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Neuromuscular Manifestations of Acquired Metabolic, Endocrine, and Nutritional Disorders
Endocrine Disorders
Table 21.1 summarizes the neuromuscular manifestation of these disorders.
Table 21.1
Neuromuscular Manifestation of Endocrine Disorders
Modified with permission from Bertorini T. E. (2008). Neuromuscular case studies . Philadelphia: Butterworth-Heinemann.
| Diabetes | Symptoms | Laboratory Test Results | EMG | Biopsy | Treatment |
|---|---|---|---|---|---|
| Acromegaly | Proximal weakness, CTS, neuropathy, muscle atrophy | Normal CK (may be elevated), elevated growth hormone, IGF-1, TSH | Normal or myopathic | Nonspecific; some fiber necrosis may be seen | Removal of tumor |
| Hypopituitarism | Weakness (may be severe); muscle fatigue | Normal CK; multiple hormone deficiencies | Not defined | Not defined | Hormone replacement |
| Adrenal insufficiency, Addison disease | Proximal weakness, cramps, fatigue | Elevated potassium, reduced cortisol levels, abnormally high corticotropin, normal CK | Normal | N/A | Mineralocorticoids, glucocorticoids, fluid and electrolyte replacement |
| Thyrotoxic periodic paralysis | Weakness with hypokalemia, usually after high-carbohydrate meals (occurs mainly in Asians, more common in men) | Elevated CK during attacks | Normal except for decreased CMAP during attacks, after exercise | Nonspecific; may show vacuolated fibers | Beta-blockers, potassium supplement, PTU, methimazole, surgery |
| Hypothyroidism (adult: Hoffmann syndrome; children: Kocher-Debre´ Semelaigne) | Proximal weakness, muscle spasms, pain (adults); myoedema, delayed relaxation of reflexes; peripheral neuropathy, entrapment neuropathies, CTS | Elevated CK, elevated thyrotropin or low T 4 | Nonspecific | Nonspecific | Thyroid replacement |
| Hyperthyroidism or thyrotoxic myopathy | Proximal weakness with little atrophy, more common in women; distal weakness in 20%, some bulbar involvement; Graves ophthalmopathy can occur, myasthenia gravis and periodic paralysis may occur; fasciculations and myokymia; peripheral neuropathy | Normal CK, high T 4 and T 3 , reduced thyrotropin | Myopathy, with fibrillations and fasciculations | Normal or nonspecific | Beta-blockers, surgery, radioactive iodine |
| Diabetes | Peripheral polyneuropathy, focal neuropathy; myopathy unusual; muscle infarcts causing unilateral weakness, swelling; proximal muscle weakness (diabetic amyotrophy) | Elevated CK | Motor unit action potentials | Diabetic control | |
| Cushing disease (primary or drug induced) | Proximal weakness, myalgia, truncal adipose tissue accumulation, moon face | Normal CK, low potassium, elevated plasma cortisol | May show myopathic motor unit action potentials | Atrophy of type II fibers, mainly IIB | Reduction of steroids, removal of tumor |
| Hyperparathyroidism, primary or secondary from renal disease | Proximal weakness and atrophy, muscle cramps, possible hypotonia | Elevated calcium levels, usually low phosphate and high alkaline phosphatase, normal or mildly elevated CK, elevated PTH and vitamin D levels | Small polyphasic motor units or potentials | Type II fiber atrophy, angular atrophic fibers, increased calcium in capillaries | Removal of the adenoma, bisphosphonates, cinacalcet, vitamin D supplementation (secondary hyperparathyroidism), calcitriol |
| Hypoparathyroidism | Hypocalcemia-induced tetany (Chvostek, Trousseau signs), cramps | Mildly elevated CK, hypocalcemia, hypomagnesemia | Multiplex discharges | ? | Calcium and vitamin D |
CK , Creatine kinase; CMAP , compound muscle action potential; CTS , carpal tunnel syndrome; EMG , electromyography; IGF-1 , insulin-like growth factor-1; PTH , parathyroid hormone; PTU , propylthiouracil; TSH , •••.
Diabetes Mellitus; Diabetic Neuropathies
Diabetic neuropathy (DN) is one of the most common complications of diabetes mellitus (DM), and its prevalence is increasing with the growing number of patients with DM. The reported prevalence of DN varies with the type and the criteria by which it is defined. Using criteria that include clinical symptoms, supported by examination and electrodiagnostic studies, reveals a prevalence of 6% to 15% at the time of diagnosis and more than 50% after 25 years of disease ( Fig. 21.1 ) ( ; ). Risk factors for the development of DN include the severity and duration of DM, smoking, and the presence of other complications, such as retinopathy and nephropathy ( ).
The precise etiology of DN remains unknown, and it is likely that DM affects the peripheral nerves by several mechanisms. Two main hypotheses, the microvascular and the metabolic, have been postulated for the development of DN. At one end of the spectrum, it appears that microangiopathy and arteriosclerosis affecting the vasa nervorum inflict ischemic insult to neurons and axons ( ; ). At the other end, oxidative stress with excessive accumulation of glycoproteins and polyol flux induce axonal degeneration ( ; ). Several investigators have provided evidence that oxidative stress damages axons, Schwann cells, and probably neurons ( ; ). Increased activation of the polyol pathway, which converts glucose to sorbitol, results in increased tissue accumulation of sorbitol and depletion of myoinositol, causing a reduction in Na + /K + -ATPase and subsequent slowing of nerve conduction ( ).
DM is associated with a wide spectrum of neuropathy syndromes, ranging from mild asymptomatic distal sensory polyneuropathy (PN) or sensorimotor neuropathy to a severe disabling neuropathy of variable symmetric or asymmetric presentation ( Box 21.1 ); these disorders often coexist.
Box 21.1
Clinical Classification of Diabetic Neuropathies
Distal Sensorimotor Polyneuropathy
Distal sensory predominant or sensorimotor PN is the most common neuropathy in patients with DM. This usually develops when DM has been present for several years, although nerve conduction study abnormalities are demonstrated in 10% to 18% of patients at the time of diagnosis of DM ( ).
Clinically, symmetric sensory symptoms typically predominate; these may include positive symptoms (prickling, tingling, pins and needles, burning, crawling, itching, or pain) or negative symptoms (numbness, decreased sensibility, painless injuries) in the toes and feet. These symptoms progress slowly and extend up to the ankles and legs, and later to the fingers and hands. Neuropathic pain can be severe, is more prominent at night, and may compromise quality of life. Painless repetitive foot injury secondary to loss of protective sensory input contributes to the development of foot ulceration, which is a common medical cause of eventual amputation ( ). Autonomic symptoms are variably encountered. Weakness usually is absent or minimal, especially in the early years of symptom onset, but in severe cases distal weakness and atrophy of the intrinsic muscles of the feet may be present. Coexisting upper limb compression mononeuropathies (median nerve at the wrist or ulnar nerve at the elbow) are relatively common ( ).
Examination demonstrates distal symmetric sensory loss or deficit in a stocking-glove pattern, diminished or absent ankle tendon reflexes, and, in more severe cases, loss of knee reflexes or upper-limb tendon reflexes. Weakness of toe and foot dorsiflexion and atrophy of the intrinsic muscles of the feet usually are noted later in the course of the disease.
Autonomic Neuropathy
Diabetic autonomic neuropathy usually coexists with sensorimotor PN from involvement of small autonomic nerve fibers, and autonomic symptoms usually become prominent with increased duration and severity of the neuropathy. Impotence is among the most common manifestations of autonomic neuropathy. Sweating abnormalities, including distal anhidrosis and truncal and gustatory sweating, are relatively common. Other manifestations include constipation alternating with diarrhea, gastroparesis and bloating, orthostatic light-headedness, postural hypotension, and bowel or urinary disturbances. Cardiac arrhythmia secondary to parasympathetic denervation contributes to increased cardiac morbidity and mortality. Diabetic patients who suffer an acute myocardial infarction are twice as likely to die as matched controls because of a combination of accelerated coronary artery atherosclerosis, hypertension, and autonomic neuropathy ( ; ). These manifestations and their treatment are covered in detail in Chapter 5 .
Acute Painful Neuropathy
A variant of acute or subacute severe painful neuropathy has been described in diabetic patients with rapid unwanted weight loss and poor glycemic control. It is characterized by intense diffuse neuropathic pain and has a monophasic course ( ); patients appear acutely ill. Typically, it manifests in two settings: one form, which occurs after the initiation of improved glycemic control, is called insulin neuritis ; the other form occurs in poorly controlled non–insulin-dependent diabetes mellitus (NIDDM) and is called diabetic neuropathic cachexia.
Insulin neuritis was first described by Caravati in 1933 ( ). It is an uncommon and highly unpleasant entity that typically appears after the initiation of aggressive insulin therapy or oral agents. Patients develop intense burning pain in the feet and legs, often requiring narcotics. Objective findings on neurologic examination and electrodiagnostic studies are mild. The pain generally resolves in a few months, although the underlying PN often remains. Nutritional supplements and blood glucose level monitoring are helpful.
Diabetic neuropathic cachexia occurs in males with poorly controlled NIDDM. It is characterized by anorexia, severe weight loss, and intense pain that requires narcotic analgesics. The neurologic examination and nerve conduction studies are unrevealing or show only mild abnormalities. Weight gain after glycemic control is usually followed by slow improvement over months ( ).
Diabetic Lumbosacral Plexopathy
Diabetic lumbosacral plexopathy (DLSP) is also known as diabetic radiculoplexus neuropathy , diabetic amyotrophy , Bruns-Garland syndrome , or asymmetric proximal diabetic neuropathy . It is an uncommon debilitating neuropathy seen in 1% of patients with NIDDM ( ). This syndrome usually involves the lumbosacral plexus and much less commonly the thoracic and cervical roots, plexus, or nerves. The condition usually occurs in patients with NIDDM who are older than 50 years and is more common in males. It presents with sudden-onset unilateral anterior thigh pain, followed by weakness and muscle atrophy. The pain is severe, sharp, burning, or aching and often subsides in a few weeks. The weakness and muscle atrophy affect the involved segments (anterior thigh muscles) and often are so severe and debilitating that the patient may require walking aids. Sensory loss usually is minimal, and knee tendon reflex is diminished or absent. The syndrome usually is monophasic, and spontaneous slow recovery occurs over several months. The pathophysiology of DLSP is mostly microvasculopathy and inflammatory changes; secondary immune response is suspected ( ; ). Variations of DLSP include spreading to the contralateral side or symmetric bilateral involvement, foot drop, upper limb involvement, and thoracic radiculopathy.
Compression Neuropathies
As mentioned before, compression neuropathies are more common in diabetic patients, particularly those with associated PN. It is unclear why diabetic patients have an increased risk of developing these neuropathies, although an increased obesity rate may be a factor.
Median neuropathy at the wrist, widely known as carpal tunnel syndrome (CTS), is the most common, and its prevalence increases with a longer duration of DM. Nerve conduction studies demonstrate CTS in nearly 30% of diabetic patients, of whom 6% to 10% are symptomatic ( ). Thus, CTS should be suspected in any diabetic patient who complains of pain, paresthesia, and numbness in the hands, worsening at night or on awakening. Weakness of the thenar muscles is rare except in long-standing severe cases. The diagnosis is best made by nerve conduction studies; however, coexistent PN may impose a diagnostic challenge, best assessed by testing other nerves in the upper limb not subject to compression.
Other compression neuropathies include ulnar neuropathy at the elbow and possibly peroneal neuropathy at the fibular head. Radial neuropathy and lateral femoral cutaneous neuropathy (meralgia paresthetica) have been described in diabetic patients and are indistinguishable from similar neuropathies in nondiabetic patients ( ).
Ulnar neuropathy at the elbow occurs less frequently than CTS and has been reported in 2% of diabetic patients. Clinically, ulnar neuropathy causes sensory symptoms in the ring and small fingers ( ). More severe ulnar neuropathy at the elbow is associated with progressive weakness and atrophy of the ulnar-innervated hand muscles and may have significant impact on hand function. Asymptomatic mild slowing of ulnar motor conduction across the elbow is common in diabetic patients.
Diabetic focal limb mononeuropathies not at common nerve entrapment sites are rare and coincidental, and other common causes should be considered. Lateral femorocutaneous neuropathy or meralgia paresthetica appears to be more common in obese patients with NIDDM. Likewise, mononeuritis multiplex is not among the common complications of DM, but does occur.
Cranial Mononeuropathies
Oculomotor neuropathy with pupillary sparing is characteristic of diabetic third cranial nerve palsy. The onset usually is acute and is associated with severe headache, diplopia, and ptosis. Recovery often is complete or near-complete over a few weeks to a few months.
Other cranial nerve palsies associated with diabetes include abducens, trochlear, and facial neuropathy. Facial neuropathy is more common in older diabetic patients, usually is unilateral, and has a clinical course similar to that of idiopathic facial palsy (Bell palsy).
The overall incidence of cranial neuropathies in diabetic patients is relatively low, in the range of 2% to 5%; however, a higher incidence of facial nerve palsy (6% to 10%) has been reported. This is even higher if individuals with abnormal glucose tolerance tests are included ( ; ). Pain often is present and is associated with upper and lower facial weakness and infrequently with loss of taste and hyperacusis.
Isolated Thoracic Radiculopathy
Isolated thoracic radiculopathy, also termed truncal radiculoneuropathy or diabetic thoracoabdominal neuropathy , is a distinctive disorder that often suggests DM. It is uncommon and usually occurs in older patients, often associated with weight loss and poor glycemic control. Patients develop segmental chest or abdominal pain, cutaneous hypersensitivity or allodynia, and sensory loss. The pain usually is intense and of a burning or aching quality and may not follow a classic dermatomal distribution. Likewise, the sensory deficit may not follow a typical dermatomal pattern. The pain presentation may mimic chest or abdominal medical or surgical emergencies. The diagnosis of isolated thoracic radiculopathy is clinical, and needle electromyographic (EMG) examination may show denervation potentials in the intercostal, abdominal, or thoracic paraspinal muscles ( ). The pathogenesis of this disorder remains uncertain but probably is similar to that of proximal DN. The site of the lesion is not firmly established, but it is likely to be at the thoracic roots, posterior rami, or both.
Diagnosis and Evaluation
Assessment of DN is mostly noninvasive; however, rarely, invasive studies are needed ( Box 21.2 ). Nerve conduction studies remain the gold standard in evaluation. They are widely available and are used in both clinical practice and clinical trials. The distal symmetric PN is sensory and predominantly axonal; a decline in the sensory nerve action potential (SNAP) amplitude is typically the earliest sensitive finding of PN. The most commonly used nerve conduction study is measurement of the sural SNAP amplitude behind the ankle. A decline of the sural SNAP amplitude 6 to 8 uV baseline to peak, with a surface skin temperature of 31°C, is considered abnormal ( ). Mild conduction slowing of the sural sensory conduction velocity or peroneal motor conduction velocity and prolonged F-waves often are noted and indicate mild demyelination. Demyelinating features out of proportion to axonal loss are rare and raise suspicion of a superimposed focal neuropathy or an autoimmune demyelinating neuropathy. Superficial radial SNAP recorded at the base of the thumb is a useful index when the sural SNAP is unobtainable. Compound muscle action potential (CMAP) amplitudes usually are preserved early in the disease course; however, reduced CMAP amplitudes, especially of the foot muscles, often are seen as the disease progresses. An associated increased conduction time across the carpal tunnel or other common entrapment sites in asymptomatic patients may be encountered. Needle EMG examination of distal leg or foot muscles often shows fibrillation potentials, large motor unit potentials, and reduced recruitment, indicating chronic mild motor axonal loss and compensatory reinnervation, particularly in chronic cases. Nonetheless, in early small-fiber sensory neuropathy, nerve conduction studies can be normal, and other diagnostic tools, such as skin biopsy to assess intraepidermal nerve fiber density or autonomic testing, often are more useful.
Box 21.2
Assessment of Diabetic Neuropathy
Autonomic testing is most useful in the evaluation of suspected selective autonomic neuropathy or autonomic manifestations associated with diabetic PN; they are, however, not widely used. Sympathetic skin response is easily tested, but this usually is unrevealing except in severe autonomic neuropathy. Evaluation of heart rate variability and blood pressure changes with deep inspiration-expiration, Valsalva maneuver, and changes in posture are more informative tests and can be used to confirm autonomic neuropathy ( ). Decreased heart rate variability for matched age is a common autonomic dysfunction in diabetic patients and appears earlier than other autonomic manifestations ( ). Tests of sudomotor function evaluate the sympathetic efferent to sweat glands, but they are somewhat cumbersome and usually performed at specialized laboratories. These are discussed in detail in Chapter 5 .
Quantitative sensory testing for vibration perception threshold, warm and cold detection thresholds, and heat pain detection threshold modalities using computers have been useful in clinical trials, but their use and reproducibility in clinical practice are limited ( ).
Electrodiagnostic studies in lumbosacral plexopathy demonstrate active denervation in affected muscles and often bilaterally despite unilateral symptoms, with only mild conduction slowing, consistent with axonal loss. Magnetic resonance imaging (MRI) should be obtained to exclude structural lesions.
Focal and isolated mononeuropathies such as CTS, ulnar neuropathy, or peroneal neuropathy are best diagnosed by nerve conduction studies. Sural nerve biopsy is used on a limited scale in the diagnosis of diabetic peripheral neuropathy and is rarely needed. This shows involvement of unmyelinated and myelinated axons with axonal degeneration with some segmental demyelination. There is duplication of the basal lamina in vessels.
Differential Diagnosis
Other causes of PN must be considered and excluded in diabetic patients. In patients with distal symmetric PN, screening laboratory studies for other metabolic, toxic, drug-induced, nutritional, neoplasm-related, or infectious causes are recommended. Typically blood count, thyroid studies (thyrotropin or thyroxine [T 4 ]), serum protein, and serum immunoelectrophoresis are necessary. Human immunodeficiency virus (HIV) antibody and urine and blood heavy metal screens are requested if indicated. Sjögren syndrome antibodies, vitamin B 6 and vitamin E levels, and screening for malignancy and measurement of Hu antibody and MAG antibodies can be considered in patients with large-fiber sensory PN. Screening for amyloidosis, porphyria, and paraneoplastic or hereditary causes also is indicated in neuropathy with prominent autonomic symptoms. A detailed family history and, at times, nerve conduction studies of suspected family members and DNA testing are essential if a hereditary neuropathy is strongly suspected.
In those whose PN has prominent demyelinating features on nerve conduction studies, screening for hepatitis and infectious mononucleosis, serum immunoelectrophoresis, and cerebrospinal fluid studies are indicated. If there is evidence of uniform slowing, DNA testing for a hereditary cause could be considered. Recommended diagnostic considerations in diabetic mononeuropathy or multiple mononeuropathy include testing for vasculitis, connective tissue disease, and infiltrative processes such as neoplasia or sarcoidosis.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is very important in the differential diagnosis, particularly in patients who have arreflexia or hyporeflexia and large fiber sensory deficit and evidence of a predominantly demyelinating neuropathy by EMG. In some cases, an LP would help because spinal fluid protein is usually more elevated in CIDP. Contrast MRI shows enhancement of the cauda equina roots in CIDP. Nerve biopsy sometimes is necessary, but because inflammation could be patchy, the diagnosis cannot be made for certain, and a therapeutic trial should be considered.
Treatment and Management
Several therapeutic trials for DN addressing the proposed pathophysiology have been conducted. These trials showed only modest stabilization ( Box 21.3 ). The aldose reductase inhibitors, alpha-linolenic acid, alpha-lipoic acid, myoinositol substitution, angiotensin-converting enzyme inhibitors, and neurotrophic nerve growth factors have been studied ( ). The aldose reductase inhibitors (sorbinil, tolrestat, ponalrestat, and epalrestat) have been used in a number of trials since 1980 and aimed to prevent excessive sorbitol flux in peripheral nerves ( ). These trials, however, have been confounded by side effects, poor trial design, and lack of convincing, clinically meaningful effects. More recently, trials of the aldose reductase inhibitors ranirestat and fidarestat showed modest improvement in nerve conduction and quantitative sensory testing ( ; ). Other clinical trials of DN treatment using dietary supplementation with myoinositol, acetylcarnitine antioxidants—gamma-linoleic acid (evening primrose oil) and alpha-lipoic acid—showed no convincing effectiveness, although some benefit was observed ( ; ; ; ; ). Protein kinase C-β inhibitors showed some benefit in animal studies; in small human studies, amelioration of sensory nerve dysfunction by C-peptide in patients with insulin-dependent DM (IDDM) was reported ( ; ). Nerve growth factor (NGF) is a neurotrophic factor that promotes survival, differentiation, and maintenance of small sensory fibers and sympathetic neurons in the peripheral nervous system. Skin biopsy specimens from patients with PN showed reduced NGF and impaired retrograde axonal transport. A 6-month phase II controlled trial of NGF in DN showed a statistical trend toward improvement; however, a large phase III multicenter trial over 1 year was not able to confirm any beneficial effects ( ; ). Treatment using gene therapy by intramuscular administration of vascular endothelial growth factor in animal models, tested for its ability to increase blood flow in DN, showed improvement in nerve conduction and histologic changes; however, no human studies have been conducted.
Box 21.3
Treatment Rationale Based on Metabolic Hypothesis
-
Polyol pathway activation → Aldose reductase inhibitors
-
Reduction of myoinositol → Myoinositol substitution
-
Reduced nerve growth factor (NGF) → Human recombinant NGF
-
Alteration in fatty acid metabolism → Gamma-linolenic acid (primrose oil)
-
Acetyl- L -carnitine depletion → Substitution of acetyl- L -carnitine
-
Free radical–mediated oxidative stress → Antioxidants (alpha-lipoic acid)
Although an immune or inflammatory response may play a primary role or accelerate some forms of neuropathy initiated by a metabolic or vascular injury, there is not an established role for immunosuppression or intravenous immunoglobulin (IVIg) therapy in clinical DN. Nonetheless, described diabetic patients with symmetric distal and proximal progressive neuropathy meeting the clinical and electrodiagnostic criteria for CIDP that responded to treatment for this disease. This should be considered in patients with prominent demyelinating features, which could represent CIDP in a diabetic patient.
The distal symmetric sensorimotor PN is generally slowly progressive, but early detection of neuropathy and implementation of close diabetic control are essential and seemingly prevent or delay the progression of neuropathy, retinopathy, and nephropathy. Maintaining strict blood glucose control has been demonstrated to stabilize, improve, and reduce the occurrence of DN and other diabetic complications in large clinical trials, such as the Diabetic Control and Complications Trial. This study followed a large number of patients with IDDM for 3.5 to 9 years to compare strict glycemic control by means of intensive insulin pump or multiple injections to routine diabetic control. In this trial, intensive insulin therapy reduced the occurrence of neuropathy at 5 years by 64% compared with conventional therapy ( ; ). However, this degree of glycemic control is practically difficult and is associated with a higher risk of hypoglycemic reactions. Additionally, 25% of patients with intensive glycemic control develop neuropathy over 6 to 9 years. Similar protective effects are yet to be documented in patients with NIDDM. The United Kingdom Prospective Diabetes Study Research Group, in a large number of patients with NIDDM followed for an average of 10 years, showed a 25% reduction in the risk of neuropathy and microvascular complications with glycosylated hemoglobin (HbA1c, 7%) when compared with the standard treatment group (HbA1c, 7.9%) ( ). Pancreatic transplant was shown to halt the progression and improve the symptoms of DN better than intensive glycemic control with insulin in patients followed for up to 10 years. Transplant patients showed marked improvement in nerve conduction indices and slight improvement on clinical examination, whereas the control group steadily worsened in all study outcomes ( ; ). Nonetheless, pancreatic transplantation is effective for DN only early in the disease, before axonal loss is extensive, and the effect was not sustained in long-term follow-up ( ).
Proximal DN initially progresses rapidly, followed by slow, varying degrees of improvement. Most patients achieve good recovery and pain usually improves, but in a small number of patients, variable degrees of residual disabling weakness persist ( ; ; ).
DLSP or proximal DN currently has no effective therapy, despite reported improvement with intravenous methylprednisolone in a controlled clinical trial, but the data are incomplete ( ). A Cochrane review demonstrated lack of consistent evidence of the benefit of immunotherapy ( ). High-dose corticosteroids may compromise diabetes control. Likewise, the role of corticosteroids or IVIg in isolated thoracic radiculopathy is uncertain.
Physical therapy is important, and protein-caloric supplements may be useful for those with associated significant weight loss.
Compression neuropathies, including CTS and ulnar neuropathy, should be treated in the same way as the idiopathic forms. Surgical decompression in symptomatic CTS is a widely used treatment, although there are no comparative outcome studies for carpal tunnel release in diabetic and nondiabetic patients. Nocturnal pain and hand paresthesia are expected to improve after surgical carpal tunnel release; however, symptoms related to the underlying PN will not change. Ulnar neuropathy at the elbow may improve with conservative treatment, including avoidance of ulnar compression and the use of soft pads at the elbow. Surgical decompression should be considered for progressive hand weakness and muscle atrophy, although the outcome is not always successful. Multiple surgical decompressions in DN are not beneficial and should be discouraged ( ; ).
Cranial mononeuropathies, including diabetic ocular mononeuropathy, have no specific treatment; however, most patients have a spontaneous complete recovery over several weeks. The recovery of facial nerve palsy depends on the degree of axonal loss, estimated by measuring the amplitude of the facial CMAP at least 1 week after the onset of weakness ( ). Physical therapy is needed, as well as the use of eye patches for corneal protection. The treatment is otherwise the same as for the idiopathic form.
Most importantly, to decrease the progression of the neuropathies, proper DM control is needed. The pharmacologic management of DM, particularly type I DM, is with the use of insulin. Intensive insulin therapy should be done by a specialist. Barriers to intensive therapy may include the need for the patients to adhere to the recommended diet, avoidance of hypoglycemia, and the cost. Insulin usually is given using a combination of regular insulin or a rapid analog with meals and intermediate insulin twice a day or a long-acting insulin analog once a day. The recommended starting dosage of insulin is 0.3 to 0.6 units/kg of body weight/day, increasing as needed. Most patients require about 0.6 to 0.7 units/kg/day ( ; ; ).
Insulin pumps using short-acting analogue insulin improve lifestyle and help achieve an HbA 1c below 7%.
In patients with type 2 DM (NIDDM), the initial treatment should be aimed at lifestyle changes, including diet, weight loss, and exercise. Bariatric surgery could be used in obese individuals, and the risks and benefits should be evaluated ( ). If there are no contraindications, metformin should be part of the initial therapy at diagnosis ( Fig. 21.2 ). The initial dose is 500 mg twice daily to avoid gastrointestinal symptoms, titrated up to 2500 mg/day if necessary over a 2–3-month period. Metformin does not usually produce hypoglycemia but can be associated with lactic acidosis in patients with kidney disease or infection and in those undergoing surgery or receiving contrast radiologic agents. Metformin could cause B 12 deficiency, and this should be monitored. If contraindications to metformin exist, sulfonylureas such as glipizide or thiazolidinediones such as pioglitazone should be used ( ; ). Meglitinides could be used if the patient has an allergy to sulfonylureas; unfortunately, these are more expensive. Insulin could be the first-line agent in patients with HbA 1c above 10%, fasting glucose over 250 mg/dL, or random glucose over 300 mg/dL or when it is difficult to distinguish between type 1 and type 2 DM.
If proper glycemic control is not achieved (HbA 1c >7%) after 3 months, a second-line agent should be started. Some consider starting dual therapy for this from the beginning. The ADA and the European Association for the Study of Diabetes (EASD) consensus guideline suggests either a basal insulin such as glargine (Lantus) or detemir (Levemir) or a sulfonylurea such as glipizide (Glucotrol) as well-validated core therapies ( ; ; ) . If target HbA1c is not achieved with a second-line agent, the ADA/EASD suggest starting or intensifying insulin therapy. The use of automatic glucose monitors (i.e., FreeStyle Libre Abbott or the Dexcom G6 CGM and the Eversense implantable CGM) allows monitoring glycemia throughout the day without using finger sticks.
The pharmacologic approach should consider comorbidities; for example, those with significant atherosclerotic cardiovascular disease, particularly if there are contraindications to the use of metformin, should use sodium-glucose cotransporter inhibitors or glucagon-like type I receptor antagonist. In those with high risk of heart failure, sodium-glucose cotransporter inhibitors are preferred ( ). In patients with chronic kidney disease (CKD), glucagon-like peptide type 1 receptor antagonists have shown to reduce kidney disease progression ( ; ) and improve cardiovascular outcomes (semaglutide). Consultation with an endocrinologist to manage this, particularly in the choice of therapy in children, is very important.
Symptomatic Treatment of Diabetic Neuropathy
Neuropathic pain is common in patients with DN. Nearly one third of patients with DN develop neuropathic pain, which may compromise the quality of daily life and requires specific therapy. The pain can be spontaneous (lancinating, burning, paroxysmal, or cramping) or evoked (allodynia, hyperalgesia, or hyperpathia). Clinical trials of pharmacologic management of painful DN have included several drugs, such as antidepressants, anticonvulsants, topical formulations, narcotic analgesics, and others including gabapentin and pregabalin ( ; ; ; ). These are discussed in detail in Chapter 6 .
Treatment of Autonomic Neuropathy
Autonomic symptoms are important and should be managed with proper therapy. Diabetic cardiac autonomic neuropathy is associated with increased arrhythmias, silent myocardial infarction, and a high mortality rate ( ). Patients should be evaluated for cardiovascular autonomic dysfunction, and preventive measurements should be taken, including the treatment of arrhythmia and the prevention of myocardial infarcts. An exercise stress test is recommended before patients with autonomic neuropathy begin an exercise program. Orthostatic hypotension should be treated with hydration, elastic stockings, increased salt intake, or, rarely, with short-acting pressor agents.
Erectile dysfunction is among the most common complaints in patients with autonomic DN. This could be confounded by a psychogenic component, and a decreased testosterone level should be ruled out or treated. Moderately effective treatments include sildenafil and similar drugs, penile injection of erectogenic agents, and vacuum devices ( ).
Gastrointestinal manifestations include anorexia, early satiety, gastroparesis, bloating, constipation, and diarrhea. These manifestations and their treatment, as well as the treatment of bladder dysfunction, are discussed in detail in Chapter 4 .
Hyperthyroidism
Hyperthyroidism caused by Graves disease is defined as the overproduction of thyroid hormone caused by antibodies against thyrotropin receptors in the thyroid gland, also resulting in its enlargement ( ). This is an autoimmune disorder most frequently seen in women and is associated with certain human leukocyte antigen titers. Hyperthyroidism can occur alone or in conjunction with other immune conditions ( ); it also can be caused by drugs, adenomas, and rarely by disorders of the pituitary gland ( ; ).
Diagnosis and Evaluation
Patients with hyperthyroidism generally appear thin, anxious, and irritable; they have hand tremors and insomnia. They may have autonomic symptoms from tachycardia and sometimes cardiac arrhythmia. The enlargement of the thyroid gland is sometimes accompanied by a bruit in the area. Patients also frequently have a variable degree of thyroid ophthalmopathy characterized by proptosis, with eyelid retraction and diplopia caused by ophthalmoparesis ( ; ), with swelling of the orbits and the extraorbital tissue.
The disorder can be associated with myasthenia gravis, and 3% of patients with myasthenia gravis have hyperthyroidism ( ; Marinó et al., 1971; ). Myasthenia should be suspected in patients with ophthalmopathy with extraocular muscle weakness that exceeds the proptosis. In these patients, proper measurement of acetylcholine receptor antibodies, edrophonium (Tensilon) test, and electrophysiologic studies are necessary ( ). The forced duction test also helps in the diagnosis.
Hyperthyroidism also may cause a PN ( ; ), diffuse muscle weakness, and fatigue. Some patients also show focal pretibial myxedema and acropachy, characterized by swelling and clubbing of the distal phalanges of the fingers and toes ( ).
Hyperthyroidism rarely causes attacks of periodic paralysis, which occur particularly, but not always, in those of Asian ethnicity ( ; ). This should be suspected in patients with an acute onset of weakness.
Measurement of thyrotropin is important in making the diagnosis, and thyroxine is always low or undetectable. Evaluation also should include measurement of T 4 and particularly free T 4 and triiodothyronine (T 3 ) level, which should be elevated ( ; ; ). An elevated level of thyroid globulin-binding antibodies confirms the presence of autoimmunity ( ).
Thyroid ultrasound helps in the diagnosis, particularly to detect not only an enlarged gland but also thyroid nodular disorders. Radioiodine uptake is not always required but can be used to rule out silent subacute thyroiditis and to diagnose factitious and drug-induced thyrotoxicosis. Serum creatine kinase (CK) and electrolytes should be measured in patients with acute paralysis.
Treatment and Management
The treatment of hyperthyroidism consists of pharmacologic suppression of hormonal secretion, radioactive iodine, or surgery ( ). Treatment choice is based on the patient’s age, response to drug therapy, and the size of the gland.
Pharmacologic management includes the use of thionamides such as methimazole and prophylthiouracyl (PTU). These agents block the synthesis of thyroid hormone. Because methimazole is 10 times more potent than PTU, its dosage is 20 to 40 mg/day compared to 200 to 400 mg/day for PTU, aiming to maintain the euthyroid state with the minimal dose ( ). Higher doses in addition to levothyroxine supplements are recommended by some ( ). This treatment should be used for 2 years; a lack of response or relapse is an indication for radiation or thyroidectomy. Inorganic iodine can be given for a short period in preparation for surgery.
In older patients, radioactive isotopes are used to destroy the gland, using dosages of 80 to 100 μCi/g; supplemental levothyroxine may be required.
Patients with severe hyperthyroidism can be treated acutely with beta-blockers, which suppress the autonomic dysfunction, or with corticosteroids, which block the conversion of T 4 to T 3 and decrease T 4 secretion.
Thyroid ophthalmopathy is treated with 30 to 40 mg of prednisone daily for a short period; in severe cases, decompression or radiation treatment is necessary. Immunosuppressant therapy also can be used ( ).
Myasthenia gravis should be treated with anticholinesterase drugs and with corticosteroids or immunosuppressants as necessary.
Attacks of thyrotoxic periodic paralysis are treated with potassium supplements; patients should receive low-sodium, low-carbohydrate diets with potassium supplementation. Propranolol can be used in acute attacks ( ; ).
Hypothyroidism
Thyroid hormone is important in neuromuscular function because it binds to intracellular and other adrenergic receptors, regulating glycogenolysis and mitochondrial oxidation ( ). It regulates the activity of calcium ATPase, and in hypothyroidism there is an increase in the ratio of inorganic phosphate to ATP in resting muscle and a decrease in phosphocreatine in working muscle ( ). The hormone also participates in the mobilization of mucopolysaccharides; in hypothyroidism, thickening of the skin is caused by deposits of these substances in the subcutaneous tissue, which might be associated with nerve entrapment such as CTS ( ).
The most common cause of hypothyroidism is dysfunction of the gland from a chronic thyroiditis, but it also can occur after thyroid surgery, radiation, infiltrations, iodine deficiency, or the use of some drugs, such as lithium and amiodarone ( ). Secondary hypothyroidism is caused by decreased production of thyrotropin by the pituitary gland, for example, from tumors or rarely by decreased secretion of thyroid hormone–releasing hormone by the hypothalamus.
Diagnosis and Evaluation
The clinical manifestations of hypothyroidism include slowness of movements; tough, thick skin; increased weight; cold intolerance; and constipation.
Neurologic complications also include encephalopathy, ataxia, and sometimes even coma. Cranial nerve dysfunction can cause hoarseness and, rarely, diaphragmatic paralysis ( ). Patients may exhibit bradycardia, myoedema, and delayed relaxation of the ankle reflex.
Neuromuscular complications include sensorimotor PN ( ; ) and entrapment neuropathies, particularly CTS ( ). Some patients also have diffuse muscle weakness and fatigue ( ; ; ; ), which can be accompanied by stiffness. Rare cases of rhabdomyolysis have been reported ( ; ; ; ).
Muscle enlargement accompanied by pain in adults with hypothyroidism is called Hoffmann syndrome ( ; ); in children, this also manifests with dysmorphic features and muscle swelling, but without pain, and is called Kocher-Debré-Semelaigne syndrome ( ).
Serum cholesterol, triglycerides, and serum CK levels frequently are elevated ( ), likely because of decreased secretion of the enzyme ( ). CK levels may be elevated in subclinical cases misdiagnosed with “idiopathic hyperCKemia.” Thyroid hormone levels should be measured in these patients, particularly those with hyperlipidemia, before placing them on cholesterol-lowering drugs.
The evaluation of hypothyroidism includes measurement of serum T 4 , particularly free thyroxine, T 3 , and particularly thyrotropin, which is elevated in the primary form. Measurement of thyroid peroxidase antibodies is used to diagnose chronic autoimmune thyroiditis ( ). Thyroid ultrasound and thyroid scans can be used in those with enlargement of the gland.
Treatment and Management
The treatment of hypothyroidism consists of eliminating possible causes, such as medications, and treating the iodine deficiency, but the most important therapy consists of hormonal replacement with oral levothyroxine, initially at a dosage of 1.3 μg/kg/day orally and later with a maintenance dose of about 125 μg daily; this dosage varies between 50 and 200 μg daily with proper monitoring of thyrotropin levels. The dosage should be adjusted according to the effects of diet, medications, and particularly weight. The combination of levothyroxine and levothyronine at a ratio of 4:1 also is used by some ( ).
Management also includes surgery for CTS, exercise, and physical therapy.
Hyperparathyroidism
Primary hyperparathyroidism is caused by an excessive release of parathyroid hormone (PTH) by adenomas or hyperplasia of the glands and rarely by parathyroid cancer ( ). These tumors may be a manifestation of familial multiple endocrine neoplasms ( ).
Normally, PTH acts in the kidneys by increasing calcium reabsorption and converting 25-hydroxy vitamin D 3 to the more potent metabolite 1,25-dihydroxy vitamin D ( ). This action is exaggerated in primary hyperparathyroidism ( ).
In renal disease, failure to convert 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D decreases calcium reabsorption and causes hypocalcemia, which increases PTH production (secondary hyperparathyroidism) ( ). In these patients, hypocalcemia and vitamin D deficiency are accompanied by hyperphosphatemia. Tertiary hyperparathyroidism refers to an autonomous production of PTH even with normal or elevated serum calcium levels ( ; ).
The mechanism by which hyperparathyroidism causes neuromuscular disease is unclear, but elevated levels of PTH with hypercalcemia and hypophosphatemia impair muscle function ( ; ; ). The proximal muscle weakness that occurs in vitamin D deficiency and osteomalacia suggests a link between abnormal vitamin D metabolism and neuromuscular disease.
Diagnosis and Evaluation
Primary hyperparathyroidism is frequently diagnosed during routine laboratory studies in asymptomatic individuals by the presence of hypercalcemia ( ). The disease can manifest clinically as bone disease (osteitis fibrosa cystica), kidney stones, peptic ulcers, and psychiatric symptoms ( ).
Neuromuscular manifestations include fatigability and prominent proximal muscle weakness, with atrophy mainly in the leg muscles (hyperparathyroid myopathy). Serum CK levels are normal ( ). This presentation occurs in both primary and secondary hyperparathyroidism ( ).
Unusual symptoms include diplopia, myotonia, and severe hypotonia. An acute necrotizing myopathy has been reported ( ; ). Rarely, symptoms resemble those of amyotrophic lateral sclerosis ( ), and “dropped head syndrome” can also occur ( ).
Short-duration polyphasic motor unit action potentials can be seen on EMG, and there could be increased neuromuscular jitter on single-fiber EMG, indicating a disorder of the neuromuscular junction ( ). Type II muscle fiber atrophy is demonstrated on muscle biopsy, which also may show scattered esterase-positive atrophic denervated muscle fibers. Another important finding is the presence of calcium deposits in vessel walls ( ); this vasculopathy in other tissues could play a role in the cardiovascular complications of hyperparathyroidism.
The laboratory diagnosis of hyperparathyroidism is based on the presence of hypercalcemia and elevated levels of PTH. However, hypercalcemia can also occur with malignancy, excessive vitamin D and A intake, and other endocrine disorders, such as thyrotoxicosis and Addison disease. In all of these, PTH levels are suppressed except for rare cases of ectopic PTH secretion in malignancy. Hypercalcemia also occurs in patients receiving lithium and thiazides and in the hypercalcemic hypocalciuric syndrome ( ; ).
Serum phosphate may be normal in primary hyperparathyroidism, but it is elevated in secondary hyperparathyroidism. Radiographs and densitometry occasionally provide valuable diagnostic clues.
Once the diagnosis is made, there are several methods for localization of the adenoma, including MRI, computed tomography (CT), and ultrasound. The most sensitive method is Tc-99 sestamibi uptake, especially when combined with initial single-photon emission CT scan.
Treatment and Management
The treatment of primary hyperparathyroidism consists of surgical removal of the adenoma ( ; ; ). In patients who cannot tolerate surgery, medical therapies include oral phosphate, which can cause gastrointestinal symptoms. Subcutaneous bisphosphonates are used for control of osteitis fibrosa, reducing bone turnover without affecting PTH secretion. Of the bisphosphonates, alendronate has been shown to increase bone density in hyperparathyroidism ( ). Estrogen replacement can be used in postmenopausal women, but this can be associated with deleterious effects. Inhibition of PTH synthesis can be obtained by drugs such as cinacalcet that act in the calcium-sensing receptor in parathyroid cells ( ).
Treatment of secondary hyperparathyroidism consists of low-phosphate diets and vitamin D replacement. Aluminum-containing phosphate-binding agents also can be used, but these can increase aluminum levels, which could cause weakness and encephalopathy and, occasionally, hypercalcemia. Currently, calcium carbonate is used in dosages not exceeding 2 g/day. Calcitriol or its analogs also can be used to inhibit PTH production. Alpha calcitriol has similar effects. Treatment also should include proper dialysis and ideally kidney transplantation.
Hypoparathyroidism
Hypoparathyroidism is defined as the decreased production of PTH; a lack of response of the target tissue to the PTH is called pseudohypoparathyroidism ( ). Both disorders result in hypocalcemia and hyperphosphatemia.
Decreased production of PTH is more often the result of unintentional damage to the parathyroid glands during neck surgery for cancer or adenomas and for hyperthyroidism, and less frequently by radiation ( ), infiltrations such as iron overload in hemochromatosis and multiple transfusions, and Wilson disease ( ). Idiopathic hypoparathyroidism represents a heterogeneous group of rare diseases, such as autoimmune familial hypoparathyroidism associated with multiglandular syndrome ( ) and congenital disorders such as DiGeorge syndrome ( ). Chronic hypermagnesemia may cause decreased production of PTH ( ), as in Kearns-Sayre syndrome, a mitochondrial disorder ( ). Hypermagnesemia also can cause decreased secretion of PTH, such as occurs, for example, with high doses of intravenous magnesium used to treat toxemia.
PTH regulates calcium concentrations in the extracellular space. About 50% is protein bound, and the rest is ionized calcium. The hormone increases calcium mobilization from bone and reabsorption from the kidneys, and its deficiency results in hypocalcemia. Hyperphosphatemia is caused by diminished phosphate clearance by the kidneys.
Pseudohypoparathryoidism occurs in a group of disorders in which there is hypocalcemia with hyperphosphatemia and is associated with increased PTH production but a reduced response to the biologic action of the hormone ( ).
Vitamin D deficiency also can cause hypocalcemia by decreasing intestinal calcium absorption, which enhances PTH production (secondary hyperparathyroidism).
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