Quantitative objective markers for upper and lower motor neuron dysfunction in ALS.

OBJECTIVE: To investigate the value of objective biomarkers for upper (UMN) and lower (LMN) motor neuron involvement in ALS. METHODS: We prospectively studied 64 patients with ALS and its subsets using clinical measures, proton MR spectroscopic imaging ((1)H MRSI), diffusion tensor imaging, transcranial magnetic stimulation, and the motor unit number estimation (MUNE) at baseline and every 3 months for 15 months and compared them with control subjects. RESULTS: (1)H MRSI measures of the primary motor cortex N-acetyl-aspartate (NAA) concentration were markedly reduced in ALS (p = 0.009) and all UMN syndromes combined (ALS, familial ALS [fALS], and primary lateral sclerosis; p = 0.03) vs control values. Central motor conduction time to the tibialis anterior was prolonged in ALS (p < 0.0005) and combined UMN syndromes (p = 0.001). MUNE was lower in ALS (p < 0.0005) and all LMN syndromes combined (ALS, fALS, and progressive muscular atrophy; p = 0.001) vs controls. All objective markers correlated well with the ALS Functional Rating Scale-Revised, finger and foot tapping, and strength testing, suggesting these markers related to disease activity. Regarding changes over time, MUNE changed rapidly, whereas neuroimaging markers changed more slowly and did not significantly differ from baseline. CONCLUSIONS: (1)H MR spectroscopic imaging measures of the primary motor cortex N-acetyl-aspartate (NAA) concentration and ratio of NAA to creatine, central motor conduction time to the tibialis anterior, and motor unit number estimation significantly differed between ALS, its subsets, and control subjects, suggesting they have potential to provide insight into the pathobiology of these disorders.

Characteristics of patients with sensory neuropathy diagnosed with abnormal small nerve fibres on skin biopsy.

Clinical, laboratory and electrodiagnostic (EDX) characteristics of 62 patients with sensory neuropathy with abnormal skin biopsies were reviewed. Reduced epidermal nerve fibre density (ENFD) was seen in 71% and morphological changes with normal ENFD were seen in 29% of the patients. Patients with small fibre sensory neuropathy may have associated large fibre loss undetected by routine EDX. Identified associations included abnormal glucose metabolism, Lyme vaccination, monoclonal gammopathy, vitamin B12 deficiency, coeliac disease, and diseases of the connective tissue, inflammatory bowel and thyroid. Sensory neuropathy remained undetermined in 50% of the patients.

Randomized controlled phase II trial of glatiramer acetate in ALS.

The authors conducted a randomized controlled trial to test the safety and immunology of glatiramer acetate in ALS. Twenty treated patients were randomly assigned to daily or biweekly injections. Ten control patients were selected from another trial and followed up concurrently. Injection reactions were the only common adverse event (p = 0.01). Treated patients showed enhanced lymphocyte proliferation (p = 0.02). The safety profile and immune effects support conducting larger trials of dose selection and efficacy.

The natural history of primary lateral sclerosis.

OBJECTIVE: To define the syndrome of primary lateral sclerosis (PLS) and disorders that contain features of both ALS and PLS, to determine the time beyond which PLS is less likely to become ALS clinically, and to determine the outcome of people with PLS and those who develop lower motor neuron (LMN) signs. METHODS: The authors reviewed the records of all 39 patients initially diagnosed with PLS in 1984 to 2004. Diagnostic subgroups were defined based on clinical features. The authors used Kaplan-Meier methods to estimate the time to diagnosis, linear regression analyses to assess function, and a Cox proportional hazard model to assess survival in subgroups. RESULTS: Of the 39 patients, 29 had only upper motor neuron (UMN) signs on initial evaluation. Thirteen of the 29 were later classified as having UMN-dominant ALS (UMN-D) because they acquired evidence of denervation by EMG (3.17 years) or examination (3.67 years). Sixteen of the 29 patients, classified as clinically pure PLS, retained only UMN signs and a normal EMG (mean follow-up 8.7 years). Ten patients who met criteria for ALS at the initial visit were used as controls. The UMN-dominant ALS group had lower functional scores (p = 0.033) than the PLS group, and similar scores to those with ALS. Survival was longer in both the PLS group (p = 0.027) and the UMN-D group (p = 0.067) than the ALS group. CONCLUSIONS: Clinically pure PLS can be defined by isolated UMN signs 4 years after symptom onset, and is a syndrome of slow progression with high levels of function. Prior to the fourth year, the diagnosis of PLS cannot be made with certainty because many patients develop LMN signs. UMN-dominant ALS, defined by predominantly UMN disease with minor LMN signs, has disability similar to ALS, but slower progression.

Objective tests for upper motor neuron involvement in amyotrophic lateral sclerosis (ALS).

OBJECTIVE: To develop objective markers for upper motor neuron (UMN) involvement in ALS, the value of single-voxel MR spectroscopy (MRS) and transcranial magnetic stimulation (TMS) was studied. METHODS: Test results of 164 ALS patients who had MRS only (n = 91), TMS only (n = 13), or both (n = 60) were analyzed; also, 11 autopsy examinations were evaluated. RESULTS: Abnormal test results consistent with UMN involvement were found in 134 patients with clinical UMN signs: 86% on MRS, 77% on TMS, and 70% on MRS and TMS together. Among 30 patients with solely LMN signs (progressive muscular atrophy), UMN results were found in 63% on MRS, 63% on TMS, and 46% on both tests together. There was a significant association of the degree of abnormal N-acetyl aspartate/creatine ratios with UMN signs (p = 0.01). The sensitivity to detect UMN involvement was 0.86 for MRS (specificity 0.37) and 0.77 for TMS (specificity 0.38). At autopsy, all 11 patients had pathologic UMN abnormalities, including 4 with normal MRS and 1 with normal TMS in life. CONCLUSIONS: MRS is highly sensitive, somewhat more than TMS, and shows good correlation with clinical UMN signs. Combining MRS and TMS results in the same patient with further refinement may help in the early diagnosis of ALS.

Celiac neuropathy.

BACKGROUND: Celiac disease (CD) is a chronic inflammatory enteropathy resulting from sensitivity to ingested gluten. Neurologic complications are estimated to occur in 10% of affected patients, with ataxia and peripheral neuropathy being the most common problems. The incidence and clinical presentation of patients with CD-associated peripheral neuropathy have not previously been investigated. OBJECTIVE: To determine the incidence of CD in patients with neuropathy and to characterize the clinical presentation. METHODS: The records of 20 patients with neuropathy and biopsy-confirmed CD were reviewed. RESULTS: Six of the 20 patients had neuropathic symptoms alone without gastrointestinal involvement, and neuropathic symptoms preceded other CD symptoms in another 3 patients. All patients had burning, tingling, and numbness in their hands and feet, with distal sensory loss, and nine had diffuse paresthesias involving the face, trunk, or lumbosacral region. Only two had weakness. Results of electrophysiologic studies were normal or mildly abnormal in 18 (90%) of the patients. Sural nerve biopsies, obtained from three patients, revealed mild to severe axonopathy. Using the agglutination assay, 13 (65%) of the patients were positive for ganglioside antibodies. Excluding patients who were referred with the diagnosis of celiac neuropathy, CD was seen in approximately 2.5% of all neuropathy patients and in 8% of patients with neuropathy and normal electrophysiologic studies seen at our center. CONCLUSION: CD is commonly associated with sensory neuropathy and should be considered even in the absence of gastrointestinal symptoms.

Electrophysiologic studies in critical illness associated weakness: myopathy or neuropathy--a reappraisal.

OBJECTIVE: Unexplained weakness in critically ill patients is recognized with increasing frequency. However, it is debated whether the condition is a peripheral neuropathy or a myopathy. Diagnostic difficulties can arise from multiple sources that are not generally a factor in other neuromuscular conditions. Conventional electrodiagnostic techniques may provide only non-specific data, clinical examination is often hampered, and muscle biopsy is not a practical screening tool. METHOD: To improve diagnostic yield, we studied 22 consecutive patients with critical illness associated weakness with additional electrodiagnostic techniques, including direct muscle stimulation, quantitative electromyography, and motor unit number estimation. RESULTS: The applied techniques supported an underlying myopathy in all the patients examined. The diagnosis was confirmed by muscle biopsy in 9 patients. Additional lesser features of neuropathy were concomitantly present in one patient who also underwent sural nerve biopsy. CONCLUSIONS: The study suggests that myopathy is much more common than polyneuropathy in critical illness. Suspicion of this entity should be high in this setting even without exposure to corticosteroids or non-depolarizing blocking agents.

Inclusion body myositis mimicking motor neuron disease.

OBJECTIVE: To describe the clinical and electrophysiologic features of patients with inclusion body myositis that was misinterpreted as motor neuron disease. PATIENTS AND METHODS: We retrospectively retrieved the medical records of 70 patients with a pathologic diagnosis of inclusion body myositis. From this group, we selected those who had been first diagnosed as having motor neuron disease or amyotrophic lateral sclerosis. We reviewed the clinical, electrophysiologic, laboratory, and morphologic studies. RESULTS: Nine (13%) of 70 patients with inclusion body myositis had been diagnosed as having motor neuron disease. Six of the 9 patients had asymmetric weakness; in 4 the distal arm muscles were affected. Eight patients had finger flexor weakness. Tendon reflexes were preserved in weak limbs in 6, hyperactive in 2, and absent in 1. Four patients had dysphagia. Fasciculation was seen in 2 patients. None had definite upper motor neuron signs or muscle cramps. Routine electromyographic studies showed fibrillation potentials and positive sharp waves in all 9. Fasciculation potentials were seen in 7 and long-duration polyphasic motor unit potentials were seen in 8. There was no evidence of a myogenic disorder in these 9 patients. Muscle biopsy was done because of slow progression or prominent weakness of the finger flexors and was diagnostic of inclusion body myositis. A quantitative electromyogram was myopathic in 4 of the 5 patients studied. CONCLUSIONS: Inclusion body myositis may mimic motor neuron disease. Muscle biopsy and quantitative electromyographic analysis are indicated in patients with atypical motor neuron disease, especially those with slow progression or early and disproportionate weakness of the finger flexors.

Recruitment of the mitochondrial-dependent apoptotic pathway in amyotrophic lateral sclerosis.

Molecular mechanisms of apoptosis may participate in motor neuron degeneration produced by mutant superoxide dismutase-1 (mSOD1), the only proven cause of amyotrophic lateral sclerosis (ALS). Consistent with this, here we show that the proapoptotic protein Bax translocates from the cytosol to the mitochondria, whereas cytochrome c translocates from the mitochondria to the cytosol in spinal cords of transgenic mSOD1 mice during the progression of the disease. Concomitantly, caspase-9 is activated in the spinal cord of transgenic mSOD1 mice. Only in end-stage transgenic mSOD1 mice is the downstream caspase-7 activated and the inhibitor of apoptosis, XIAP, cleaved. These results indicate a sequential recruitment of molecular elements of the mitochondrial-dependent apoptotic pathway in transgenic mSOD1 mice. We also provide immunohistochemical evidence that cytochrome c translocation occurs in the spinal cord of sporadic ALS patients. Collectively, these data suggest that the mitochondrial-dependent apoptotic pathway may contribute to the demise of motor neurons in ALS and that targeting key molecules of this cascade may prove to be neuroprotective.

Myopathy with tubulin-reactive crystalline inclusions.

A 61-year-old man with muscle aches and persistently elevated serum creatine kinase had aggregates of randomly oriented, rhomboidal or rectangular protein crystalline inclusions in the sarcoplasm of type II fibers. Immunochemical studies showed strong reactivity of the inclusions to tubulin antibodies, suggesting that these unique crystalline inclusions may be a consequence of altered synthesis, processing, or degradation of tubulin.

Increased expression of the pro-inflammatory enzyme cyclooxygenase-2 in amyotrophic lateral sclerosis.

Mutations in the copper/zinc superoxide dismutase (mSOD1) gene are associated with a familial form of amyotrophic lateral sclerosis (ALS), and their expression in transgenic mice produces an ALS-like syndrome. Recent observations suggest a role for inflammatory-related events in the progression and propagation of the neurodegenerative process in ALS. Consistent with this view, the present study demonstrates that, during the course of the disease, the expression of cyclooxygenase type 2 (Cox-2), a key enzyme in the synthesis of prostanoids, which are potent mediators of inflammation, is dramatically increased. In both early symptomatic and end-stage transgenic mSOD1 mice, neurons and, to a lesser extent, glial cells in the anterior horn of the spinal cord exhibit robust Cox-2 immunoreactivity. Cox-2 mRNA and protein levels and catalytic activity are also significantly increased in the spinal cord of the transgenic mSOD1 mice. The time course of the spinal cord Cox-2 upregulation parallels that of motor neuronal loss in transgenic mSOD1 mice. We also show that Cox-2 activity is dramatically increased in postmortem spinal cord samples from sporadic ALS patients. We speculate that Cox-2 upregulation, through its pivotal role in inflammation, is instrumental in the ALS neurodegenerative process and that Cox-2 inhibition may be a valuable therapeutic avenue for the treatment of ALS.

Absence of echovirus sequences in brain and spinal cord of amyotrophic lateral sclerosis patients.

The role of enteroviruses in pathogenesis of amyotrophic lateral sclerosis (ALS) is controversial. A recent study, based on reverse transcription-polymerase chain reaction (RT-PCR) analysis of spinal cord, reported identification of a novel echovirus in 15 of 17 French subjects with ALS and only 1 of 29 subjects with other neurologic diseases. We established a real-time RT-PCR method based on this novel echovirus sequence and used this method and that previously employed for analysis of the French subjects to determine the prevalence of echoviral sequences in spinal cord and motor cortex of sporadic ALS subjects from the United States. No echoviral sequences were found in 20 spinal cord and 10 motor cortex samples from autopsy-confirmed cases of ALS or 13 spinal cord and 5 motor cortex samples from subjects with no motor neuron disease.

Primary central nervous system lymphoma in childhood presenting as progressive panhypopituitarism.

We report a 15-year-old boy who had isolated central diabetes insipidus initially diagnosed at age 11 years. A brain magnetic resonance imaging (MRI) was normal at the time. At age 12 years, growth hormone (GH) testing was performed because of a decline in linear growth rate and demonstrated GH deficiency. After a repeat normal brain MRI, GH therapy was begun. Three years later, hormonal testing revealed prepubertal gonadotropins and low testosterone levels, free thyroxine index, and morning cortisol levels. Repeat brain MRI demonstrated a 9-mm enhancing lesion in the region of the pituitary stalk. The pathologic diagnosis was that of a high-grade malignant B-cell lymphoma, suggestive of Burkitt Lymphoma. Growth hormone therapy has not been associated with an increased incidence of lymphoma. This report underscores the need for vigilance in follow-up brain imaging and hormonal evaluation in children with diabetes insipidus, especially those with evolving anterior hormone deficiencies.

Molecular and genetic characterization of sarcospan: insights into sarcoglycan-sarcospan interactions.

Autosomal recessive limb girdle muscular dystrophies 2C-2F represent a family of diseases caused by primary mutations in the sarcoglycan genes. We show that sarcospan, a novel tetraspan-like protein, is also lost in patients with either a complete or partial loss of the sarcoglycans. In particular, sarcospan was absent in a gamma-sarcoglycanopathy patient with normal levels of alpha-, beta- and delta-sarcoglycan. Thus, it is likely that assembly of the complete, tetrameric sarcoglycan complex is a prerequisite for membrane targeting and localization of sarcospan. Based on our findings that sarcospan is integrally associated with the sarcoglycans, we screened >50 autosomal recessive muscular dystrophy cases for mutations in sarcospan. Although we identified three intragenic polymorphisms, we did not find any cases of muscular dystrophy associated with primary mutations in the sarcospan gene. Finally, we have identified an important case of limb girdle muscular dystrophy and cardiomyopathy with normal expression of sarcospan. This patient has a primary mutation in the gamma-sarcoglycan gene, which causes premature truncation of gamma-sarcoglycan without affecting assembly of the mutant gamma-sarcoglycan into a complex with alpha-, beta- and delta-sarcoglycan and sarcospan. This is the first demonstration that membrane expression of a mutant sarcoglycan-sarcospan complex is insufficient in preventing muscular dystrophy and cardiomyopathy and that the C-terminus of gamma-sarcoglycan is critical for the functioning of the entire sarcoglycan-sarcospan complex. These findings are important as they contribute to a greater understanding of the structural determinants required for proper sarcoglycan-sarcospan expression and function.

Structural abnormalities of subicular dendrites in subjects with schizophrenia and mood disorders: preliminary findings.

BACKGROUND: Postmortem studies of the subiculum from subjects with schizophrenia have detected smaller pyramidal cell bodies and diminished immunoreactivity for the dendritic protein, microtubule-associated protein 2. While these findings suggest that subicular pyramidal cell dendrites may be structurally altered in subjects with schizophrenia, this possibility had not been tested directly. METHODS: Rapid Golgi impregnation of archival brain specimens was used to compare the morphologic characteristics of subicular dendrites in subjects with schizophrenia (n = 13) and mood disorders (n = 6) with subjects without psychiatric disease (n = 8). The specimens were processed and analyzed by physicians blind to diagnosis. The extent of dendritic trees in the subiculum and fusiform gyrus was examined by Sholl analysis. Spine density on apical dendrites of subicular pyramidal cells was determined at a fixed distance from the cell body. RESULTS: Spine density and arborization of subicular apical dendrites were significantly related to diagnostic group. Spine density was significantly lower in the schizophrenia and mood disorder groups than in the nonpsychiatric group. Among the mood disorder cases, diminished spine density was apparently related to a strong family history of major psychiatric diseases. There were no significant effects of diagnostic group on Sholl analysis of nonapical subicular dendrites nor on Sholl analysis of dendrites of neocortical pyramidal cells in the fusiform gyrus. CONCLUSIONS: We have observed an association between schizophrenia and major mood disorders and structural abnormalities of subicular apical dendrites. Further studies are needed to test this association in a larger sample and to evaluate the potential role of family history and of confounding factors, such as medications and chronic institutionalization.

Antisulfatide antibodies in neuropathy: clinical and electrophysiologic correlates.

OBJECTIVE: To investigate the clinical and electrophysiologic characteristics of the neuropathy associated with elevated serum antisulfatide antibodies. METHODS: Clinical, electrophysiologic, morphologic, and laboratory data of 25 patients with significantly elevated (>25,600) antisulfatide antibodies were reviewed. RESULTS: Four groups were distinguished based on clinical and electrophysiologic data: Group 1, eight patients with predominantly small fiber sensory neuropathy (32%); Group 2, five patients with mixed large and small fiber sensory neuropathy (20%); Group 3, seven patients with axonal sensorimotor neuropathy (28%); and Group 4, three patients with demyelinating sensorimotor neuropathy (12%). One additional patient had mononeuritis multiplex and one had ALS. An immunoglobulin M (IgM) monoclonal gammopathy was found in 30% of the patients tested, but not in any of the Group 1 patients with small fiber sensory neuropathy. Serum IgM level was elevated in 12 patients, of whom six had a concomitant monoclonal gammopathy. Morphologic studies in five patients showed predominantly axonal degeneration, with three of the patients also exhibiting additional features of demyelination. CONCLUSIONS: Antisulfatide antibodies are associated with several subtypes of peripheral neuropathy. Predominantly sensory or sensorimotor axonal neuropathies are most common in this series, with the sensory component either small fiber or mixed fiber type. A smaller demyelinating group indistinguishable from patients with chronic inflammatory demyelinating polyradiculopathy was also seen. One third of patients had a concomitant IgM monoclonal gammopathy, and approximately one half had elevated serum IgM.

Local activation of the complement system in endoneurial microvessels of diabetic neuropathy.

Quantitative immunocytochemical analysis of complement proteins (CP) was performed on sural nerve biopsies from 15 patients with diabetic neuropathy (DN) and 18 nondiabetic patients with other forms of chronic neuropathy (ON). The mean age of the patients and the pathological severity of the neuropathy were similar in both groups. The percentage of patients that expressed strongly immunoreactive CP in the walls of endoneurial microvessels was significantly greater in DN than in ON for all proteins tested. C3d neoantigen was expressed in 100% of DN cases compared with 17% of ON; and membrane attack complex (MAC), C5b-9 neoantigen, in 93% of DN and 17% of ON. In the cases with DN, 81% of endoneurial microvessels, as identified by the endothelial marker, Ulex europaeus, contained C5b-9 neoantigen deposits, compared with 22% in those of ON, and the staining in DN was significantly more intense. Expression of the neoantigens of C3d and C5b-9 in nerve implies local activation of the complement system. In DN, activation of the complement pathway and formation of the MAC could injure blood vessels and adversely affect the circulation in the endoneurium.

Amyotrophic lateral sclerosis with multiple sclerosis: a clinical and pathological report.

We report a 62-year-old woman with a past history of painful central visual loss who developed progressive quadriparesis and bulbar palsy. Neurological examination revealed widespread upper and lower motor neuron signs in the bulbar region and extremities. Electromyography demonstrated widespread active and chronic motor axon loss. Magnetic resonance neuroimaging studies revealed enhancing callosal and periventricular white matter lesions and cervical and thoracic cord hyperintensities. Cerebrospinal fluid analysis was consistent with multiple sclerosis. The patient died of respiratory failure two years after presentation, and autopsy revealed multifocal demyelination involving the corpus callosum, cerebellum and spinal cord as well as pathologic findings typical of amyotrophic lateral sclerosis. A review of the literature confirms the exceedingly unusual combination of amyotrophic lateral sclerosis with multiple sclerosis.

Amyotrophic lateral sclerosis in an adult following acute paralytic poliomyelitis in early childhood.

About 30% of polio survivors develop a post-polio syndrome. Some of these patients develop slowly progressive muscle weakness known as post-poliomyelitis muscular atrophy (PPMA). We describe an unusual form of amyotrophic lateral sclerosis (ALS) in a patient with acute poliomyelitis in childhood. An 80-year-old woman had acute poliomyelitis at 2 years of age and developed weakness limited to the lower extremities. Residual weakness was stable until the age of 75 when she developed rapidly progressive weakness that first affected her left arm and subsequently the right arm. Neurological examination revealed both upper and lower motor neuron signs. These clinical features were more consistent with ALS than PPMA. At autopsy, there was marked atrophy of the precentral gyrus. Microscopic examination revealed a severe loss of all nerve cells and pronounced fibrillary astrocytosis of the lumbar ventral horns in the spinal cord, presumably a result of poliomyelitis. Superimposed on these spinal cord alterations were the pathological features of ALS, consisting of loss of Betz cells, corticospinal tract degeneration and loss of motor neurons of other levels of the spinal cord. The findings included some atypical features for ALS, namely, sparing of the hypoglossal nucleus, absence of Bunina bodies and absence of ubiquitin-immunoreactive inclusions. Although poliomyelitis and ALS may be coincidental, the unusual pathological expression of ALS raise the possibility that it is related to the antecedent poliomyelitis.