Peripheral Neuropathies 4

Question 1

Alcoholic peripheral neuropathy: pathogenesis, clinical findings, treatment

Answer 1

1) Pathogenesis:
Alcoholic peripheral neuropathy is caused by alcohol neurotoxicity, but it is sometimes complicated by vitamin deficiency. It is primarily an axonal neuropathy, complicated by demyelination when there is coexisting nutritional deficiency.

2) Clinical features
A gradually progressive disorder of sensory, motor, and autonomic nerves. The clinical abnormalities are usually symmetric and predominantly distal. Symptoms include numbness, paresthesia, burning dysesthesia, pain, weakness, muscle cramps, and gait ataxia. The most common neurologic signs are loss of tendon reflexes, beginning with the ankle jerks, defective perception of touch and vibration sensation, and weakness

Alcoholic polyneuropathy also renders patients susceptible to compression of peripheral nerves at common sites of entrapment, including the median nerve at the carpal tunnel, the ulnar nerve at the elbow, and the peroneal nerve at the fibular head

3)
Thiamine supplementation
Improved nutrition
Cessation of drinking

Low doses of tricyclic antidepressants, mexiletine , or gabapentin are sometimes effective in controlling the burning dysesthesias of alcoholic peripheral neuropathy

Question 2

B12 deficiency neuropathy pathophysiology

Answer 2

Vitamin B12 deficiency is known to affect neuronal function, but the exact mechanisms remain elusive.

Reduced methylation of neuronal lipids and neuronal proteins, such as myelin basic protein, have been hypothesized to play a role in some of the neurologic deficits. Myelin basic protein makes up approximately one-third of myelin, and demyelination in the setting of vitamin B12 deficiency may explain many of the neurologic findings

Question 3

B12 deficiency neuropathy clinical findings

Answer 3

Distal symmetric numbness and gait instability (and if untreated for a long period distal weakness).

Examination usually reveals reduced proprioception
and vibration sense, with distal weakness and muscular atrophy
in more advanced cases.

Because of the frequent simultaneous occurrence of subacute combined degeneration of the spinal cord (corticospinal tracts and dorsal columns), patients may exhibit the unusual combination of diminished deep tendon reflexes at the ankle in the face of robust Babinski signs.

Question 4

B12 deficiency diagnostic studies

Answer 4

Nerve conduction studies typically show axonal neuropathy,
with reduced sensory amplitudes and normal or mildly
reduced conduction velocities.

About 35% of patients with neurologic symptoms of vitamin
B12 deficiency have a serum level in the borderline range
(150–200 pg/mL), and in these patients, megaloblastic anemia may not be apparent. In such patients, levels of methylmalonic acid and homocysteine are elevated.

Question 5

Which conditions are associated with pyridoxine (B6) deficiency

Answer 5

Pyridoxine deficiency may occur during isoniazid, hydralazine,
or, rarely, penicillamine therapy

Question 6

Enviromental toxins causing peripheral neuropathy

Answer 6

Question 7

Therapeutic drugs associated with polyneuropathy

Answer 7

Question 8

Diabetic neuropathic syndromes

Answer 8

Question 9

Diabetic symmetric neuropathy clinical findings

Answer 9

Begins with numbness, paresthesias, or dysesthesias (alone or in combination) in the feet. Over months or years, symptoms ascend up the leg and eventually affect the upper extremities.
Painful diabetic neuropathy may also develop at this early stage
Loss of light touch, pain, and temperature typically occurs early, followed by loss of proprioception, which may cause gait ataxia.
Distal weakness and atrophy follow, with gradual subsequent ascension.

(Loss of protective foot sensation in diabetic patients increases the chance of unrecognized cutaneous ulceration, which, along with impaired cutaneous healing, can result in infection and limb amputation)

Question 10

Diabetic small fiber neuropathy clinical findings

Answer 10

The small cutaneous nerve fibers that sense pain and temperature are often damaged in diabetic patients, resulting in the loss of distal pinprick and temperature sensation and the development of burning, electric, aching, stabbing, and pins-and-needles dysesthesias and pain, which can be incapacitating.
Patients may have allodynia (the perception of a nonpainful stimulation as painful), especially at night, and foot contact with
bedsheets may interfere with sleep.

Question 11

Diabetic neuropathic cachexia

Answer 11

The syndrome of diabetic neuropathic cachexia consists of rapidly progressive severe neuropathic pain throughout the body and profound weight loss. It is often precipitated by efforts to tighten glucose control (eg, the first use of insulin, aggressive increases in dosing of oral hypoglycemic agents).
This syndrome closely mimics paraneoplastic sensory neuropathy

Question 12

Diabetic autonomic neuropathy clinical findings

Answer 12

Autonomic neuropathy affects nearly 50% of diabetic patients, commonly causing genitourinary dysfunction (erectile dysfunction and neurogenic bladder), postural hypotension, and gastrointestinal dysmotility.
Autonomic derangement can contribute to silent cardiac ischemia and cardiac arrhythmia, the most common causes of death in diabetic patients.

Question 13

Diabetic ischemic mononeuropathy presentation

Answer 13

Cranial (eg, CNs III, VI, VII) Diplopia, pupil-sparing third nerve
palsy, hemifacial weakness

Radicular (thoracic, lumbosacral) Pain, followed by numbness or weakness in a radicular distribution

Peripheral (eg, femoral) Pain, followed by numbness, weakness, or both in territory of a single nerve

Question 14

Diabetic regional neuropathic syndromes

Answer 14

1) Diabetic amyotrophy: Subacute weakness and atrophy of proximal leg muscles

2) Diabetic thoracoabdominal neuropathy: Subacute weakness, numbness, and atrophy in thorax and abdomen

Question 15

Distal symmetric diabetic neuropathy electrophysiologic findings

Answer 15

Distal symmetric diabetic neuropathy begins as an axonal disorder, with decreased sensory and motor amplitudes.
Demyelinating change causing nerve conduction slowing often follows, and patients frequently have both axonal and demyelinative features at electrodiagnostic testing.

Question 16

Small fiber neuropathy diagnosis

Answer 16

can be diagnosed through
* quantitative sensory testing (QSART) a noninvasive autonomic study used to assess the volume of sweat produced in the limbs in response to acetylcholine
* quantitation of small nerve fiber density via epidermal skin biopsy

Question 17

Painful diabetic neuropathy management

Answer 17

Effective pharmacotherapy options for patients with painful diabetic neuropathy include the following

*Serotonin-norepinephrine reuptake inhibitors (duloxetine, venlafaxine)

*Tricyclic antidepressants (amitriptyline, desipramine, nortriptyline)

*Gabapentinoid antiseizure medications (pregabalin, gabapentin)

Question 18

Peripheral neuropathy in hypothyroidism clinical findings and diagnosis

Answer 18

1) Carpal tunnel syndrome (the most common neuropathy in hypothyroidism)
clinical and electrodiagnostic improvement or resolution of the CTS following thyroid replacement and return to a euthyroid state

2) Polyneuropathy

Clinical features – sensory disturbance in a symmetric, distal-predominant distribution, affecting the feet earlier and more severely than the hands.
Sensory loss, tingling, and painful dysesthesias are common complaints.
Findings on neurologic examination: loss or reduction of deep tendon reflexes and a symmetric “stocking-glove” distribution of sensory loss.
Delayed relaxation of the reflexes is a characteristic feature of hypothyroidism. Rarely, in more severe cases, distal weakness and atrophy may be present

Electrophysiology and other testing – Combination of axonal and demyelinating features. These abnormalities can be seen in patients with subclinical as well as overt hypothyroidism and in patients without symptoms of neuropathy.

A subset of patients with hypothyroidism complains of typical neuropathic pain, but have normal NCS. This suggests that some patients may have an isolated small fiber polyneuropathy.

Diagnosis
The presence of distal sensory loss and reduced or absent deep tendon reflexes suggests a sensory polyneuropathy in a patient with known hypothyroidism.
Electrophysiologic tests help to confirm as well as characterize the polyneuropathy.

Question 19

Peripheral neurologic manifestations of hyperthyroidism

Answer 19

1) Sensory polyneuropathy
symmetric distal sensory disturbance and reduced Achilles reflexes are the most common features. Electrodiagnostic testing is usually consistent with an axonal pathology
Treatment of hyperthyroidism with return to a euthyroid state leads to improvement of symptoms.

2) Carpal tunnel syndrome

3) Unusual neuropathies — The term “Basedow paraplegia” has been used to describe an acute development of severe leg weakness and areflexia, which occurs in the setting of severe hyperthyroidism or thyroid storm . The arms are usually also weak, but are less severely affected. Patients recover with treatment of hyperthyroidism. Guillain-Barré syndrome should be considered as an alternative diagnosis in patients with this presentation

4) Motor neuron manifestations — Clinical features in patients with hyperthyroidism may include upper motor neuron signs related to pyramidal tract dysfunction as well as lower motor neuron signs related to a peripheral neuropathy, which may overlap with those of amyotrophic lateral sclerosis

Question 20

Peripheral neuropathy in rheumatoid arthritis

Answer 20

1) distal, symmetric sensory or sensorimotor neuropathy that
is usually mild and often less troubling to patients than their
other symptoms.
Atrophy of the intrinsic hand muscles may also occur as a direct result of rheumatoid arthritis, unrelated to a more systemic neuropathy.

2) carpal tunnel syndrome

3) mononeuropathy multiplex that requires aggressive immunosuppressive therapy (less commonly)

Question 21

Peripheral neuropathy in 1) Systemic lupus erythematosus 2) Sjogren syndrome

Answer 21

1) distal symmetric sensory or sensorimotor neuropathy (and, rarely, mononeuropathy multiplex)

2) small-fiber or axonal sensory neuropathy as well as autonomic neuropathy. It can also cause a sensory ganglionopathy.

Question 22

Peripheral neuropathy in sarcoidosis

Answer 22

1) Cranial mononeuropathy — Peripheral facial nerve palsy develops in 25 to 50 percent of patients with neurosarcoidosis. The facial nerve palsy can be unilateral or bilateral (simultaneous or sequential) and recurrent.
Optic neuropathy and cranial nerve VIII dysfunction can lead to intermittent or progressive visual, auditory, or vestibular dysfunction

2) Peripheral neuropathy — Peripheral neuropathic presentations include a mononeuropathy, mononeuritis multiplex, and generalized sensory, sensorimotor, and motor polyneuropathies.
The symptoms can be acute, subacute, or chronic; electromyography usually reveals an axonal neuropathy.
Perhaps the most unrecognized neuropathy presentation is that of a small fiber disorder manifesting as impaired perception of distal limb pain and temperature, often associated with paresthesias and hyperesthesia/dysesthesia, and autonomic dysfunction. When severe, symptoms and signs can extend to the torso

3) Carpal tunnel syndrome appears to be more common among patients with sarcoidosis than the general population

Question 23

Critical illness polyneuropathy

Answer 23

The disorder is associated with multiple organ dysfunction, prolonged mechanical ventilation, and sepsis

A. Clinical findings
difficulty weaning patients from mechanical ventilation.
On examination, distal or even generalized weakness
(sparing of cranial nerve muscles), distal sensory loss, and
areflexia.

B. Diagnostic Studies
Nerve conduction studies usually reveal an axonal polyneuropathy.
In some patients, there may be a purely motor neuropathy,
but in others, sensory involvement is present. Motor unit
assessment via needle EMG is usually limited, because
patients are often unable to follow commands for volitional
activation of the muscle.
CSF is normal

C. Differential Diagnosis
CIP remains a diagnosis of exclusion. It is often a challenging
disorder to confirm, because patients are often
afflicted with disorders that may also cause neuropathy
(eg, diabetes, renal failure), including greater risk for the
development of AIDP. Most patients may also develop a
critical illness myopathy, either exclusively or in concert
with CIP.

D. Treatment & Prognosis
There is no treatment for CIP other than treatment of the
underlying illness and careful glucose control. In patients who survive, CIP improves over several months as the underlying illness is treated; about half of surviving patients recover completely.

Question 24

Hallmarks of CMT1 and CMT2

Answer 24

1) Weakness beginning in small foot and fibular muscles and progressing to hand and forearm muscles
2) distal symmetric sensory loss
3) diminished or absent tendon reflexes

Foot deformities such as pes cavus and hammer toe are frequently found.
Patients complain primarily of weakness, but they may have sensory ataxia, which, along with foot drop, can interfere with gait

Question 25

CMT1

Answer 25

CMT1 is a demyelinating disorder characterized by calf muscle atrophy, pes cavus foot deformity, hammer toes, and loss of reflexes.
Affected patients typically present in the first or early second decade, but infants may be symptomatic.
Sensory loss is gradual and mainly involves proprioception and vibration.
Later changes include atrophy of the intrinsic hand and foot muscles.
Palpable enlargement of the peripheral nerves may occur.
Sural nerve biopsy shows “onion bulb” demyelination that affects primarily the large nerve fibers.

The most common type of CMT1, CMT1A, is most frequently caused by a duplication of the PMP22 gene.
CMT1B is most often caused by single-nucleotide variants in the myelin protein zero (P0) gene

Question 26

CMT2

Answer 26

CMT2, also called axonal CMT, is characterized by predominating sensory loss along with distal weakness, atrophy, decreased deep tendon reflexes, and variable foot deformity. The onset of symptoms usually is in the second or third decade of life.
The genetic basis of CMT2 is heterogeneous, though MFN2 pathogenic variants appear to be the most common cause.

Question 27

CMTX1

Answer 27

CMTX1 is an X-linked dominant demyelinating and axonal disorder, characterized by gait impairment and foot deformities.

Children and young adults with CMTX1 can experience transient stroke-like episodes.

It is caused by pathogenic variants in the GJB1 or connexin 32 gene

Question 28

CMT3 – Dejerine-Sottas syndrome

Answer 28

Dejerine-Sottas syndrome and congenital hypomyelinating neuropathy, classified as CMT3, are severe, early-onset peripheral neuropathies that present in infancy with hypotonia. They are caused by several genetic variants including PMP22, MPZ, and EGR2 genes that lead to thin, poorly formed myelin.

Question 29

HNPP

Answer 29

HNPP is an autosomal dominant neuropathy that usually presents in patients between 20 and 40 years of age.
Patients have multiple, painless, focal peripheral nerve lesions after minimal trauma or compression, which most often involve
the median nerve at the carpal tunnel, the ulnar nerve at the
elbow, or the fibular nerve at the fibular head.
Symptoms typically improve over days to months. Rarely, brachial plexopathy can be the initial presentation of HNPP. Some patients have a slowly progressive symmetric peripheral neuropathy that is clinically similar to CMT.

Electrophysiologic studies confirm multiple focal mononeuropathies at common anatomic sites of compression. Sural nerve biopsy (no longer necessary for diagnosis) shows tomaculi or characteristic focal thickening of the myelin sheath.

Therapy includes avoiding activities that place the nerve at risk for compression, with careful observance of ergonomic measures at all times, and the use of bracing, padding, and surgical release when needed.

Genetic testing may confirm the diagnosis PMP22 deletion

Question 30

Familial amyloid polyneuropathy pathogenesis

Answer 30

Familial amyloid polyneuropathy is an autosomal dominant
disorder that causes a life-threatening sensorimotor and autonomic neuropathy.
Most commonly, it is the result of a mutation in the transthyretin (TTR) gene, producing the most severe form of the disorder. TTR is a protein that handles thyroxin and retinol transport and is primarily synthesized in the liver. Mutations in this gene can cause neuropathy and cardiomyopathy through the deposition of amyloid within affected organs.

Question 31

Familial amyloid polyneuropathy clinical findings and diagnosis

Answer 31

A. Symptoms and Signs
Patients, without treatment typically die in 3 to 15 years.
It causes a length dependent sensorimotor and autonomic neuropathy, with orthostatic hypotension and night diarrhea and has a variable presentation, depending on which organs are affected first.
The incidence of carpal tunnel syndrome is dramatically increased in these patients.
Heart failure with preserved ejection fraction is common, and gastrointestinal, renal, leptomeningeal and ocular injury also occurs.

B. Diagnostic Studies
Neurophysiologic testing shows a sensorimotor neuropathy
with axonal features.
Nerve biopsy examination shows characteristic amyloid deposits, with mass spectrometry demonstrating the transthyretin protein. There is involvement of unmyelinated and small myelinated fibers.
Molecular genetic testing can establish a definitive diagnosis

Question 32

Familial amyloid polyneuropathy treatment

Answer 32

●Transthyretin amyloidosis – approaches for the treatment of hereditary TTR amyloidosis (ATTR) include the use of ribonucleic acid (RNA)-targeted therapies that interfere with hepatic TTR synthesis and other agents that reduce formation of TTR amyloid through stabilization of the tetramer configuration, preventing release of amyloidogenic monomers.

Liver transplantation has also been used for the treatment of hereditary (variant or mutant) ATTR (ATTRv) as a form of “surgical gene therapy.”

*RNA-targeted therapies – include patisiran, vutrisiran, inotersen, and eplontersen

-Patisiran is administered every three weeks by intravenous infusion.
-Inotersen is administered once weekly by subcutaneous injection
-Vutrisiran: every-three-month subcutaneous injection

*Stabilization of transthyretin tetramers – Tafamidis and diflunisal each can reduce formation of TTR amyloid through stabilization of the TTR tetramer configuration, preventing release of amyloidogenic monomers