Correlating phenotype and genotype in the periodic paralyses.

BACKGROUND: Periodic paralyses and paramyotonia congenita are rare disorders causing disabling weakness and myotonia. Mutations in sodium, calcium, and potassium channels have been recognized as causing disease. OBJECTIVE: To analyze the clinical phenotype of patients with and without discernible genotype and to identify other mutations in ion channel genes associated with disease. METHODS: The authors have reviewed clinical data in patients with a diagnosis of hypokalemic periodic paralysis (56 kindreds, 71 patients), hyperkalemic periodic paralysis (47 kindreds, 99 patients), and paramyotonia congenita (24 kindreds, 56 patients). For those patients without one of the classically known mutations, the authors analyzed the entire coding region of the SCN4A, KCNE3, and KCNJ2 genes and portions of the coding region of the CACNA1S gene in order to identify new mutations. RESULTS: Mutations were identified in approximately two thirds of kindreds with periodic paralysis or paramyotonia congenita. The authors found differences between the disorders and between those with and without identified mutations in terms of age at onset, frequency of attacks, duration of attacks, fixed proximal weakness, precipitants of attacks, myotonia, electrophysiologic studies, serum potassium levels, muscle biopsy, response to potassium administration, and response to treatment with acetazolamide. CONCLUSIONS: Hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and paramyotonia congenita may be distinguished based on clinical data. This series of 226 patients (127 kindreds) confirms some clinical features of this disorder with notable exceptions: In this series, patients without mutations had a less typical clinical presentation including an older age at onset, no changes in diet as a precipitant, and absence of vacuolar myopathy on muscle biopsy.

Abdominal wall muscle activity in irritable bowel syndrome with bloating.

OBJECTIVE: Recurrent episodes of bloating and visible abdominal distension are common and distressing in irritable bowel syndrome, but the mechanisms are unknown. Patients often note that the distension is most pronounced in the upright posture, suggesting that the bloating may be the result of a decrease or absence of the normal rise in electromyograph activity in the abdominal wall muscles when standing. There are no reports of noninvasive electromyograph recordings of abdominal wall muscles in irritable bowel syndrome. We examined the hypothesis that abdominal distension is the result of relaxation of anterior abdominal wall musculature. METHODS: Studies were performed on patients with irritable bowel syndrome and a history of visible distension (n = 11, mean age 48.6 yr, body mass index 24.8) and normal volunteers (n = 13, mean age 39.9 yr, body mass index 24.6). Surface recordings of muscle activity were made while subjects were lying, performing voluntary contraction of the abdominal wall, and standing. The examiners were blind as to the clinical status of the subjects. RESULTS: There were no differences in abdominal wall muscle activity (by electromyograph voltage) when comparing patients with irritable bowel syndrome to normal volunteers (e.g., relaxed lower abdomen supine mean electromyograph voltage in irritable bowel syndrome was 14.0 vs 14.6 in controls, p = 0.7, and relaxed lower abdomen standing in irritable bowel syndrome was 29.6 vs 25.2 in controls, p = 0.4). There was increased activity in both groups when contracting the muscles and when standing. CONCLUSIONS: Patterns of abdominal wall muscle activity do not differ between normal subjects and patients with irritable bowel syndrome. However, there is a clear increase in muscle activity in the standing position. Episodic distension is unlikely to be due to permanent anterior abdominal muscle weakness or a persistent inability of the muscles to activate with standing in irritable bowel syndrome.

Utility of an EMG mapping study in treating cervical dystonia.

Intramuscular injections of botulinum toxin are the cornerstone of treatment for cervical dystonia. Controversy exists regarding the necessity for EMG-guided injections. We compared the clinical examination of four movement disorder specialists to an electromyographic (EMG) mapping study. Clinical predictions of individual muscle involvement were only 59% sensitive and 75% specific. Muscle hypertrophy, shoulder elevation, and dominant head vector did not bolster clinical accuracy. An EMG mapping study facilitates identification of dystonic muscles in cervical dystonia, which may enhance botulinum toxin therapy.

Randomized trials of dichlorphenamide in the periodic paralyses. Working Group on Periodic Paralysis.

Although the carbonic anhydrase inhibitors have been used in the treatment of the primary periodic paralyses (PPs), their efficacy has not been demonstrated in double-blind, placebo-controlled trials. Therefore, we tested the efficacy of dichlorphenamide (DCP; Daranide), a potent carbonic anhydrase inhibitor, in the treatment of episodic weakness in the primary PPs. We performed two multicenter, randomized, double-blind, placebo-controlled crossover trials, one involving 42 subjects with hypokalemic periodic paralysis (HypoPP) and the other involving 31 subjects with potassium-sensitive periodic paralysis (PSPP). In each trial, two 8-week treatment periods were separated by an active washout period of at least 9 weeks. The primary outcome variable in the HypoPP trial was the occurrence of an intolerable increase in attack severity or frequency (end point). The primary outcome variable in the PSPP trial was the number of attacks per week. In the HypoPP trial, there were 13 subjects who exhibited a preference (in terms of the end point) for either DCP or placebo, and 11 of these preferred DCP. In the PSPP trial, DCP significantly reduced attack rates relative to placebo. DCP also significantly reduced attack rates relative to placebo in the HypoPP subjects. We conclude that DCP is effective in the prevention of episodic weakness in both HypoPP and PSPP.

Clinical neurophysiologic findings in patients with rapidly progressive familial parkinsonism and dementia with pallido-ponto-nigral degeneration.

OBJECTIVE: To present clinical electrophysiologic studies performed on the pallido-ponto-nigral degeneration (PPND) family linked to chromosome 17q21-22. METHODS: Nine patients from this kindred were studied with 11 electroencephalograms (EEGs), 4 electroencephalographic background frequency analysis (BFA) studies, 4 electromyographic recordings (EMGs) including nerve conduction studies (NCSs), 4 electromyographic multichannel surface recordings (MSRs), one pattern visual evoked potential (VEP) study and one median nerve somatosensory evoked potential (SEP) study. RESULTS: EEGs revealed normal findings early in the disease and diffuse slowing which became more prominent with disease progression. BFA studies demonstrated rapid decrease in mean parietal frequencies with disease progression. EMGs and NCSs showed no abnormalities. MSRs revealed action myoclonus and a dystonic process. Long loop reflexes were absent in resting hand muscles. VEPs and SEPs were normal. CONCLUSIONS: Clinical neurophysiologic studies were consistent with a cortical and subcortical degenerative process. With clinical deterioration, there is a progressive decline in the mean parietal frequency and background rhythms. Tremor studies were consistent with action myoclonus and a dystonic process and did not show parkinsonian features of resting tremor or agonist-antagonist cocontraction. There was no evidence of peripheral nerve involvement or slowing in central sensory pathways. Electrophysiologic findings are characteristic for this illness.

Blood flow and autoregulation in somatic and autonomic ganglia. Comparison with sciatic nerve.

We studied blood flow rates along the sciatic nerve and in the superior cervical and L-5 dorsal root ganglia of rats at rest and during reductions and increases in mean arterial pressure induced by partial exsanguination or blood transfusion. Blood flow was measured by the tissue distribution of [14C]iodoantipyrine and autoradiography. At rest, blood flow did not vary along the peripheral nerve, but was two to three times greater in dorsal root and superior cervical ganglia. In peripheral nerve, blood flow increased with increases in blood pressure. In contrast, blood flow in dorsal root and sympathetic ganglia did not vary with changes in pressure. Thus, peripheral nerve cell bodies have greater blood flow than their axons; ganglion blood flow is autoregulated within the range of blood pressure tested. Nerve ganglia appear to be protected against ischaemic stress by autoregulation rather than by a blood flow "safety margin', as in peripheral nerve.

Intrathecal baclofen therapy in stiff-man syndrome: a double-blind, placebo-controlled trial.

We performed a double-blind, placebo-controlled trial of intrathecal baclofen (ITB) in stiff-man syndrome. Three patients, unresponsive to current therapy, received 50 micrograms of ITB or placebo on sequential days. Following ITB, all patients demonstrated improvement in reflex EMG activity. The mean reduction in total EMG activity (from all muscles) following stimulation of the medial plantar nerve (cutaneous flexor reflex) was 72% following 50 micrograms of ITB compared with 18% following placebo (ANOVA: significance of F, p < 0.0001). The mean latency to onset of the response was also significantly prolonged for all muscles following ITB (ANOVA: significance of F, p < 0.05). Although reflex EMG activity was reduced in all patients, clinical improvement was evident in only one patient, who differed from the others studied by a longer duration of disease, greater severity of stiffness, less fear of falling, and greater electrophysiologic improvement.

Experimental ischemic neuropathy: salvage with hyperbaric oxygenation.

Hyperbaric oxygenation is effective in augmenting the delivery of oxygen to tissue, but also causes oxidative stress. As part of our focus on improving peripheral nerve salvage from ischemic fiber degeneration, we evaluated whether hyperbaric oxygenation rescues peripheral nerve, rendered ischemic by microembolization, from ischemic fiber degeneration. The supplying arteries of rat sciatic nerve were embolized with microspheres of 14 microns diameter at moderate (2 x 10(6)) and high (5.6 x 10(6)) doses. Rats were randomized to receive hyperbaric oxygenation treatment (2.5 atm 100% oxygen for 2 hours/day for 7 days beginning within 30 minutes of ischemia), or room air. End points for the embolized limb were (1) behavioral scores (0-11 in increasing levels of limb function), (2) nerve action potential of sciatic-tibial nerve, (3) nerve blood flow, and (4) histological grade as percentage of fibers undergoing ischemic fiber degeneration (0 = < 5%; 1 = 5-25%; 2 = 26-50%; 3 = 51-75%; 4 = > 76%). Nerve blood flow and nerve action potential were uniformly absent and more than 90% of fibers had degenerated in both control and treatment groups receiving high doses. Control and treatment groups receiving moderate doses were well matched by level of ischemia (8.5 +/- 0.3 [N = 18] vs 7.7 +/- 0.4 ml/100 gm/min [N = 18], p > 0.05) but were significantly different by behavior score (5.6 +/- 0.7 vs 9.2 +/- 0.5 [N = 19], p < 0.001), nerve action potential (1.4 +/- 1.0 vs 3.9 +/- 0.5 [N = 6], p < 0.05), and histology (2.4 +/- 0.4 [N = 5] vs 0.8 +/- 0.5 [N = 4], p < 0.05). On single teased fiber evaluation, the predominant abnormality was E (axonal degeneration). We conclude that hyperbaric oxygenation will effectively rescue fibers from ischemic fiber degeneration, providing the ischemia is not extreme.

Neuropathy associated with hyperlipidemia.

We describe six patients with painful polyneuropathy associated with hyperlipidemia. Each had mild, slowly progressive neuropathy characterized by pain in feet, without proximal extension or involvement of hands. Weakness and autonomic symptoms and signs were absent. Three patients had normal tendon reflexes; three others had decreased ankle reflexes. Serum cholesterol levels were moderately increased; serum triglyceride levels were exceedingly high. In one patient, symptoms resolved with correction of hypertriglyceridemia. No other cause of peripheral neuropathy was found. Marked increases in serum triglycerides may cause painful small-fiber neuropathy.

Laboratory findings in reflex sympathetic dystrophy: a preliminary report.

OBJECTIVE: The purpose of our study was to compare sudomotor and vasomotor indices in patients with clinical reflex sympathetic dystrophy. DESIGN: Vasomotor tone was determined by measuring skin blood flow with laser Doppler flowmeters and skin temperature by infrared thermometry. Resting and evoked sweat output was measured with the quantitative sudomotor axon reflex test. Control values were determined from studies on 223 normal subjects. SETTING: The setting was a tertiary/academic medical center. PATIENTS: There were 12 patients with clinical reflex sympathetic dystrophy in an extremity. MAIN OUTCOME MEASURES: These were skin vasomotor tone and evoked sweat output. RESULTS: Resting sweat output asymmetry was seen in 67% of patients, quantitative sudomotor axon reflex test asymmetry was seen in 75%, and vasomotor changes in 80%. When sudomotor and vasomotor indices were combined, abnormalities were seen in all patients. CONCLUSIONS: Laboratory quantitation of autonomic indices enhances the clinical evaluation of patients with reflex sympathetic dystrophy.

Sodium channel mutations in acetazolamide-responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis.

Hyperkalemic periodic paralysis (hyperKPP) and paramyotonia congenita (PC) are genetic muscle disorders sharing the common features of myotonia and episodic weakness. In hyperKPP, patient symptoms and signs are worsened by elevated serum potassium, whereas in PC, muscle cooling exacerbates the condition. There are patients in whom features of both hyperKPP and PC are present. These diseases result from molecular alterations in the adult skeletal muscle sodium channel. This report summarizes our sodium channel mutation analysis in 25 families with hyperKPP and PC. We also report the putative disease-causing mutation in acetazolamide-responsive myotonia congenita, a related disease in which myotonia is worsened by potassium but in which episodic weakness does not occur. This missense mutation (I1160V) occurs at a very highly conserved position in the sodium channel, cosegregates with the disease, and was not present in any of a large panel of normal DNAs. Electrophysiologic characterization of specific mutations will lead to better understanding of the biophysics of this voltage-gated ion channel.

Dihydropyridine receptor mutations cause hypokalemic periodic paralysis.

Hypokalemic periodic paralysis (hypoKPP) is an autosomal dominant skeletal muscle disorder manifested by episodic weakness associated with low serum potassium. Genetic linkage analysis has localized the hypoKPP gene to chromosome 1q31-q32 near a dihydropyridine (DHP) receptor gene. This receptor functions as a voltage-gated calcium channel and is also critical for excitation-contraction coupling in a voltage-sensitive and calcium-independent manner. We have characterized patient-specific DHP receptor mutations in 11 probands of 33 independent hypoKPP kindreds that occur at one of two adjacent nucleotides within the same codon and predict substitution of a highly conserved arginine in the S4 segment of domain 4 with either histidine or glycine. In one kindred, the mutation arose de novo. Taken together, these data establish this DHP receptor as the hypoKPP gene. We are unaware of any other human diseases presently known to result from DHP receptor mutations.

Sciatic nerve lesions during cardiac surgery.

Sciatic nerve lesions occur only rarely in cardiac surgery patients. To evaluate potential causes for sciatic neuropathy, we reviewed the cardiac surgery performed at one institution during the last 15 years and found only six instances of sciatic neuropathy. We examined medical records for these six patients for potential etiologic factors and determined that four of the six patients had undergone prolonged periods of intra-aortic balloon pump therapy with a catheter placed through the femoral artery ipsilateral to the sciatic nerve lesion, and the other two patients had an ipsilateral femoral artery occlusion. In addition, four of the six patients had severe symptomatic peripheral vascular disease, and one of the other patients had severe and prolonged perioperative hypoxia. Although all these patients had pure sciatic neuropathy clinically, two of the four patients studied with electromyography had evidence of damage to the femoral nerve or quadriceps muscles ipsilaterally. In addition to the neurogenic changes, there were electromyographic findings suggestive of muscle ischemia. These results indicate that patients undergoing cardiac surgery may be at risk for development of a sciatic neuropathy if they have compromised blood flow through the femoral artery together with another cause for tissue hypoxia. Furthermore, asymptomatic ischemia of the femoral nerve or quadriceps muscles may occur in this clinical setting.

Orthostatic tremor: clinical and electrophysiologic characteristics.

Orthostatic tremor, sometimes known as "shaky legs syndrome," is a disorder of middle-aged or elderly people characterized by feelings of unsteadiness in the legs and a fear of falling when standing. Patients stand on a wide base but walk normally. These symptoms are due to high-frequency (13-18 Hz) burst firing in weight-bearing muscles. They are attenuated by walking and are abolished immediately by sitting. Some authors believe that the disorder is a variant of essential tremor. This study reports the clinical and electrophysiologic features of orthostatic tremor in 30 patients. The findings indicate that orthostatic tremor is distinct from essential tremor, both clinically and electrophysiologically. The major differences are the frequency of electromyographic burst firing, the invariable involvement of lower limb and paraspinal muscles, and the task-specific nature of the tremor in orthostatic tremor. The study shows that the diagnosis can be established rapidly with surface electromyographic recordings.

Sodium channel mutations in paramyotonia congenita and hyperkalemic periodic paralysis.

Clinical and electrophysiological data have outlined a spectrum of similar yet distinct periodic paralyses, including potassium-sensitive (hyperkalemic periodic paralysis [HYPP]) and temperature-sensitive (paramyotonia congenita [PC]) forms. Recent work has revealed that these disorders result from allelic defects in the alpha-subunit of the adult, human skeletal muscle sodium channel. We report an additional mutation, a leucine-->arginine substitution in the S3 segment of domain 4 (L1433R), that results in the PC phenotype. Five other HYPP and PC families have been ascertained, and previously reported sodium channel mutations have been identified in each. Characterization of these mutations and phenotypic variations in such families will contribute to the understanding of sodium channel structure and function relationships, as well as channel malfunction in the periodic paralyses.

The distinctive clinical features of paraneoplastic sensory neuronopathy.

A 15-year experience with paraneoplastic sensory neuronopathy at the Mayo Clinic is reviewed. Of 26 patients with paraneoplastic sensory neuropathy, 19 had small cell lung cancer, 4 had breast cancer, and 3 had other neoplasms. There was a striking predominance of females (20:6). Neuropathic symptoms (pain, paresthesia, sensory loss) were asymmetric at onset, with a predilection for the upper limbs; in three patients, symptoms were confined to the arms. Electrophysiologic testing revealed absent sensory responses and normal or minimally altered motor responses. Slightly more than half the patients had associated autonomic, cerebellar, or cerebral abnormalities. In some patients, treatment of the neoplasm seemed to halt progression of the neuronopathy, but none had neurologic improvement and most continued to worsen, even when the oncologic response was good. Distinguishing between paraneoplastic and nonparaneoplastic sensory neuronopathies can be difficult, but prominent neuropathic pain, neurologic dysfunction involving more than the peripheral sensory system, or an increased cerebrospinal fluid protein value should prompt a careful search for a cancer.

Cryptococcal meningitis manifesting as epilepsia partialis continua of the abdomen.

We report a case of epilepsia partialis continua that primarily involved the abdominal muscles. Thorough assessment ultimately showed that the condition was due to cryptococcal meningitis. Surface electrode electromyography and electroencephalography were helpful in analyzing this unusual epileptic phenomenon. An 8-week treatment regimen of amphotericin B and a 30-day course of 5-fluorocytosine abolished the epilepsia partialis continua and cured the meningitis. This case should alert physicians to the fact that patients with epilepsia partialis continua may have clonic movements of only the trunk and that the spectrum of neurologic manifestations of cryptococcal infection must now include this seizure disorder.

Clinical neurophysiologic studies in stiff-man syndrome: use of simultaneous video-electroencephalographic-surface electromyographic recording.

Three patients with a clinical diagnosis of stiff-man syndrome were studied with simultaneous video-electroencephalographic-surface electromyographic recordings in addition to routine electromyography in order to obtain objective data to confirm their diagnosis, to improve our understanding of the diagnosis of stiff-man syndrome, and to define reproducible clinical and neurophysiologic criteria for the stiff-man syndrome. These patients had the following features of this syndrome: (1) continuous muscle activity that varied with awake and sleep states, posture, passive and active movements, and medications; (2) superimposed intermittent generalized contractions while awake, which continued into drowsiness and interfered with onset of sleep; and (3) abnormal cocontractions of antagonistic muscles. The characteristic findings in the stiff-man syndrome can be recorded by using video-electroencephalographic-surface electromyographic techniques, a useful application of equipment already available in most electroencephalography laboratories. Neurophysiologic techniques can help in elucidating the clinical findings in the stiff-man syndrome. Further systematic study in patients before and during treatment is needed to identify common diagnostic criteria for this syndrome.

Trigeminal sensory neuropathy associated with decreased oral sensation and impairment of the masseter inhibitory reflex.

We describe 4 patients with severe trigeminal sensory neuropathy whose main disability resulted from impaired intraoral sensation associated with disturbances of mastication and swallowing. Each patient had an abnormal blink reflex and jaw jerk. In addition, the masseter inhibitory reflex was absent in 3 patients and abnormal in the 4th. This reflex plays a role in the reflex control of mastication and can easily be elicited in normal subjects by stimulation of the skin and mucous membrane in the distribution of the 2nd and 3rd divisions of the trigeminal nerve while the jaw-closing muscles are contracting. Disturbed intraoral sensation combined with impaired trigeminal reflexes (particularly the masseter inhibitory reflex) interferes with neural mechanisms that regulate chewing and can be a source of severe disability in patients with trigeminal sensory neuropathy.