What is spontaneous recovery and when does it occur?

Treatment of early MS

Spontaneous recovery is generally the norm following an acute relapse, especially during the early stages of relapse-onset MS. However, corticosteroids may hasten the recovery process. The ONTT showed that treatment with 3 days of intravenous methylprednisolone followed by a short course of oral steroids was associated with a more rapid recovery of vision (Beck et al., 1992, 1993a). However, there was no significant effect on long-term visual outcome or subsequent conversion to MS (Beck et al., 1993b; Beck, 1995).

In a double-blind, placebo-controlled trial of intravenous immunoglobulin, Roed et al. (2004) found no significant benefit of treatment on visual outcome at 6 months after an episode of acute ON.

Weinshenker et al. have reported a beneficial effect of plasma exchange in patients with severe relapses not responding to corticosteroids (Weinshenker et al., 1999; Keegan et al., 2002), maximal benefit occurred when treatment was initiated within 2 weeks of symptom onset. They also found that the response to plasma exchange was determined by the pathologic subtype as defined by Lucchinetti et al. (2000), with treatment responders demonstrating evidence of antibody-mediated disease (Keegan et al., 2002).

Two randomized, double-blind, placebo-controlled trials of interferon-β1A in CIS patients with abnormal MRI found that treatment delayed the development of CDMS (CHAMPS trial: Jacobs et al., 2000; ETOMS trial: Comi et al., 2001). The effect was however modest. In the CHAMPS trial, 35% of treated patients developed CDMS at 3 years compared with 50% of the placebo group. Similarly, in the ETOMS trial, the treatment group was 24% less likely to develop CDMS. Subgroup analyses have shown that the greatest benefit was seen in those with increased activity on T2-weighted and gadolinium-enhanced MRI (CHAMPS Study Group, 2002; Barkhof et al., 2003b). The ETOMS trial also found that early treatment reduced brain atrophy by 30% at 2 years. The follow-up period in these trials was not long enough to assess the effects of treatment on long-term disability.

The BENEFIT trial has looked at the effects of interferon-β1B on CIS patients and reported similar beneficial effects (Kappos et al., 2005). Similarly, the PreCISe trial examined the impact of glatriamer acetate on CIS patients and, as with the other trials, found a clear benefit of therapy in delaying the onset of definite MS (Comi et al., 2009, 2013).

Given the highly variable natural history of MS, it has proven difficult to establish clear guidelines with regard to the initiation of disease-modifying agents at the earliest stages of the disease. However, with the wealth of data emerging from clinical, imaging, and immunological research studies with regard to early prognosis in MS, it should become more feasible to identify high-risk individuals who would benefit from early intervention with disease-modifying agents.

1.2 Recovery, Persistence of Memory Disorders, and the Possibility for Treatment

Spontaneous recovery from memory deficits after acquired brain damage has not been studied extensively. The figures of the review by Snaphaan and de Leeuw (2007) show that after a stroke some recovery occurs in around one-third of the patients. The amount of recovery will depend on the size and the localization of the lesion that causes the memory deficit. In HM, the famous US patient that developed anterograde amnesia after a surgical resection of the mediobasal temporal lobes, no recovery was noticed over the course of multiple decades. On the other hand, many patients show distinguished learning deficits or even anterograde amnesia immediately after a TBI, which disappears a few days after the event. Animal research provides the possibility to investigate the amount of recovery under more controlled conditions. Hildebrandt (2017) and Hildebrandt, Lehmann, and Kastrup (2012) recently reviewed the persistence of memory disorders in animals after stroke, TBI, and focal resection of brain tissue. The possibility of recovery was directly proportional to the lesion location: In the case of middle cerebral artery strokes there was an almost complete recovery if the animals (mostly rats) were provided with a stimulating environment (“enriched environment”). Rats that were kept in simple cages without the possibility of running and exploring the environment did not show recovery from memory dysfunctions. It should be noted that in rats (as in humans) the middle cerebral artery does not supply the hippocampus or other structures of the Papez circuit with blood. On the other hand, as the review of Snaphaan and de Leeuw (2007) shows, memory disorders in humans remain present for a considerable number of patients even suffering from middle cerebral artery infarcts.

In animals with artificial TBI, the recovery from memory dysfunctions was similar to stroke recovery, but it was somewhat slower. The chance for recovery was low to absent if the lesion concerned the hippocampus or the Papez circuit directly, either by surgical lesioning or by TBI. After focal and bilateral lesions of the essential structures for memory, recovery could only be noted after many weeks of enriched environment placement (if at all). Moreover, recovery was limited to easy memory tasks. Tasks that are developed to test episodic memory-like processes in animals, such as the Morris Water Maze test, did not show improvements.

In some of the animal studies, treatment effects of enriched environment could also be documented on a biological level, reducing beta amyloid load and stabilizing newly generated cells in the choroid plexus that migrated into the surrounding brain tissue (Hildebrandt, 2017). Thus, one lesson of the animal studies is that memory rehabilitation may even interact with neurobiological processes of reorganization on a cellular level and is not restricted in the sense of just using already existing cognitive tricks to compensate for the impairment.

Summing up these lessons from animal research, it seems fair to state that there is a good chance of recovery from memory deficits if animals suffer from unspecific lesions that do not damage the limbic structures per se and if animals are kept in an enriched environment (which might be compared to rehabilitative efforts in humans). Animals with unilateral lesions of the limbic system also show some recovery, but it is delayed compared to animals with nonfocal lesions. Moreover, bilateral lesions of the limbic system seem to lead to long-lasting impairments that can be treated only partially (if at all).

The review of animal research on the recovery of memory performance after suffering brain damage conforms with the clinical impression of memory-impaired patients. The German guideline for memory rehabilitation (Thöne-Otto, 2012) (Fig. II.1.2) distinguishes between post-acute and chronic patients, as well as between patients with moderate to mild memory impairment and those with dense anterograde amnesia. For both patient groups, memory rehabilitation should look for the possibility to introduce external memory aids and memory organizers to reduce the functional load experienced by the patients. For patients in a post-acute stage where the prognosis of the memory impairment is still unclear, and for patients in a chronic stage with only moderate to mild memory impairments, the guideline proposes to try compensatory training concentrating on visual imagery or semantic structuring.

In the following sections, we will first concentrate on patients with low to moderate levels of memory impairment, followed by a look at patients with complete anterograde amnesia.

Therapy

Spontaneous recovery from CMS almost always occurs after a varying length of time (Steinbok et al., 2003; De Smet et al., 2007). However, once CMS is present, there is no established treatment to diminish severity or shorten the length of the mute and recovery periods. To treat cerebellar mutism in its acute stage, a D2 dopamine agonist such as bromocriptine has been used in various dosages and durations in some children, with inconsistent success (Echiverri et al., 1988; Catsman-Berrevoets et al., 1992; Caner et al., 1999; Adachi et al., 2005). Fluoxetine was reported to alleviate symptoms in 1 child (Akhaddar et al., 2012). Also zolpidem, a nonbenzodiazepine GABAergic drug, reversed CMS in a single child (Shyu et al., 2011). Characteristically, in all children in whom success of bromocriptine or zolpidem was reported, reversal of symptoms of CMS could only be seen at least 24 hours after first administration of the drug.

More recently, Nicita et al. (2017) reported a sudden (within minutes) resolution of postoperative CMS after intravenous administration of midazolam in a 17-year-old boy after resection of a fourth-ventricle choroid plexus papilloma. SPECT images showed hypoperfusion of the left parietal and occipital lobes, the thalami, and the right paramedian cerebellar region with improvement on SPECT after midazolam infusion parallel to almost complete reversal of the severe clinical picture. MRI did not reveal postoperative ischemic lesions, and an electroencephalogram during CMS showed generalized slowing without evidence of epileptic status.

Midazolam acts by enhancing the ionotropic GABAergic (i.e., inhibitory) neuronal activity and has an anxiolytic, amnestic, hypnotic and anticonvulsant effect. The authors speculate that the unexpected effect on CMS symptoms in their patient may be due to an inhibitory effect of midazolam on the direct and indirect basal ganglia pathways that regulate the excitatory output of the thalamus, resulting in a net reduction of inhibition of the thalamus via the striatum. By this mechanism midazolam may have caused an increased excitation of the cortex by way of the thalamus, comparable to the effect derived from bromocriptine administration (Nicita et al., 2017). The efficacy of this mechanism provides further support to the concept proposed by Miller et al. (2010), that a global supratentorial cortical depression in the context of cerebellocerebral diaschisis may be the most likely pathophysiologic explanation of CMS.

Nonpharmacologic treatment modalities of CMS are at present far more important than drugs. Well-trained, experienced nurses or nurse practitioners, specialized in caring for children treated for posterior fossa tumors, play an integral role in recognizing the syndrome and helping affected children and their families through the treatment and management of the permanent sequelae of CMS (Mortimer, 2011). Walker and collaborators (2014) emphasize that, to help restore basic motor function and communication in children with CMS, early restitution relies heavily upon physiotherapy and occupational, speech, and language therapy.

In general, few studies on cognitive rehabilitation techniques and packages have been performed in patients with brain tumors or in patients after CMS (Gudrunardottir et al., 2011b; Walker et al., 2014; Catsman-Berrevoets, 2017). Therefore, at long-term follow-up appointments, rehabilitation after CMS should be tailored to patients’ individual needs because a variety of functions, including memory, attention, executive functions, visuospatial skills, perceptual abilities, and communication skills, may be impaired to varying severities (Vandeinse and Hornyak, 1997; Grill et al., 2004; Palmer et al., 2010; De Smet et al., 2012).

To achieve the best possible outcome for survivors and minimize the long-term consequences of CMS, new interventions to stimulate neurorecovery and plasticity must be developed and their efficacy tested (Lassaletta et al., 2015). Additionally, because evidence exists showing that children who had CMS are at risk for emotional, behavioral, and social problems longer after completion of their cancer treatment than are children who did not have CMS, attention should also be paid to the detection and management of these late sequelae (Wolfe-Christensen et al., 2007). Particular attention should be paid to providing individually tailored educational support to children who live with long-term consequences after CMS in order to improve their quality of life and participation in the various spheres of social life (Gudrunardottir et al., 2014; Ross et al., 2014; Lanier and Abrams, 2017).

7 Long-Term Recovery from Alcoholism

Although spontaneous recovery from alcoholism occurs, the only assurance of long-term abstinence supported by empirical data and clinical experience is continuous attendance in AA. Surveys of its members reveal an 83% probability of abstinence for the next year if an individual is abstinent between 1 and 5 years with regular attendance of at least one AA meeting per week and a 91% probability of an additional year if the individual is abstinent in AA for more than 5 years.

Clinical experience shows that relapse to alcohol use is very uncommon for someone who attends AA meetings regularly, particularly after being abstinent in AA for more than a year. However, for those who relapse, their attendance at AA meetings had ceased for a substantial period prior to the relapse, typically years before the actual relapse to alcohol use. Also, use of other addicting drugs, such as cocaine, cannabis, heroin, and nicotine, and/or use of addicting medications, such as opiate analgesics and benzodiazepines, render continuous abstinence difficult and reliably predict relapse to alcohol.

Reinstatement of the Extinguished Memory is Context Dependent

In addition to spontaneous recovery, reinstatement is a second phenomenon that relates to extinction. In reinstatement, the CR reappears when the US is presented during the interval between the extinction session and a subsequent retention test, but only when US presentation and retention test take place in the same context3 (Figure 33.1B). Thus, the occurrence of reinstatement again demonstrates that the extinguished reward memory is not destructed after extinction and that, more important, the context is critical for memory retrieval after extinction.

Reinstatement has only recently been demonstrated in honeybees19 using the PER conditioning paradigm. Honeybees were trained with one CS–US conditioning trial and extinguished 3 hr later with three extinction trials. Ten minutes later, the PER was elicited with the US (i.e., a sucrose solution), and memory retention was tested 2 hr later. Reappearance of the CR in the final retention test was observed in significantly more animals that received the US than in those that did not receive the US. However, the reappearance of the CR was observed only when the US was presented in the context of acquisition, extinction, and the final memory test. When the US was presented in a different context, the reappearance of the CR was not observed.19 Thus, in honeybees, the US induces the recovery of the CR in a context-dependent manner. Because the US presentation induces the reappearance of the CR, reinstatement is another indication that the initial acquisition memory still exists after extinction in honeybees. Because the initial reward memory is not visible directly after extinction, it is most likely suppressed by the extinction memory. Most important, reinstatement is context dependent in honeybees,19 as it has been demonstrated in vertebrates.2,20 Accordingly, also in honeybees, the context is learned and plays a role in determining to what extent the initial reward memory and the extinction memory contribute to control behavior after extinction.

Differentiating between Acute Mental Health Symptoms That Will Probably Abate and Those That Will Develop into Long-Term or Pathological Mental Health Consequences

The high rate of spontaneous recovery in the aftermath of terrorism raises an important question with respect to how initial symptoms should be understood and treated. If the initial symptoms are understood as transient reflections of distress, it is not clear that such symptoms require mental health intervention. Alternatively, it can be argued that treating early symptoms, even in those who will experience spontaneous recovery, might help prevent long-term responses in the 7–12% who generally remain symptomatic or deteriorate as the broad population begins to improve. Clarifying the causes of high levels of immediate and long-term symptoms will no doubt lead to ideas about potential preventative treatments because it is now clear that the intensity of the exposure to trauma does not sufficiently predict who will develop or sustain symptoms.

In the absence of a linear relationship between acute stress reactions and longer-term adjustment, there are two theoretical models for pathological responses in the aftermath of a trauma. The first defines a pathological response to trauma by the persistence of the same symptoms that within a specified period of time immediately following the event would otherwise be considered normal. The second defines posttraumatic pathology by the presence of a fundamentally different initial response to stress, resulting in persistent symptoms of hyperarousal, recollection of intrusive events, and avoidance of reminders. Both models are consistent with the idea that posttraumatic mental health consequences are based on a failure to recover from the universal distress in the immediate aftermath of trauma. In the first case, the persistence of symptoms probably results from postexposure factors that prevent recovery, such as lack of social support or other coping resources. In contrast, the second model implies that the initial symptoms are fundamentally different at the outset and probably result from pre- or peritraumatic factors.

Supporting the idea that persistent responses are simply continuations of initial reactions are the findings that people who show high-magnitude posttraumatic stress disorder (PTSD) symptoms (i.e., intrusive, avoidance, and hyperarousal) in the first few days and from 1 to 2 weeks after the event are those at greatest risk for subsequent symptom severity. However, many researchers performing longitudinal studies of acute trauma survivors have not been able to identify specific symptoms that can convincingly predict pathological mental health outcomes. More promising clinical predictors appear to be the presence of a panic attack and/or intense dissociation during or immediately after a trauma, which suggests additional or fundamentally different immediate responses. Both panic attacks and dissociative responses reflect catastrophic or negative interpretations of the event. Such interpretations may further perpetuate arousal associated with stress responses and reduce the body's ability to achieve homeostasis following the trauma. The presence of catastrophic attributions (e.g., that posttraumatic symptoms signify a major problem and will not ultimately resolve) provides a way of drawing a distinction between being terrorized and being terrified. People exposed to a traumatic event are not traumatized unless they are deeply distraught at the time of the event and then make catastrophic interpretations that may result in fundamentally different biological stress responses.

Indeed, although trauma exposure certainly results in the release of stress hormones such as catecholamines and cortisol, it has been noted that dissociation and panic attacks are specifically associated with increased catecholamine levels. It may be that a peritraumatic panic attack or other intense distress during and immediately after the traumatic event leads to higher levels of stress hormones that might, in turn, strengthen traumatic memories and increase the probability of intrusive recollections. On the other hand, extreme reactions of panic and dissociation may be facilitated by relatively lower levels of stress hormones, such as cortisol, that play an important role in containing the catecholamine response to stress.

What is spontaneous recovery and why might it occur?

What is the meaning of spontaneous recovery?

What is spontaneous recovery and give an example?

Which is the best example of spontaneous recovery?