Handbook of clinical neurology
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Small fiber neuropathy represents a significant component of diabetic sensorimotor polyneuropathy (DSPN) which has to date been ignored in most recommendations for the diagnosis of DSPN. Small fibers predominate in the peripheral nerve, serve crucial and highly clinically relevant functions such as pain, and regulate microvascular blood flow, mediating the mechanisms underlying foot ulceration. ⋯ Because small fiber damage precedes large fiber damage, diagnostic tests for DSPN show good sensitivity but moderate specificity, because the gold standard which is used to define DSPN is large fiber-weighted. Hence new diagnostic algorithms for DSPN should acknowledge this emerging data and incorporate small fiber evaluation as a key measure in the diagnosis of DSPN, especially early neuropathy.
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Alcoholism, more generically drug addiction, can be defined as a chronically relapsing disorder characterized by: (1) compulsion to seek and take the drug (alcohol); (2) loss of control in limiting (alcohol) intake; and (3) emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability), reflecting a motivational withdrawal syndrome, when access to the drug (alcohol) is prevented (defined here as dependence). The compulsive drug seeking associated with alcoholism can be derived from multiple neuroadaptations, but the thesis argued here, derived largely from animal models, is that a key component involves decreased brain reward function, increased brain stress function, and compromised executive function, all of which contribute to the construct of negative reinforcement. Negative reinforcement is defined as drug taking that alleviates a negative emotional state. ⋯ A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the compulsivity of alcoholism. Other components of brain stress systems in the extended amygdala that interact with CRF and may contribute to the negative motivational state of withdrawal include increases in norepinephrine function, increases in dynorphin activity, and decreases in neuropeptide Y. The combination of impairment of function in reward circuitry and recruitment of brain stress system circuitry provides a powerful neurochemical basis for the negative emotional states that are responsible for the negative reinforcement that drives the compulsivity of alcoholism.
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Independent of the underlying condition, critical illness is characterized by a uniform dysregulation of the hypothalamic-pituitary-peripheral axes. In most axes a clear biphasic pattern can be distinguished. The acute phase of critical illness is characterized by low peripheral effector hormone levels such as T3, IGF-1 and testosterone, despite an actively secreting pituitary. ⋯ In the prolonged phase of critical illness, low peripheral effector hormone levels coincide with a uniform suppression of the neuroendocrine axes, predominantly of hypothalamic origin. The severity of the alterations in the different neuroendocrine axes is associated with a high risk of morbidity and mortality, but it remains unknown whether the observed changes are cause or consequence of adverse outcome. Several studies have identified therapeutic potential of hypothalamic releasing factors, but clinical outcome remains to be investigated with sufficiently powered randomized controlled trials.