Keywords
Systemic disease, renal failure, diabetes mellitus, critical illness polyneuropathy, paraneoplastic, vitamin deficiencies, connective tissue diseases
Introduction
There is a clear distinction between a peripheral neuropathy that is clinically significant and which is a presenting feature of the underlying condition (e.g. those associated with diabetes mellitus, lymphoma, and uremia) and a peripheral neuropathy that is asymptomatic and detected only by careful neurologic examination and electrophysiologic studies. Peripheral polyneuropathy is frequently asymptomatic in children with systemic disorders. This chapter reviews some of the relatively uncommon but clinically significant polyneuropathies that may be encountered in pediatric patients with various systemic illnesses. A summary of these neuropathies is provided in Table 22.1 . Neuropathies seen in response to infections and metabolic and neurodegenerative disorders are also part of systemic processes, but these are described in other chapters.
| Systemic Disease | Predominant Neuropathy Type a | Onset and Course | Pathology |
|---|---|---|---|
| Metabolic Disorders | |||
| Uremia b | Sensory (sensorimotor) | Chronic (acute) | AD, SD |
| Hypoglycemia | Motor | Chronic | AD |
| Endocrine Disorders | |||
| Hypothyroidism | Sensory | Chronic | AD |
| Acromegaly | Sensory | Chronic | AD |
| Diabetes mellitus b | Sensory, motor | Chronic | AD, SD |
| Malignancies and Reticuloses | |||
| Carcinoma | Sensory, sensorimotor | Subacute or chronic | AD (SD in acute relapsing type) |
| Lymphoma b | Sensorimotor | Acute, subacute | AD, SD (acute relapsing type) |
| Chronic lymphatic leukemia | Sensorimotor | Acute (subacute) | AD |
| Deficiency States | |||
| Vitamin B12 b | Sensory | Chronic | AD |
| Thiamine b | Sensorimotor | Chronic | AD |
| Folic acid | Sensory | Chronic | AD |
| Vitamin E b | Sensory | Chronic | AD |
| Connective Tissue Disorders | |||
| Rheumatoid arthritis b | Sensory, mononeuritis | Chronic, acute | SD, AD |
| Polyarteritis nodosa b | Mononeuritis | Acute, chronic | AD, SD |
| Systemic lupus erythematosus b | Sensory, motor | Chronic, acute | AD, SD |
| Miscellaneous | |||
| Chronic liver disease b | Sensory (sensorimotor) | Chronic | AD, SD |
| Primary biliary cirrhosis b | Sensory | Chronic | AD |
| Viral hepatitis | Sensory or sensorimotor | Acute | SD |
| Celiac disease b | Sensorimotor | Chronic | AD |
| Chronic obstructive lung disease | Sensory (sensorimotor) | Chronic | AD |
| Sarcoidosis b | Sensorimotor, motor | Acute or chronic | AD |
| Amyloidosis b | Sensorimotor | Chronic | AD |
| Paraproteinemias and Dysproteinemias | |||
| Multiple myeloma | Sensorimotor (sensory) | Chronic | AD |
| Cryoglobulinemia | Sensorimotor | Chronic | AD |
| Macroglobulinemia | Sensorimotor | Subacute or chronic | AD, SD |
| Monoclonal Gammopathy | |||
| IgA | Sensorimotor | Chronic | AD |
| IgG | Sensorimotor | Chronic | AD, SD |
| IgM | Sensorimotor | Chronic | SD |
a Words in parentheses indicate less common types.
Critical Illness Polyneuropathy
Critical illness polyneuropathy (CIP) occurs in patients with sepsis, asthma, organ transplantation, and multiple organ failure as part of a systemic inflammatory response syndrome (see Chapter 50 ). Initially reported in adults with severe systemic illnesses in intensive care units, it is often first recognized when it proves difficult to wean a child from mechanical ventilation. The accompanying signs of generalized weakness, muscle wasting, and depressed or absent reflexes may be difficult to detect or misinterpreted in the intensive care setting. Onset may manifest as early as within the first week of illness, with a range of 4 to 26 days documented. The differential diagnosis includes paraparesis or tetraparesis secondary to spinal cord lesions, prolonged neuromuscular blockade, steroid- or relaxant-induced myopathy, acute necrotizing myopathy, hypophosphatemia, toxic and thiamine-deficiency neuropathies, asthma-amyotrophy (Hopkins’) syndrome, and Guillain-Barré syndrome ( Box 22.1 ). A similar condition may occasionally follow severe burns. A careful and systematic investigation includes testing of the serum creatine kinase, which is normal in most cases, magnesium and phosphate levels, neurophysiologic studies (nerve conduction studies, electromyography [EMG], and occasionally electroencephalography), and relevant imaging modalities. If diagnostic doubt persists, nerve and/or muscle biopsy sometimes provide diagnostic information. In typical cases of critical illness polyneuropathy, nerve conduction studies and histopathologic observations confirm widespread axonal degeneration with extensive muscle denervation.
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Spinal cord lesions
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Prolonged neuromuscular blockade
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Steroid or relaxant-induced myopathy
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Acute necrotizing myopathy
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Hypophosphatemia, hypermagnesemia
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Toxic and thiamine-deficiency neuropathies
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Asthma-amyotrophy (Hopkins’) syndrome
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Guillain-Barré syndrome
CIP and critical illness myopathy are on a continuum of neuromuscular disorders. While far more data are available on affected adult patients, the limited studies in the pediatric age group suggest that the condition causes significant morbidity in critically ill children. Treatment is mainly supportive, but early correction of abnormal osmolar states, glycemic levels, and electrolyte imbalance is considered important, as well as early mobilization. Recovery, where reported, is spontaneous and of variable timing. See Case Example 22.1 .
An 18-month-old boy with Down syndrome, global developmental delay, epilepsy, and cortical blindness was admitted for septicemia and multiorgan failure. He had previously had recurrent aspiration pneumonia necessitating a fundoplication and gastrostomy, and a urinary tract infection. He received antibiotics (ceftriaxone, vancomycin, and gentamicin) as well as corticosteroids. He required massive inotropic support (adrenaline, dopamine, and dobutamine), platelets, fresh frozen plasma, and colloid infusions to stabilize his condition. Various metabolic and electrolyte problems were corrected. Hypoglycemic episodes developed, requiring glucose infusions.
Two weeks after admission, he developed an adult respiratory distress-like syndrome and was started on prednisone (2 mg/kg/day). He was slowly weaned from the ventilator but continued to have episodes of central apnea and hypercapnea. Alveolar lavage showed persistent Pseudomonas colonization. Ceftazidime and gentamicin were administered. Recurrent seizures necessitated treatment with multiple anticonvulsants. He developed generalized weakness with minimal movements limited to his left arm. The muscle stretch reflexes were absent. A cranial computed tomography scan demonstrated generalized cortical atrophy with diffuse white matter changes compatible with a hypoxic insult. An electroencephalogram was nondiagnostic. Cervical spine radiographs were unremarkable. Based on his stormy clinical course, the persistent difficulty weaning him from the ventilator, and his associated apneic spells during sleep, a diagnosis of critical illness polyneuropathy was considered.
Motor nerve conduction studies demonstrated findings consistent with an axonal polyneuropathy with markedly reduced compound muscle action potential amplitudes on all motor studies in the upper limbs, and an absent common peroneal motor response. Needle EMG of the tibialis anterior and biceps brachii muscles demonstrated fibrillations.
Although he had some improvement, he was still bedridden owing to weakness 3 months after the onset of his illness.
Comment
This is a fairly typical course for a child with critical illness polyneuropathy.
Renal Disorders
Chronic Renal Failure
The neuropathy of chronic renal failure is typically an axonal degenerative type, which in most children is asymptomatic. Nerve conduction studies in long-term hemodialysis-dependent children generally show normal or only mildly impaired values. The evaluation of the “H” reflex has been reported as a useful indicator of clinically asymptomatic uremic polyneuropathy, identifying this complication in almost 60% of one series of children with chronic renal failure.
This neuropathy usually remains stable or improves with treatment; if not, increasing the frequency and duration of dialysis may result in improvement. Rapid improvement usually follows successful renal transplantation, even in patients with long-standing neuropathy.
Endocrine Disorders
Diabetes Mellitus
Diabetic neuropathy may manifest as a polyneuropathy, focal neuropathy, or autonomic neuropathy. The latter is the most common and has the most serious side effects, related to unawareness of hypoglycemia and cardiovascular dysfunction. Children with a length-dependent polyneuropathy suffer distal sensory loss (numbness) and paraesthesiae; they may also have pain manifesting as burning, aching, and electric-sharp sensations. Weakness, clumsiness, loss of balance, and falls may be associated with distal anhidrosis, postprandial bloating, constipation, diarrhea, and lack of awareness of hypoglycemia. Glove and stocking sensory loss, loss of deep tendon reflexes, distal weakness, and even foot ulcers may occur.
Between 10% and 68% of children with diabetes suffer from neuropathies. In one large cohort of 146 children (under 18 years of age) with diabetes, 27.4% had peripheral neuropathy. Of this affected group, 62.5% had subclinical disease, a minority being clinically affected.
Although patients with diabetic neuropathy may not complain of it, their physical examination may reveal variable degrees of sensory loss. In one study, 30.8% of subjects had numbness and about 7% to 10% showed large myelinated nerve fiber dysfunction, while only 1.4% had impairment in pain or temperature sensation. Nerve conduction studies most often show abnormalities of the peroneal and sural nerves.
Large studies have suggested that neuropathy can develop in young children with short illness duration and despite good glycemic control. As such, the concept of the duration of illness as a key disease-inducing factor has not been established; it has been suggested that the nerve damage can occur acutely and rapidly at the onset of the diabetes, subsequent to which the neuropathy develops more slowly or may even plateau. The best way to prevent this complication is still strict blood glucose control.
Since the neuropathy can progress and ultimately affect quality of life, but is often initially subclinical, regular nerve conduction studies are recommended in order to monitor for development of this serious disease complication.
Multiple Endocrine Neoplasia Type 2B
Multiple endocrine neoplasia (MEN) type 2B is a rare, dominantly inherited syndrome accounting for 5% of all cases of MEN 2, characterized by medullary thyroid carcinoma, pheochromocytoma, ganglioneuromatosis, and a variety of skeletal and connective tissue abnormalities. MEN 2B cases usually carry either an M918T or A883T mutation of the RET (REarranged during Transfection) oncogene. Affected patients have an arresting appearance because of a diffuse, thick, fleshy enlargement of the everted lips, apparent eversion of the eyelids, and a marfanoid habitus. Other oral manifestations include a high arched palate and small, whitish-yellow, firm, protruding neuromatous nodules on the tongue. Fibular atrophy, pes cavus, scoliosis, and proximal or distal muscle atrophy are common.
A polyneuropathy, with mild weakness of ankle dorsiflexion or occasionally of the intrinsic hand muscles, may be the presenting manifestation of this disorder. Nerve conduction studies demonstrate mild abnormalities of motor and sensory nerve conduction. Chronic denervation is apparent on needle EMG.
Sural nerve biopsy reveals moderate loss of small- and large-diameter myelinated fibers. At autopsy, unusual plaques of hyperplastic interlacing bands of Schwann cells and myelinated fibers overlie the posterior columns of the spinal cord. Autonomic nerves are also involved and are responsible for the severe constipation or diarrhea frequently seen in these patients.
Early diagnosis is extremely important because of the high risk of malignancy. Medullary thyroid carcinoma is almost always present at the time of diagnosis.
Vitamin Deficiency States
Vitamin B1 (Thiamine) Deficiency
Childhood thiamine deficiency, or beriberi neuropathy, is rare in resource-equipped settings except in special circumstances, such as prolonged parenteral nutrition without adequate vitamin supplementation. Such complications, related to inadequate thiamine intake or uptake, are reported in preterm infants, children after gastric surgery, and patients undergoing allogeneic hematopoietic stem cell transplantation. Infantile encephalitic beriberi (IEBB) is a rare form of thiamine deficiency reported in “Third-world” countries in the breast-fed infants of thiamine-deficient mothers. IEBB appears suddenly, after an episode of gastroenteritis, with cardiac symptoms, neck stiffness, and acute peripheral neuritis. IEBB can mimic Leigh syndrome, with life-threatening respiratory and central nervous system symptoms. There is a dramatic response to thiamine. Epidemic spastic paraparesis (konzo) is a neurological condition associated with the consumption of cassava roots and minimal protein consumption. The condition is prevalent in Nigeria, Tanzania, Sierra Leone, Mozambique, Central African Republic, and the Democratic Republic of the Congo. It occurs in children aged 4 to 12 years and in young women, causing asymmetrical spastic paraparesis with marked sensory polyneuropathy and ataxia. There is overlap with the features of dry beriberi. There is a strong case that the condition is, at least in part, the result of thiamine deficiency resulting from the overconsumption of cassava roots.
Nerve conduction studies show a mainly sensory neuropathy with a superimposed acute motor axonopathy. Pathologically, peripheral nerves demonstrate the typical changes of large-fiber-predominant axonal degeneration and subperineurial edema. A prompt response to therapy is reported in most cases.
Vitamin B2 (Riboflavin) Deficiency
The Brown-Vialetto-Van Laere syndrome is a rare neurodegenerative disorder that usually causes death from respiratory disease in early childhood. Fazio-Londe syndrome is considered the same disease entity (but without deafness). Affected patients have a rapidly progressive axonal sensorimotor neuropathy manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles often with distinctly preserved strength in the lower limbs, bulbar palsy, hearing loss, optic atrophy, and respiratory insufficiency. Presentations are protean and include a severe infantile form, a slowly progressive sensorimotor neuropathy with prominent ataxia, resembling Friedreich ataxia and a slowly progressive ponto-bulbar palsy, often evidenced by tongue fasciculations (Brown-Vialetto-van Laere syndrome). Sensorineural deafness and optic atrophy are common associations resulting in a form of the optico-acoustic neuropathy syndrome. Patients with these conditions have been found to carry mutations in the SLC52A2 and SLC52A3 genes, which encode two of the three known riboflavin transporter genes (RFVT). These mutations cause reduced riboflavin uptake and transporter protein expression. High-dose riboflavin supplementation in affected patients results in significant and sustained clinical and biochemical improvements.
Vitamin B6 (Pyridoxine) Deficiency
Vitamin B6 supplementation is recommended for patients treated with isoniazid, to avoid development of a painful sensory neuropathy. However, there are a few reports whereby pyridoxine therapy itself resulted in the development of a dorsal root ganglionopathy in adults but not children.
Vitamin B12 (Cobalamin) Deficiency
Although vitamin B12 deficiency anemia in childhood due to familial malabsorption of cobalamin or inadequate dietary intake is well reported, descriptions of peripheral neuropathy in association with the recognized neurologic complications in children are infrequent. Children from resource-poor countries with dietary insufficiency, malabsorption, and malnutrition may have neurological sequelae inclusive of neuropathy. The clinical, pathologic, and electrophysiologic features of the neuropathy due to vitamin B12 deficiency are better described in adults.
Vitamin E Deficiency
A progressive neurologic syndrome secondary to deficient vitamin E absorption occurs in children with longstanding obstructive liver disease, chronic intestinal malabsorption, and cystic fibrosis. (See Case Example 22.2 .) Children suffering from protein-energy malnutrition are also at risk of vitamin E deficiency. Vitamin E deficiency is a major factor in the pathogenesis of the polyneuropathy associated with abetalipoproteinemia. Affected patients may develop nystagmus, gaze paresis, retinitis pigmentosa, an ataxic gait, and areflexia, and have impaired position and vibration awareness.
A female child became jaundiced soon after birth and was eventually diagnosed with Alagille’s syndrome with chronic cholestasis. At 8 years of age, she was noted to be walking on her toes and a tendon-lengthening procedure was performed.
From the age of 10 years she fell frequently, developed a squint, and had trouble straightening her arms. There was evidence of night blindness.
At the age of 13 years, she had tigroid pigmentation of the peripheral retina. There was limitation of abduction and elevation of both eyes. Her horizontal extraocular movements were jerky. There was slight dysarthria, and mild ataxia on finger-nose-finger and tandem gait testing. Vibration sense and muscle stretch reflexes were absent. The plantar responses were equivocal.
Motor nerve conduction velocities were 52 and 42 m/s in the median and common peroneal nerves, respectively. Sensory nerve conduction velocities were normal in the median, ulnar, and sural nerves, but the amplitudes of the responses were slightly low at 10, 7, and 6 mV, respectively. The serum vitamin E level was 0.5 units (normal range, 12–36 units).
The child was treated with vitamin E (2000 units/day). Twelve months later, there was slight improvement in her ataxia and an increase in the amplitude of the sensory nerve action potentials from the median and ulnar nerves.
In rare cases, vitamin E malabsorption appears to be an isolated defect, a condition known as ataxia with vitamin E deficiency (AVED) or familial isolated vitamin E deficiency related to mutations in the alpha-tocopherol transfer protein gene ( TTP1 ). Vitamin E has antioxidant properties and modulates glutamate neurotoxicity. The defect in AVED impairs incorporation of vitamin E into plasma low-density lipoproteins. Subsequently, although vitamin E is absorbed in the intestine, normal recycling of vitamin E, which is dependent on the alpha-tocopherol transfer protein, is deficient. Thus, vitamin E is rapidly eliminated and levels are low.
AVED is characterized by progressive ataxia, dysarthria, weakness, areflexia, and proprioceptive loss with undetectable or very low serum vitamin E levels, in the absence of hypolipidemia or fat malabsorption. Onset of symptoms is usually between 3 and 13 years of age. In contrast to patients with vitamin E deficiency secondary to other gastrointestinal disorders, patients with AVED do not usually have retinopathy, ophthalmoplegia, or abnormal peripheral sensory conduction. Extensor plantar responses, tremor, and dystonic movements may be present. Abnormal posterior column function is confirmed by somatosensory evoked potential studies. Later, some children are found to have alterations of sensory conduction.
Nerve conduction studies typically show a sensory neuronopathy with normal motor conduction and absent or markedly reduced sensory nerve action potentials (SNAPs). Sural nerve biopsy from a 22-year-old man with isolated vitamin E deficiency revealed loss of large myelinated fibers and evidence of remyelination. This case study differed from others in that it suggested a demyelinating process rather than axonal disease, as is described in other reports.
Autopsy findings include loss of large myelinated fibers and axonal degeneration in the peripheral nerves, loss of dorsal root ganglion cells, posterior column degeneration, and swollen dystrophic axons (spheroids) and astrocytosis in the gracile and cuneate nuclei, posterior columns, and Clarke’s column.
Dietary vitamin E supplementation can lead to clinical and electrophysiological recovery of sensory conduction and evoked potentials.
Malignancies and Reticuloses
The peripheral nervous system is commonly involved in patients with cancer because of direct infiltration, compression, paraneoplastic syndromes, the complications of treatment, and a number of unpredictable complications such as infections and the impact of poor nutrition. Complications related to direct infiltration and the toxic effects of cancer therapies are addressed in Chapter 12 , Chapter 23 . Most data are from adult studies. When drug toxicity and local neoplastic infiltration are excluded as factors, peripheral neuropathies in the context of childhood malignancies are rare. A review of 96 long-term survivors of childhood malignancy found no clinical or electrophysiologic evidence of neuropathy in the 49 patients who had not received vincristine. In contrast, there was a high rate of areflexia and sensory conduction velocity abnormalities in the 47 children treated with vincristine, although these children were generally not clinically compromised.
Lymphoma
About 5% of adults with lymphoma develop a peripheral neuropathy. This association is extremely rare in childhood. As in carcinomatous neuropathy, two main clinical types are recognized: a sensory neuropathy and a sensorimotor neuropathy.
Sensory Neuropathy
Pure sensory neuropathy is considerably less common in lymphoma than in carcinoma. The clinical features of paresthesia, dysesthesia, pain, and sensory ataxia are similar to those seen in carcinoma.
Sensorimotor Neuropathy
Acute polyneuropathy of the Guillain-Barré type is occasionally found in association with lymphoma, particularly Hodgkin’s disease. Various reports have described the challenge of differentiation between acute inflammatory polyradiculoneuropathy (AIDP) and vincristine toxicity in children with acute lymphoblastic leukemia, non-Hodgkin’s lymphoma, and Hodgkin’s lymphoma who develop a predominantly lower limb sensorimotor neuropathy. This contrasts with other malignant tumors, which have no association with Guillain-Barré syndrome. The distinction can be difficult. The polyneuropathy probably occurs as a result of the underlying disturbances of immune function in patients with diseases of the lymphoreticular system. Children with AIDP may have absent F waves if studied early in their course, and may respond well to intravenous immunoglobulin. Occasionally children develop more chronic demyelinating or axonal neuropathies in association with lymphoma. Malignant infiltration of nerve roots and peripheral nerves occurs more commonly in lymphoma than in carcinoma.
Paraneoplastic Neuropathies
Paraneoplastic neurological syndromes affect about 1% of patients with cancer. In adults, these syndromes often cause peripheral neuropathies mediated by antibodies to either intracellular (Hu-D and CV2-CRMP5) or cell membrane antigens (voltage-gated calcium channel, LG1 and CASPR2 proteins). The malignancies most commonly associated with paraneoplastic peripheral neuropathy, such as small cell lung cancer, are much more common in adults. Children with paraneoplastic neurologic syndromes are more likely to present with limbic encephalitis than neuropathy, but occasional cases are reported. A 13-year-old boy with Hodgkin’s disease developed an acute polyneuropathy and autoimmune hemolytic anemia. Sural nerve biopsy and post-mortem examination demonstrated axonal degeneration in the nerves and dorsal funiculus, without metastatic involvement or cellular inflammation in the nerves. A 14-year-old boy suffered from a chronic demyelinating neuropathy during the 14-month period before he was diagnosed with Hodgkin’s disease. This case raises the issue of whether cases of apparent AIDP and CIDP in association with lymphoreticular malignancies might represent paraneoplastic conditions.
Graft-versus-Host Disease
Acute immune-mediated neuropathies can arise as a complication of allogeneic hematopoietic stem cell transplantation in both children and adults. All variants of GBS are reported in the context of graft-versus-host disease (GVHD), often after preceding infections. Recognition of an acquired immune-mediated process through the usual evaluation (clinical, CSF, and neurophysiologic) is important, as patients usually respond well to parenteral immunoglobulins. Chronic inflammatory neuropathy following bone marrow transplantation complicated by severe graft-versus-host disease has also been reported in a 7-month-old girl.
Although children are at risk of peripheral neuropathy as part of a graft-versus-host response, other causative or contributory factors (such as toxins, infections, and paraneoplastic processes) must also be considered and excluded.
Neurofibromatosis
The autosomal dominant condition neurofibromatosis type 1 (NF1) is associated with benign nerve-sheath tumors ( Figure 22.1 ), which undergo malignant change in about 8% to 13% of cases. This malignant transformation is associated pathologically with mutations in the p53 and INK4a genes, and aberrant signaling in the Notch pathway. Malignant peripheral nerve-sheath tumors (MPNST) are invasive sarcomas and carry a poor prognosis. A study of 123 Chinese children with NF1 detected MPNST in 3 patients (2.4%). Affected individuals usually present with severe pain and rapid growth of the soft-tissue lesion. Various serum markers have been suggested to aid early detection of risk of malignant change.
