomyelitis and subacute dysautonomia due to an occult atypical carcinoid tumour of the lung.

A case of paraneoplastic encephalomyelitis and subacute pandysautonomia associated with an occult atypical carcinoid tumour of the lung is described. The main clinical features were lethargy, impaired memory, constipation, and orthostatic hypotension. Neurological investigation was unremarkable except for mononuclear pleocytosis and increased protein level in the cerebrospinal fluid (CSF). Tests of autonomic function revealed a low plasma norepinephrine level, a marked drop of blood pressure (BP) to vertical tilt and Valsalva maneuver, and a marked rise of BP to dilute norepinephrine infusion. A few days prior to death, the patient became hypothermic and had repeated episodes of respiratory arrest associated with transient atrioventricular block on the electrocardiogram (ECG). A polysomnographic study confirmed a sleep apnea syndrome. Autopsy revealed an atypical carcinoid tumour in one tracheobronchial lymph node, widespread lymphocytic infiltrates and loss of neurons in the cerebral, cerebellar and brainstem grey matter, the spinal cord and roots, and the paravertebral sympathetic ganglia as well as microglial and astrocytic proliferation in the central nervous system.

The neuropathology of "typical" Friedreich's ataxia in Quebec.

We present the pathological data from the autopsies performed on 6 Friedreich's disease patients since the start of the Quebec Cooperative Study. All patients met the strict diagnostic criteria of the QCSFA. The anatomical lesions found in the peripheral and central nervous system were similar in all 6 cases and do not differ from those described in the literature. The clinical findings correlate closely with the histological lesions found in the peripheral nervous system and spinal cord. The evidence of segmental demyelination and remyelination in the spinal ganglia and posterior roots further supports the dying-back axonopathy hypothesis.

Meningo-ependymitis in Whipple's disease.

Six years after apparent complete recovery from intestinal Whipple's disease, a 56 year old man developed insidious progressive somnolence and gait ataxia. Studies showed hydrocephalus with obstruction of the aqueduct and CSF leukocytosis and elevated protein. Arachnoid biopsy during craniotomy revealed chronic inflammatory infiltration with PAS-positive macrophages. The patient died 5 years later despite two courses of antibiotic therapy. This is the first report of histologically confirmed cerebral Whipple's disease during life. Whipple's disease is a systemic infectious disorder. Cerebral involvement even in neurologically asymptomatic patients should be sought with periodic CSF cytologic studies and a search for hydrocephalus. The possibility of cerebral Whipple's disease should be considered in the presence of unexplained hydrocephalus and/or chronic inflammatory changes in the spinal fluid, especially in those with past or active intestinal disease.

Cystic schwannoma of the brainstem.

A rare case of cystic schwannoma occurring in the brainstem in the absence of von Recklinghausen's disease is reported. This appears to be the first case in the literature of a cystic schwannoma ever described in this location. While the exact origin of this tumor in this unusual location remains uncertain, different hypotheses are discussed and the possible origin of this tumor from perivascular elements in the brainstem is seriously considered.

Pattern electroretinogram and optic nerve section in pigeons.

We studied the effect of optic nerve section on the pattern electroretinogram (PERG) of 10 pigeons. Base line PERG and flash ERG were measured prior to surgery and then one optic nerve was cut. We measured PERG at various time intervals up to 24 weeks after the section. There was a sharp drop in PERG amplitude immediately following the section. It gradually returned to normal levels in the following 24 weeks. Significant decreases in time to peak were noted at 1 and 16 weeks for 0.5 cycle per degree checks and at 1, 2 and 9 weeks for 0.25 cycle per degree checks. The ERG generated by a TV stimulus did not change in amplitude but had a shorter time to peak at 24 weeks for a high intensity stimulus and at 16, 18, 24 weeks for a low intensity stimulus. Light and electron microscopic sections (at 24 weeks) revealed an almost complete loss of nerve fibers in the optic nerve. Retinal sections revealed only a few surviving ganglion cells and a few nerve fibers. This suggests that in pigeons, PERG is not generated by ganglion cells.

Sympathetic uveitis 66 years after injury.

We report a case of sympathetic uveitis occurring 66 years after perforating trauma to the other eye. To our knowledge this is the longest interval ever cited in the literature.

Carcinomatous neuropathy. An ultrastructural study of ten cases.

Superficial peroneal nerve biopsies were studied from 10 patients with carcinomatous neuropathy. There were 6 patients with the sensorimotor form and 4 patients with the sensory form. In both forms of neuropathy, histometric studies showed a variable loss of myelinated fibers which was generally most severe in the sensory form. In most of the cases of the sensorimotor form, ultrastructural studies showed segmental demyelination with onion bulb formation and regeneration of myelinated fibers. In the sensory form, there was no segmental demyelination, the regeneration of myelinated fibers was minimal and all the cases showed a loss of unmyelinated fibers. In sensory neuropathy, the histometric and ultrastructural changes reflect the massive acute destruction of ganglion cells in the dorsal root ganglia. In sensorimotor neuropathy, the alterations indicate a slowly progressive degenerating process in which both axonal degeneration and segmental demyelination occurred.

[Significance of polyglucosan bodies in neuropathology. Clinico-pathologic study of seven cases]. / Signification des inclusions de polymères de glucose en neuropathologie. Sept observations anatomo-cliniques.

Seven observations, having in common an accumulation of polyglucosan bodies in the nervous system, are reported. In 2 cases of adult polyglucosan body disease, characteristic polyglucosan bodies were found on the peripheral nerve biopsies, and also on the cerebral biopsy in one of these patients who was demented. The 5 other cases presented medically intractable temporal lobe epilepsy. Recovery was obtained by a temporal lobectomy in which a massive accumulation of polyglucosan bodies was discovered. These personal observations are discussed with regard to other conditions characterized by accumulation of polyglucosan bodies in the nervous system. The non specificity of these formations is emphasized.