Online newspaper of professor Yasser Metwally

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

February  8, 2010 — Overflow incontinence is related most commonly to bladder neuropathy. Diabetes mellitus is a common etiology of the neurogenic bladder. Lumbosacral nerve disease from tumors, meningomyelocele, MS, and prolapsed intravertebral disks also can result in bladder neuropathy and overflow incontinence. High spinal cord injuries are another etiology. Severe cases of outlet obstruction ultimately can cause severe retention, local neurologic injury, and overflow. In most cases, both sensory and motor neuropathy are present. The maximal physical capacity of the bladder is reached, often times without the individual realizing that this has occurred.

Incontinence occurs off the top of a chronically over-filled bladder. Effective emptying is not possible because of an acontractile detrusor muscle. In early bladder neuropathy, DI may coexist with a hypofunctioning detrusor muscle. Early in the course of diabetes-related bladder neuropathy, symptoms and the functioning of the detrusor may wax and wane. The result is periods when urinary retention and overflow incontinence are severe and periods when detrusor function and voiding effectiveness temporarily improve.

References

1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 10.1a January 2010 [Click to have a look at the home page]

2. Acute and Chronic Bladder Effects of L-Dopa Differ in Parkinson’s Patients [Full text]

3. Incontinence medication and Cognition in the Elderly [Full text]

4. Voiding dysfunction in spinal cord disorders [Full text]

5. Iatrogenic voiding (Bladder) dysfunction [Full text]

6. Neurogenic bladders due to Supraspinal lesions (Detrusal hyperreflexia) [Full text]

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

February  8, 2010 —  Detrusor hyperreflexia is a condition of uninhibited detrusor contractions (resulting in frequency, urgency and urge incontinence) in the presence of a neurologic lesion believed to be causative. In these cases, the pathophysiology of the incontinence can be traced back to a pathologic process involving the suprasacral spinal cord or CNS (Pyramidal or extrapyramidal lesions). Such disorders include spinal cord injuries, MS, cerebrovascular disease, stroke, Parkinson disease, dementia, and CNS/spinal neoplasia. (Click for more details)

• Definition of detrusor hyperreflexia & Detrusor instability and Urge incontinence

The International Continence Society (ICS), describes the unstable bladder as one that has been shown objectively to contract spontaneously during the filling phase of cystometry, while the patient is inhibiting or attempting to inhibit voiding. If these contractions result in urinary leakage, then the term urge incontinence is used. In the patient who is nonneuropathic, this disorder is called Detrusor instability (DI). In situations where a definable causative neuropathic disorder exists, the coexisting urinary incontinence disorder is termed detrusor hyperreflexia. These disorders can be quite debilitating. Recently, a study using a quality of life assessment of women with incontinence showed that women with Detrusor instability (DI) consistently had a worse quality of life than did women with other urodynamic diagnoses. In light of such data, understanding the pathophysiology of urge incontinence takes on great importance.

• Aetiology of Detrusor hyperreflexia

Spinal cord injuries interrupt the sacral reflex arc from the suprasacral spinal cord, cerebral cortex, and higher centers. These pathways are crucial for voluntary and involuntary inhibition. In the initial phase of spinal cord injury, the bladder is areflexic and overflow incontinence results. Later, detrusor hyperreflexia usually is found upon urodynamic evaluation.

The pathophysiology of MS is that of demyelinating plaques in the white matter of the cerebral cortex, cerebellum, brain stem, spinal cord, and optic nerve. Plaques involving the frontal lobe or lateral columns can produce lower urinary tract disorders. Incontinence may be the presenting symptom of MS in about 5% of the cases. Approximately 90% of individuals with MS experience urinary tract dysfunction during the course of the disease. A summary of the published series of urodynamic findings in MS demonstrated that in patients with lower urinary tract dysfunction, the most common urodynamic diagnosis is detrusor hyperreflexia (62%). Detrusor-sphincter dyssynergia (25%) and detrusor hyporeflexia (20%) also are common. Obstructive findings are much more common in males. Of note, the urodynamic diagnosis may change over time as the disease progresses.

Hemorrhage, infarction, or vascular compromise to certain areas of the brain can result in lower urinary tract dysfunction. The frontal lobe, internal capsule, brainstem, and cerebellum commonly are involved sites. Initially, urinary retention due to detrusor areflexia is observed. This may be followed by detrusor hyperreflexia.

Approximately 40-70% of patients with Parkinson disease have lower urinary tract dysfunction. Controversy exists as to whether specific neurologic problems in patients with Parkinson disease lead to bladder dysfunction or if bladder symptoms simply are related to aging. The extrapyramidal system is believed to have an inhibitory effect on the micturition center; theoretically, loss of dopaminergic activity in this area could result in loss of detrusor inhibition.

In patients with dementia, incontinence and urinary tract dysfunction may be due to specific involvement of the areas of the cerebral cortex involved in bladder control. Alternatively, incontinence may be related to global deterioration of memory, intellectual capacity, and behavior. Urodynamically, both detrusor hyperreflexia and areflexia have been found. In the case of neoplasms, CNS tumors of the superior medial frontal lobe, spinal cord tumors above the conus medullaris, and cervical spondylosis can cause detrusor hyperreflexia.

References

1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 10.1a January 2010 [Click to have a look at the home page]

2. Acute and Chronic Bladder Effects of L-Dopa Differ in Parkinson’s Patients [Full text]

3. Incontinence medication and Cognition in the Elderly [Full text]

4. Voiding dysfunction in spinal cord disorders [Full text]

5. Iatrogenic voiding (Bladder) dysfunction [Full text]

6. Neurogenic bladders due to Supraspinal lesions (Detrusal hyperreflexia) [Full text]

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

February 6, 2010 —  A number of mutations have been identified in CLCN1 gene in patients with Becker and Thomsen myotonia congenita. The chloride channel is responsible for the high resting membrane potential of skeletal muscle cells. Current data suggests that both the recessive (Becker) and dominant (Thomsen) forms may have complete or near-complete loss of chloride conductance. The reduced chloride conductance results in delayed repolarization of the muscle fiber membrane, resulting in a prolonged hyperexcitability and generation of repeated action potentials.

Only 1 mutant monomer is found in most of the patients with dominant (Thomsen) Myotonic congenita. The mutant monomer complexes with normal monomers to destroy the function of the tetrameric chloride channel (dominant negative effect). In recessive (Becker) Myotonic congenita, homozygous or compound heterozygous mutations result in 100% loss of function of the chloride channel while carriers with only 50% loss of function are asymptomatic.

References

1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 11.1a January 2010 [Click to have a look at the home page]

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

February 6, 2010 —  The calcium channel (CACNL1A3) gene is a complex of 5 subunits (alpha-1, alpha-2, beta, gamma, and delta). The skeletal muscle dihydropyridine (DHP) receptor is located primarily in the transverse tubular membrane. The alpha-1 subunit has binding sites for dihydropyridine drugs (DHP receptor) and conducts the slow L-type Ca⁺⁺ current. It also participates in excitation-contraction (EC) coupling and acts as a voltage sensor through its linkage with the ryanodine receptor of sarcoplasmic reticulum (calcium release channel). Any changes in the membrane potential are linked to intracellular calcium release, enabling excitation-contraction coupling. Point mutations in DHP receptor/calcium channel alpha 1 subunit cause hypokalemic periodic paralysis.

The physiological basis of disease is still not understood, but is more likely due to a failure of excitation rather than a failure of EC coupling. However, hypokalemia-induced depolarization may reduce calcium release, directly affecting the voltage control of the channel or indirectly through inactivation of sodium channel. Insulin and adrenaline may act in a similar manner. There are some similarities as compared to SCN4A mutations. Mutations modify channel inactivation but not voltage-dependent activation. Recordings from myotube cultures from the patients revealed a 30% reduction in the DHP-sensitive L-type calcium current. Channels are inactivated at low membrane potentials. It is not understood how this inactivation is related to hypokalemia-induced attacks.

References

1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 11.1a January 2010 [Click to have a look at the home page]

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

February 6, 2010 — The sodium channel has an alpha subunit and a beta subunit. The alpha subunit of sodium channel is a 260 kDa glycoprotein with about 1800-2000 amino acids. There is a high degree of evolutionary conservation of this channel from Drosophila to human. It has 4 homologous domains that fold to form central pore, each with 225-325 amino acids. Each domain consists of 6 hydrophobic segments (S1-S6) traversing the cell membrane. The main functions of the channel include voltage-sensitive gating, inactivation, and ion selectivity. The extracellular loop between S5 and S6 dips into the plasma membrane and participates in the formation of the pore. The S4 segment contains positively charged amino acids at every third position and functions as a voltage sensor. Conformation changes may occur during depolarization resulting in activation and inactivation of the channel. The cellular loop between domain III-S6 and domain IV-S1 acts as an inactivating gate.

The sodium channel has 2 gates (activation and inactivation) and can exist in 3 states. At rest with the membrane polarized, the activation gate is closed and the inactivation gate is opened. With depolarization, the activation gate opens allowing sodium ions to pass through the ion channel and also exposing a docking site for the inactivation gate. With continued depolarization, the inactivation gate closes blocking the entry of sodium into the cell and causing the channel to enter the fast inactivation state. This inactivation of the channel allows the membrane to become repolarized resulting in a return to the resting state with the activation gate closed and the inactivation gate opened.

There are several general features of sodium channel mutations. Most of the mutations are in the "inactivating" linker between repeats III and IV, in the "voltage-sensing" segment S4 of repeat IV or at the inner membrane where they could impair the docking site for the inactivation gate. The clinical phenotype differs based on the amino acid substitution and while there may be some overlap between hyperkalemic Periodic paralysis, paramyotonia congenita, and Potassium-aggravated myotonias (PAM), the 3 phenotypes are generally distinct (as described below). Nearly all mutant channels have impaired fast-inactivation of sodium current. Most of the patients are sensitive to systemic potassium or to cold temperature.

Keeping in mind that there are 2 populations of channels, mutant and wild-type, the impaired fast inactivation results in prolonged depolarization of the mutant muscle fiber membranes and can explain the 2 cardinal symptoms of these disorders, myotonia and weakness. Mild depolarization (5-10 mV) of the myofiber membrane that may be caused by increased extracellular potassium concentrations, results in the mutant channels being maintained in the noninactivated mode. The persistent inward sodium current causes repetitive firing of the wild-type sodium channels, which is perceived as stiffness (myotonia).

If a more severe depolarization (20-30 mV) is present, both normal and abnormal channels are fixed in a state of inactivation, causing weakness or paralysis. Thus, subtle differences in severity of membrane depolarization may make the difference from myotonia versus paralysis. Temperature sensitivity is a hallmark of paramyotonia congenita. Cold exacerbates myotonia and induces weakness. A number of mutations are associated with this condition and 3 of them at the same site (1448) in the S4 segment. These mutations replace arginine with other amino acids and neutralize this highly conserved S4 positive charge. Mutations of these residues are the commonest cause of paramyotonia congenita. Some of the possible mechanisms responsible for temperature sensitivity include the following:

1. Temperature may differentially affect the conformational change in the mutant channel
2. Lower temperatures may stabilize the mutant channels in an abnormal state
3. Mutations may alter the sensitivity of the channel to other cellular processes, such as phosphorylation or second messengers

References

1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 11.1a January 2010 [Click to have a look at the home page]

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

February 6, 2010 —  This heterogeneous group of muscle diseases is characterized by episodes of flaccid muscle weakness occurring at irregular intervals. Most of the conditions are hereditary and they are more episodic than periodic. They can be conveniently divided into primary and secondary.  General characteristics of primary periodic paralyses (PP) include (1) hereditary, (2) most of them are associated with alteration in the serum potassium levels, (3) myotonia sometimes coexists, and (4) both myotonia and periodic paralysis result from defective ion channels.

Primary Periodic Paralyses

• Hyperkalemic periodic paralyses

Age at onset is before 10 years. Patients usually describe a sense of heaviness or stiffness in the muscles. Weakness starts in the thighs and calves, which then spreads to arms and neck. Proximal weakness predominates; distal muscles may become involved after vigorous exercise.

In children, a myotonic lid lag (lagging of upper eyelid on downward gaze) may be the earliest symptom. Complete paralysis is rare and some residual mobility remains. Respiratory muscle involvement is rare. The attacks last less than 2 hours and in the majority, the duration is less than 1 hour. Sphincters are not involved and any bowel and bladder dysfunction is due to abdominal muscle weakness.

Weakness occurs during rest after a period of strenuous exercise or during fasting. It may also be provoked by potassium, cold, ethanol, carbohydrates, or stress. It may be relieved by mild prolonged exercise or carbohydrate intake. Patients may also complain of muscle pains and paresthesias. Between attacks, clinical and electrical myotonia is present in the majority of patients. Some families show no myotonia. Interictal weakness, if present, is not as severe as in hypokalemic PP.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

February 6, 2010 — Benign familial neonatal convulsions (BFNC) is an autosomal dominant condition characterized by neonatal seizures in otherwise healthy newborns. Seizures usually begin between the first and fourteenth days of life and typically remit spontaneously by 6 weeks of age. The risk of subsequent epilepsy is about 15%. The seizures are clinically heterogeneous and include eye deviation, tonic posturing, focal clonic activity and apnea with evolution to generalized convulsions. [1-3]

Early studies demonstrated BFNC to be genetically heterogeneous. The two genes on chromosomes 20q and 8q encode highly homologous potassium channel subunits, KCNQ2 and KCNQ3. [2–3] Expression of either subunit alone in Xenopus oocytes results in small currents, but co-expression of the two genes yields a channel with currents 10–50 times larger, [4] and with the gating properties of the neuronal M-channel. [24] In-situ hybridization has demonstrated overlapping patterns of expression of KCNQ2 and KCNQ3. [4,5] These data cohere to suggest that KCNQ2 and KCNQ3 coassemble in vivo to form the M-channel. This molecular mechanism would explain why patients with BFNC linked to the loci on chromosomes 20q and 8q are clinically indistinguishable.

Functional expression of the disease causing missense mutations in these subunits are associated with a variable reduction (20–95%) in current magnitude. [3,6] Coexpression of mutant and wild-type subunits yielded potassium currents of similar amplitude, essentially excluding a dominant negative effect. [6,7] Rather, these results are consistent with neuronal excitability being critically dependent on the absolute magnitude of KCNQ2/KCNQ3 potassium channel current.

Reduced activity of the M-channel would be expected to cause neurons to become slightly depolarized and to fire multiple action potentials rhythmically after receiving excitatory inputs. The known functional effects of the KCNQ2 and KCNQ3 mutations are thus consistent with the clinical phenotype of seizures. It is unclear, however, why these mutations preferentially lead to seizures in the neonatal period. Possibilities include that the neonatal brain simply has a lower seizure threshold, or that potassium channel subunit expression is developmentally regulated, with neuronal excitability more dependent on the M-channel than on other voltage-sensitive potassium channels in the neonatal period.

References

1. Ronen G, Rosales T, Connolly M, Anderson V, Leppert M. Seizure characteristics in chromosome 20 benign familial neonatal convulsions. Neurology1993; 43:1355–60.

2. Charlier C, Singh N, Ryan S, Lewis T, Reus B, Leach R, Leppert M. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nature Genet1998; 18:53–5.

3. Singh N, Charlier C, Stauffer D, DuPont B, Leach R, Melis R, Ronene G, Bjerre I, Quattlebaum T, Murphy J. A novel potassium channel gene, KNQ2, is mutated in an inherited epilepsy of newborns. Nature Genet1998; 18:25–9.

4. Biervert C, Schroeder B, Kubisch C, Berkovic S, Propping P, Jentsch T, Steinlein O. A potassium channel mutation in neonatal human epilepsy. Science1998; 279:403–6.

5. Schroeder B, Kubisch C, Stein V, Jentsch T. Moderate loss of function of cyclic-AMP modulated KCNQ2/KCNQ3 K+ channels cause epilepsy. Nature1998; 396:687–90.

6. Wang H, Pan Z, Shi W, Brown B, Wymore R, Cohen I, Dixon J, McKinnon D. KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science1998; 282:1890–3.

7. Lerche H, Biervert C, Alekov A, Schleithoff L, Lindner M, Klingler W, Bretschneider F, Mitrovic N, Jurkat-Rott K, Bode H, Lehmann-Horn F, Steinlein O. A reduced K+ current due to a novel mutation in KCNQ2 causes neonatal convulsions. Ann Neurol1999; 46:305–12.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

February 6, 2010 — The overall incidence of cavernous malformations (CMs) (cavernoma) is approximately 4%,[2] and the spinal cord harbors approximately 3% to 5% of cavernous malformations (CMs). [4] They are discrete masses consisting of endothelial-lined sinusoidal vascular channels without intervening neuronal tissue. Cavernous malformations are congenital lesions with a peak incidence in the third and fifth decades. Interestingly, although intracranial lesions show equal male and female predominance, spinal cord CMs are more common in females [2] and are usually intra-medullary. [1] Clinically, cavernous malformations (CMs) can present with a wide range of symptoms. Acute symptoms are often secondary to hemorrhage, while a progressive course may be due to microhemorrhages.[1]

• Imaging of cavernomas

MRI is the study of choice for imaging for cavernous malformations (CMs), as arteriovenous (AV) shunting is not characteristic and, thus, remains occult on conventional arteriography. Intracranial and spinal-cord CMs have similar MRI features that classically include central signal heterogeneity (reflecting various stages of blood products) surrounded by a peripheral dark hemosiderin ring without significant edema, mass effect, vascular flow voids, or enhancement (Figure 1). On gradient-recalled images, cavernous malformations (CMs) bloom secondary to blood products within the lesion. On CT, cavernous malformations (CMs) often show focal high attenuation with or without associated calcifications.[1,2]

• Management of cavernomas

Treatment of cavernous malformations (CMs) in the spinal cord depends on the symptoms and age of the patient. Asymptomatic lesions are usually left alone while symptomatic ones can be explored surgically because of the threat of future hemorrhage and resultant neurologic decline.[1] One study proposes a hemorrhage rate for spinal CMs of 1.6% per year.[3,5]

Figure 1. Cavernous malformation. (A) Sagittal T2-weighted sequence shows exophytic lesion in upper cervical cord (upper arrow) with associated intramedullary signal abnormality (lower arrow). (B) "Popcorn" appearance is seen on T1-weighted sagittal image (arrow). (C) Axial T1-weighted sequence shows exophytic T1 hyperintense lesion (arrow). (Click on figures to enlarge)

References

1. Bemporad JA, Sze G. MR imaging of spinal cord vascular malformations with an emphasis on the cervical spine. MRI Clin North Am. 2000;8:581-596.
2. Atlas SW, Do HM. Intracranial vascular malformations and aneurysms. In: Atlas SW, ed. Magnetic Resonance Imaging of the Brain and Spine. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2002:833-917.
3. Canavero S, Pagni CA, Duca S, Bradac GB. Spinal intramedullary cavernous angiomas: A literature meta-analysis. Surg Neurol. 1994;41:381-388.
4. Wong JH, Awad IA. Spinal vascular malformations. In: Jafar JJ, Awad IA, Rosenwasser RH, eds. Vascular Malformations of the Central Nervous System. Philadelphia, PA: Lippincot Williams & Wilkins; 1999:155-160.
5. Case record of the week…Intramedullary cavernoma [Click to download in PDF format]
6. Case record of the week….Occipital lobe cavernoma. [Click to download in PDF format]